The DOI matches its Crossref record; 232 of the 236 references it cites were found in a registry or an index; 146 of the 190 sources its claims cite were checked for support.
Tumor microenvironment complexity and therapeutic implications at a glance
Open accessAbstract
The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.
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Claims the paper makes
50 Supported · 47 Partly supported · 19 No full text of the sources · 14 Own interpretation · 6 Supported so far · 6 Couldn’t confirm · 5 Not supported · 4 No basis given · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Chemotherapeutic agents can also be targeted to ECM of the tumor cells through the membrane-bound receptors such as tenascin-C [132].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Disputedcites [132] Raavé R, van Kuppevelt TH, Daamen WF. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting. J Control Release. 2018;274:1–8. sourceExperimental — accuracy not yet measured
Section 4, “Alternative tumor targeting strategy,” explicitly says ECM targeting is not aimed at membrane-bound receptors on tumor cells. Section 4.2 identifies tenascin-C as a glycoprotein in the tumor ECM that can be targeted to deliver a chemotherapeutic compound, not as a membrane-bound receptor. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Importantly, combination treatment with CPI and IL-2 resulted in complete elimination of tumors in a considerable number of animals (9 of 13) bearing orthotopic breast cancer [137].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Disputedcites [137] Ishihara J, Ishihara A, Sasaki K, Lee SS-Y, Williford J-M, Yasui M, Abe H, Potin L, Hosseinchi P, Fukunaga K, et al. Targeted antibody and cytokine cancer immunotherapies through collagen affinity. Sci Transl Med. 2019;11:eaau3259. sourceExperimental — accuracy not yet measured
The Results section distinguishes the two combinations: CBD-CPI plus CBD-IL-2 produced complete remission in 9 of 13 mice with MMTV-PyMT breast tumors, whereas unmodified CPI plus IL-2 did so in only 1 of 13. The cited sentence assigns the 9-of-13 result to CPI plus IL-2 without the essential CBD modification. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
plaindirectn = 13- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“LOX enzymes are widely used to block collagen crosslinking in various preclinical settings [130, 131].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Not checked — no full text of the sourcecites [130] Hajdú I, Kardos J, Major B, Fabó G, Lőrincz Z, Cseh S, Dormán G. Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited. Bioorg Med Chem Lett. 2018;28:3113–8. source
- Disputedcites [131] Puente A, Fortea JI, Cabezas J, Arias Loste MT, Iruzubieta P, Llerena S, Huelin P, Fábrega E, Crespo J. LOXL2—a new target in Antifibrogenic therapy? Int J Mol Sci. 2019;20:1634. sourceExperimental — accuracy not yet measured
Section 3, “Fibrosis Reversion—Lysyl Oxidase 2” (page not provided), says LOXL2 promotes collagen crosslinks, rather than blocking them. It describes preclinical use of an antibody that inhibits LOXL2—not use of LOX enzymes to block crosslinking. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“These include circulating tumor cells (CTCs), exosomes, cell-free DNA (cfDNA) and apoptotic bodies as novel horizontal gene transfer (HGT) mediators derived from tumor cells and delivering information to distant target cells including tumor cells and/or normal cells [6, 7].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Background
What the sources say
- Could not verifycites [6] Denisenko TV, Budkevich IN, Zhivotovsky BJCd, disease: Cell death-based treatment of lung adenocarcinoma. 2018, 9:117. sourceExperimental — accuracy not yet measured
The Combination therapies section discusses communication between malignant and neighboring nonmalignant cells through cytokines, chemokines, growth factors, and enzymes, but does not describe horizontal gene transfer. Searches for circulating tumor cells, exosomes, cell-free DNA, and apoptotic bodies found no passage identifying them as mediators that deliver information to distant cells. No page number was available in our copy. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [7] Balkwill FR, Capasso M, Hagemann T: The tumor microenvironment at a glance. The Company of Biologists Ltd; 2012. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Pericytes are vital multifunctional cells in TME that envelop the surface of endothelial cells using cytoplasmic processes that extend along the abluminal surface of the endothelium [23].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Pericytes
What the sources say
- Could not verifycites [23] Abbasi MM, Helli S, Monfaredan A, Jahanban-Esfahlan R. Hesa-a improves clinical outcome of Oral carcinoma by affecting p53 gene expression in vivo. Asian Pac J Cancer Prev. 2015;16:4169–72. sourceExperimental — accuracy not yet measured
The Introduction and Discussion address Hesa-A treatment and p53 expression in oral carcinoma, not pericytes. Searches for pericytes, their cytoplasmic processes, and their relationship to endothelial cells found no passage addressing the cited claim. (LLM, conf=0.76)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Along with endothelial cells, pericytes are involved in the basement membrane remodeling during angiogenesis [24] and tumorigenesis [25].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Pericytes
What the sources say
- Supportedcites [24] Kloc M, Kubiak JZ, Li XC, Ghobrial RM. Pericytes, microvasular dysfunction and chronic rejection. Transplantation. 2015;99:658. source
The citation following “angiogenesis” is supported by the section “Pericyte localization, structure and markers,” which says endothelial cells produce an immature basement membrane and recruited pericytes co-participate in its maturation. The separate tumorigenesis clause has its own citation and is not assessed against this source. (LLM, conf=0.91)
- Supportedcites [25] Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol. 2003;163:1801–15. source
The introduction (Am J Pathol 2003, pp. 1801–1815) describes vascular basement membrane as formed by endothelial cells and pericytes. In “Basement Membrane on Endothelial Sprouts,” the authors report that pericytes contribute to basement membrane synthesis and were associated with most sprouts they observed in tumors, supporting their involvement in remodeling of tumor vessels. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The process of tumor formation and progression is influenced by two factors, namely genetic/epigenetic changes in the tumor cells and the rearrangement of the components of the tumor microenvironment (TME) through mutual and dynamic crosstalk [1].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Background
What the sources say
- Could not verifycites [1] Jahanban-Esfahlan R, Seidi K, Monhemi H, Adli ADF, Minofar B, Zare P, Farajzadeh D, Farajnia S, Behzadi R, Abbasi MM, et al. RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice. Sci Rep. 2017;7:8126. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) notes that implanted tumors can have different microenvironments and interactions with stroma, but it does not say that genetic or epigenetic changes and dynamic crosstalk rearranging microenvironment components drive tumor formation and progression. Searches for those terms found no passage in our copy addressing that account. (LLM, conf=0.72)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Recent advances on three dimensional (3D) platforms through the use of lab-on-chip and microfluidic devices [17] have provided an enormous opportunity to better stimulate the function and biology of TME and to bridge the translational gap between preclinical and clinical settings [18].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Background
What the sources say
- Not checked — no full text of the sourcecites [17] Ayubi Joshagani MH, Dianat-Moghadam H, Seidi K, Jahanban-Esfahlan A, Zare P, Jahanban-Esfahlan R. Cell-free protein synthesis: the transition from batch reactions to minimal cells and microfluidic devices. Biotechnol Bioeng. 2019;117:1204–29. source
- Supportedcites [18] Sleeboom JJF, Eslami Amirabadi H, Nair P, Sahlgren CM, den Toonder JMJ. Metastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches. Disease Models Mechanisms. 2018;11:dmm033100. source
The Introduction describes microfluidic cancer-on-a-chip models that reproduce and control features of the tumor microenvironment, including 3D cultures. The Conclusion says these models could reduce reliance on animal models and, when combined with clinical material, help investigate patient-specific cancer progression and test drug efficacy. That supports the claimed opportunity to improve TME modeling and connect preclinical work with clinical applications; it does not claim the gap has already been closed. (LLM, conf=0.87)
boostedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: In vitro 3D and microfluidic models sufficiently recapitulate the in vivo tumor microenvironment to inform therapeutic development.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The loss of tissue integrity, carcinogenesis and further progress occurs as a consequence of reciprocal interactions between tumor cells with non-cellular (ECM) and cellular components of the TME [9, 10].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Background
What the sources say
- Partly supportedcites [9] Jahanban-Esfahlan R, Seidi K, Manjili MH, Jahanban-Esfahlan A, Javaheri T, Zare P. Tumor cell dormancy: threat or opportunity in the fight against Cancer. Cancers. 2019;11:1207. sourceExperimental — accuracy not yet measured
Section 5, “ECM Remodeling” (page unavailable), links tumor-cell interactions with the ECM to metastatic outgrowth. Section 3, “Cancer Immune-Mediated Dormancy” (page unavailable), describes interactions with stromal and immune cells that can affect cancer growth. These passages support the progression aspect, but do not establish that those interactions cause loss of tissue integrity or carcinogenesis. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [10] Seidi K, Neubauer HA, Moriggl R, Jahanban-Esfahlan R, Javaheri T. Tumor target amplification: implications for nano drug delivery systems. J Control Release. 2018;275:142–61. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Therefore, on the other side of the argument, interactions in reactive non-neoplastic cells, genetically-altered tumor cells, and ECM control the majority of the stages of tumorigenesis effectively including clonal evolution, cancer heterogeneity, epithelial-mesenchymal-transition (EMT), migration, invasion, development of metastasis, neovascularization, apoptosis and chemotherapeutic drug resist”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Background
What the sources say
- Partly supportedcites [11] Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R. Interaction of tumor cells with the microenvironment. Cell CommunSignaling. 2011;9:18. sourceExperimental — accuracy not yet measured
The Abstract states that interactions among genetically altered tumor cells, reactive non-neoplastic cells, and the ECM control most aspects of tumorigenesis, and lists EMT, migration, invasion, metastasis, neovascularization, apoptosis, and chemotherapeutic drug resistance. It does not include clonal evolution or cancer heterogeneity; searches for those terms found no supporting passage in our copy. No page number is provided. (LLM, conf=0.90)
- Partly supportedcites [12] Li W, Ng JM-K, Wong CC, Ng EKW, Yu JJO: Molecular alterations of cancer cell and tumour microenvironment in metastatic gastric cancer 2018:1. sourceExperimental — accuracy not yet measured
The Stromal environment and Local invasion sections (page not available in our copy) describe cross-talk between gastric cancer cells and stroma, and link EMT, ECM-related processes, and stromal interactions to invasion and progression. The paper does not support the stronger claim that these interactions control most stages of tumorigenesis, particularly clonal evolution, cancer heterogeneity, and chemotherapeutic drug resistance. (LLM, conf=0.87)
- Partly supportedcites [13] Tsao AS, Scagliotti GV, Bunn Jr PA, Carbone DP, Warren GW, Bai C, De Koning HJ, Yousaf-Khan AU, McWilliams A, Tsao MSJJoTO: Scientific advances in lung cancer 2015. 2016, 11:613–638. sourceExperimental — accuracy not yet measured
The Hirsch section (page unavailable) says that interactions between malignant and neighboring nonmalignant cells create a dynamic tumor microenvironment, and it mentions matrix-remodeling enzymes. It does not say that those interactions control the majority of tumorigenesis stages or establish the claimed list of effects, including clonal evolution, EMT, metastasis, and chemotherapy resistance. (LLM, conf=0.84)
- Partly supportedcites [14] Cova TF, Bento DJ, Nunes SC. Computational approaches in Theranostics: mining and predicting Cancer data. Pharmaceutics. 2019;11:119. sourceExperimental — accuracy not yet measured
The Introduction (page not available) says that interactions between cells and their surrounding medium affect cancer growth and tissue invasion. Section 2 (page not available) also discusses tumor heterogeneity, angiogenesis, and drug resistance. But the copy does not say that interactions among reactive non-neoplastic cells, genetically altered tumor cells, and ECM control the majority of the listed stages of tumorigenesis; several listed stages, including clonal evolution and epithelial–mesenchymal transition, are not established by these passages. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
- It may state two separate claims as one. 49
- Probably not a substantial claim. 6
- The quote only partly states this claim. 1
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Besides, exosomes are involved in acquired drug resistance, as evidenced by the observation that the transfer of the oncogene MET by exosomes modify surrounding icotinib-sensitive cells to promote icotinib-resistant lung cancer cells, that produce MET-containing exosomes and elicit the migration and invasion properties in vitro [175].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Disputedcites [175] Yu Y, Abudula M, Li C, Chen Z, Zhang Y, Chen Y. Icotinib-resistant HCC827 cells produce exosomes with mRNA MET oncogenes and mediate the migration and invasion of NSCLC. Respir Res. 2019;20:217. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Mechanistically, miR-122 downregulate the glycolytic enzyme pyruvate kinase and restores glucose uptake by lungs and brain and lessen disease progression [177].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Disputedcites [177] Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O’Connor STF, Li S, Chin ARJNcb: Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol. 2015;17:183–94. sourceExperimental — accuracy not yet measured
The Results section confirms that miR-122 downregulates pyruvate kinase, but reports that miR-122 reduces glucose uptake by niche cells and promotes metastasis—the opposite of the claimed effects. In “Systemic miR-122 intervention,” inhibiting miR-122 reduced the incidence of brain and lung metastasis and alleviated suppressed glucose uptake in the brain; restoration of uptake in the lungs was not significant. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Abstract
What the sources say
- Could not verifycites [1] Jahanban-Esfahlan R, Seidi K, Monhemi H, Adli ADF, Minofar B, Zare P, Farajzadeh D, Farajnia S, Behzadi R, Abbasi MM, et al. RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice. Sci Rep. 2017;7:8126. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“While several studies have shown that greater pericytes coverage corresponds to a better diagnosis [30]”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Pericytes
What the sources say
- Partly supportedcites [30] Mezheyeuski A, Lindh MB, Guren TK, Dragomir A, Pfeiffer P, Kure EH, Ikdahl T, Skovlund E, Corvigno S, Strell C. Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer. Oncotarget. 2016;7:41948. sourceExperimental — accuracy not yet measured
The Results (page unavailable) associate greater PDGFR-β-defined vessel coverage with longer overall survival in patients with metastatic colorectal cancer. The claim is broader than that finding: the paper does not establish that greater pericyte coverage generally predicts a better prognosis, and its Discussion notes opposite associations in some other cancers. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thus, gold NPs block VEGF-VEGFR2 signaling from TME cells to endothelial cells and inhibit angiogenesis as reflected in reduced migration and tube formation of ECs when co-cultured with TCs in vitro [52].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Partly supportedcites [52] Zhang Y, Xiong X, Huai Y, Dey A, Hossen MN, Roy RV, Elechalawar CK, Rao G, Bhattacharya R, Mukherjee P. Gold nanoparticles disrupt tumor microenvironment - endothelial cell cross talk to inhibit Angiogenic phenotypes in vitro. Bioconjug Chem. 2019;30:1724–33. sourceExperimental — accuracy not yet measured
The Discussion reports that gold nanoparticles reduced VEGF-dependent VEGFR2 signaling and inhibited endothelial angiogenic phenotypes in vitro. The Results show reduced endothelial migration in co-culture with treated tumor cells, but the tube-formation assay used conditioned media rather than co-culture; that experimental detail in the claim is not supported. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“3D spheroids have provided a more reliable physiological environment for studying the interaction of TECs with tumor stroma, where the shape and surface texture of the spheroids indicates spatial invasiveness of cells in ECM [55].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Partly supportedcites [55] Shoval H, Karsch-Bluman A, Brill-Karniely Y, Stern T, Zamir G, Hubert A, Benny O. Tumor cells and their crosstalk with endothelial cells in 3D spheroids. Sci Rep. 2017;7:10428. sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says hybrid 3D spheroids model tumor–endothelial interactions and that spheroid shape and surface texture may indicate spatial invasiveness in ECM. The claim is stronger than the paper’s tentative finding, and the study used human umbilical vein endothelial cells (HUVEC), not endothelial cells isolated from tumors (TECs). (LLM, conf=0.87)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The results indicated inhibitory role of adenosine on extravasation as blocking A3 adenosine receptors increased extravasation rates of breast cancer cells into the myoblast, mimicking microenvironments compared with untreated cells [57].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Supportedcites [57] Jeon JS, Bersini S, Gilardi M, Dubini G, Charest JL, Moretti M, Kamm RD. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc Natl Acad Sci U S A. 2015;112:214–9. source
The Results (p. 5) report that blocking A3 adenosine receptors increased breast cancer cell extravasation in C2C12 muscle-mimicking matrices from 8.2 ± 2.3% untreated to 32.4 ± 7.7%. The paper interprets this as evidence of a protective role for adenosine against extravasation. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“As outstanding components of TME, TECs not only support the tumor with nutrients but also influence the immune cell infiltration and tumor’s stromal cell arrangement [47].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Could not verifycites [47] Abbasi MM, Mehdipour M, Monfaredan A, Jahanban-Esfahlan R. Hesa-a Down-regulates erb/b2 oncogene expression and improves outcome of Oral carcinoma in a rat model. Asian Pac J Cancer Prev. 2015;16:6947–51. sourceExperimental — accuracy not yet measured
The Introduction and Discussion address Hesa-A treatment and erb/b2 expression in a rat model of oral carcinoma, not the functions of tumor endothelial cells (TECs). Searches for TECs, nutrient supply, immune-cell infiltration, and stromal arrangement found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition, 3D microfluidic system has enabled a high resolution, real-time imaging, and precise quantification of endothelial barrier function, which is essential for investigating the interaction of tumor cells during the metastasis process.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Supportedcites [56] Zervantonakis IK, Hughes-Alford SK, Charest JL, Condeelis JS, Gertler FB, Kamm RD. Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc Natl Acad Sci. 2012;109:13515–20. source
The Abstract says the 3D microfluidic assay allows high-resolution, real-time imaging and precise quantification of endothelial barrier function. The Discussion says it uses these capabilities to investigate tumor–endothelial interactions during intravasation, a step in metastasis. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These properties promote the tumor cell heterogeneity, cancer resistance and impair efficient drug delivery [2, 8, 46].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Not checked — no full text of the sourcecites [2] Jahanban-Esfahlan R, Seidi K, Banimohamad-Shotorbani B, Jahanban-Esfahlan A, Yousefi B. Combination of nanotechnology with vascular targeting agents for effective cancer therapy. J Cell Physiol. 2017;233:2982–92. source
- Not checked — no full text of the sourcecites [8] Jahanban-Esfahlan R, de la Guardia M, Ahmadi D, Yousefi B. Modulating tumor hypoxia by nanomedicine for effective cancer therapy. J Cell Physiol. 2017;233:2019–31. source
- Partly supportedcites [46] Abdalla AME, Xiao L, Ullah MW, Yu M, Ouyang C, Yang G. Current challenges of Cancer anti-angiogenic therapy and the promise of Nanotherapeutics. Theranostics. 2018;8:533–48. sourceExperimental — accuracy not yet measured
The section “Abnormality of tumor vessels and their microenvironment” (page unavailable) says abnormal vessels and physiological barriers impede delivery of therapeutic agents, and that hypoxia arising from impaired blood supply mediates drug resistance. It describes gradients in proliferation, hypoxia and acidity, but does not say these properties promote tumor cell heterogeneity. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TECs contain stem cell-like populations and overexpress MDR1 and aldehyde dehydrogenase (ALDH) and become resistant to chemotherapeutics such as paclitaxel and 5-fluorouracil in vitro [43, 44].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Partly supportedcites [43] Akiyama K, Ohga N, Hida Y, Kawamoto T, Sadamoto Y, Ishikawa S, Maishi N, Akino T, Kondoh M, Matsuda A, et al. Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. Am J Pathol. 2012;180:1283–93. sourceExperimental — accuracy not yet measured
The section “TECs Are Resistant to Anticancer Drugs” reports higher MDR1 expression and greater paclitaxel resistance in TECs than in normal endothelial cells. The introductory passage reports 5-fluorouracil resistance in hepatocellular carcinoma endothelial cells, but this paper does not establish that the studied TECs resist 5-fluorouracil. The passages do not support the stem cell-like population or ALDH-overexpression claims. (LLM, conf=0.87)
- Supportedcites [44] Hida K, Maishi N, Akiyama K, Ohmura-Kakutani H, Torii C, Ohga N, Osawa T, Kikuchi H, Morimoto H, Morimoto M, et al. Tumor endothelial cells with high aldehyde dehydrogenase activity show drug resistance. Cancer Sci. 2017;108:2195–203. source
The paper describes stem cell-like TEC populations and elevated ALDH activity (p. 2). The Discussion (p. 8) reports paclitaxel resistance in a TEC subgroup with ABCB1/MDR1 upregulation, while the Results (p. 6) show that ALDH-high TEC resist 5-fluorouracil in vitro. These are distinct reported findings, rather than evidence that both markers confer resistance to both drugs. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TECs are not only involved in the angiogenesis process to support primary tumor growth, but also promote tumor progression, metastasis and drug resistance [41].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Partly supportedcites [41] Dudley AC. Tumor endothelial cells. Cold Spring Harbor perspectives in medicine. 2012;2:a006536. sourceExperimental — accuracy not yet measured
The section “TEC Abnormalities May Contribute to Tumor Progression” links abnormal tumor vessels to invasion and metastasis, and describes a hypothesis that vessel leakiness impairs chemotherapy delivery. The paper also discusses TEC involvement in angiogenesis, but it does not establish the stronger claim that TECs promote drug resistance; its account of impaired drug delivery is explicitly hypothetical. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The results indicated that secretion of tumor necrosis factor-alpha (TNFα) by macrophages can impair endothelial barrier as validated by a higher number and faster dynamics of TC-EC interactions in highly invasive fibrosarcoma cells [56].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Supportedcites [56] Zervantonakis IK, Hughes-Alford SK, Charest JL, Condeelis JS, Gertler FB, Kamm RD. Three-dimensional microfluidic model for tumor cell intravasation and endothelial barrier function. Proc Natl Acad Sci. 2012;109:13515–20. source
The Results report that neutralizing soluble TNF-α in macrophage experiments reduced endothelial permeability, supporting a role for macrophage-secreted TNF-α in barrier impairment. In separate Results experiments with highly invasive HT1080 fibrosarcoma cells, TNF-α-stimulated endothelium had more tumor–endothelial interactions and faster tumor-cell passage across the barrier. (LLM, conf=0.89)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The combination of chemotherapeutic like α-cyano-4-hydroxycinnamate (CHC) alone and in combination with metformin is reported to hinder autophagic flux in CAFs and hampers tumor cell proliferation, irrespective of chemotherapeutic agents in in vitro and in syngeneic pancreatic cancer model [86].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Cancer-associated fibroblast (CAFs)
What the sources say
- Partly supportedcites [86] Zhang X, Schönrogge M, Eichberg J, Wendt EHU, Kumstel S, Stenzel J, Lindner T, Jaster R, Krause BJ, Vollmar BJFio. Blocking autophagy in cancer-associated fibroblasts supports chemotherapy of pancreatic cancer cells. Front Oncol. 2018;8:590. sourceExperimental — accuracy not yet measured
The ‘Chemotherapeutical Agents Modulate Autophagy’ section reports that CHC alone and with metformin blocked autophagic flux in CAFs, and the proliferation results show that both treatments inhibited pancreatic cancer-cell proliferation in vitro. The Discussion reports that blocking CAF autophagy inhibited proliferation with or without the tested drugs, but does not establish that CHC’s effect was independent of other agents. In the syngeneic model, CHC alone or with metformin produced only a minor decrease in tumor weight; the paper does not demonstrate the claimed CAF-flux and proliferation effects in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CAFs residing in TME are heterogeneous cells with different origins, different functions (pro or anti-tumor activities) and different surface markers such as alpha-smooth muscle actin (α-SMA), myosin light chain 9 (MYL9), myosin light chain kinase (MYLK), matrix metalloproteinase 2 (MMP2), decorin (DCN) and collagen type I alpha 2 (COL1A2) [60–63].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Cancer-associated fibroblast (CAFs)
What the sources say
- Partly supportedcites [60] Liu T, Zhou L, Li D, Andl T, Zhang Y. Cancer-associated fibroblasts build and secure the tumor microenvironment. Front Cell Dev Biol. 2019;7:60. sourceExperimental — accuracy not yet measured
The HETEROGENEITY OF STROMAL FIBROBLASTS, MYOFIBROBLASTS, AND CAFs section describes CAFs as having different origins and functions, including tumor-supporting and tumor-suppressing activity. It reports α-SMA, MYLK, and MYL9 expression in tumor myofibroblasts, and MMP2, DCN, and COL1A2 in a CAF population. It does not describe all six as CAF surface markers; the cited findings distinguish myofibroblasts from CAFs. (LLM, conf=0.86)
- Partly supportedcites [61] Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer. 2020;146:895–905. sourceExperimental — accuracy not yet measured
The Background describes CAFs as heterogeneous, and the Conclusion describes both tumor-promoting and tumor-suppressing roles. Figure 2 names α-SMA, MMP2, DCN and COL1A2 in connection with CAF subtypes. However, the Positive markers table explicitly says α-SMA is not a surface marker, and searches for MYL9 and MYLK found no passage identifying them as CAF markers. Page numbers were not available in our copy. (LLM, conf=0.88)
- Partly supportedcites [62] Nishishita R, Morohashi S, Seino H, Wu Y, Yoshizawa T, Haga T, Saito K, Hakamada K, Fukuda S, Kijima H. Expression of cancer-associated fibroblast markers in advanced colorectal cancer. Oncol Lett. 2018;15:6195–202. sourceExperimental — accuracy not yet measured
The Introduction identifies α-SMA as a CAF marker, and the Discussion reports varying CAF-marker expression in advanced colorectal cancer. The paper does not establish different CAF origins or both pro- and anti-tumor activities, and it does not identify MYL9, MYLK, MMP2, DCN, or COL1A2 as CAF markers; it studies collagen I rather than COL1A2 specifically. (LLM, conf=0.88)
- Partly supportedcites [63] Brunel A, Samain R, Neuzillet C. Bousquet CJTCR: identification of two cancer-associated fibroblast markers revealing stromal heterogeneity in sustaining cancer progression and chemoresistance. Trans Cancer Res. 2018:S718–21. sourceExperimental — accuracy not yet measured
The editorial (pp. S718–S721) describes heterogeneous CAF subsets with distinct functions and identifies α-SMA as a commonly described marker. It says anti-tumor CAF functions are suspected but remain unproven; it does not establish different CAF origins or identify MYL9, MYLK, MMP2, DCN, or COL1A2 as CAF markers. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“CAFs produce ECM proteins, which prompts immunosuppression of tumor cells by recruiting immunosuppressive cells [64, 65] such as monocytes and inducing immunosuppressive PD-1+ TAMs, as recently shown in breast cancer cells in vitro [66].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Cancer-associated fibroblast (CAFs)
What the sources say
- Partly supportedcites [64] Monteran L, Erez N. The dark side of fibroblasts: Cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front Immunol. 2019;10:1835. sourceExperimental — accuracy not yet measured
The Tumor-Associated Macrophages section (page unavailable) reports that CAF-derived Chi3L1 promotes macrophage recruitment and differentiation toward an immunosuppressive M2-like phenotype in a mouse model of breast cancer. It does not identify those macrophages as PD-1+ TAMs or describe that breast-cancer finding as an in vitro experiment. The sentence cites other sources for the earlier recruitment claim; the unsupported details are in the clause attached to this citation. (LLM, conf=0.84)
- Partly supportedcites [65] Liu T, Han C, Wang S, Fang P, Ma Z, Xu L, Yin R. Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019;12:86. sourceExperimental — accuracy not yet measured
The CAF-related anti-tumor immune response sections state that CAFs produce ECM components and can recruit monocytes and promote their differentiation into TAMs (pages unavailable in our copy). They do not report induction of PD-1+ TAMs in breast cancer cells in vitro; the cited review discusses TAM recruitment in other contexts. (LLM, conf=0.86)
- Supportedcites [66] Gok Yavuz B, Gunaydin G, Gedik ME, Kosemehmetoglu K, Karakoc D, Ozgur F, Guc D. Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs. Sci Rep. 2019;9:3172. source
The citation to this paper is attached to the claim about monocyte recruitment and immunosuppressive PD-1+ TAMs, not the preceding ECM-protein claim. The Discussion (page unavailable) reports that CAFs recruit monocytes and differentiate them into immunosuppressive M2-like macrophages; it describes the study as using breast-cancer samples and in vitro cell lines. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In this report, activation of IL1/leukemia inhibitory factor (LIF)/janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling generate inflammatory CAFs while TGFβ signaling antagonizes this process by downregulating interleukin 1 receptor, type I (IL1R1) expression and promoting differentiation into myofibroblasts [73].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Cancer-associated fibroblast (CAFs)
What the sources say
- Supportedcites [73] Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, Preall J, Tuveson DA. IL-1-induced JAK/STAT signaling is antagonized by TGF-beta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2018:9:282–301. source
The Results section states that tumor-secreted IL-1 activates an autocrine LIF/JAK/STAT cascade that maintains the inflammatory CAF phenotype (Figure 7J). It also states that TGF-β downregulates IL-1R1, prevents that cascade, and shifts CAFs toward a myofibroblastic state (Figures 7J and 5H). (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It has been recognized that TAMs may have both promoting (M1 type) and impairing roles (M2 type) when interfering with cancer treatments [92].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor-associated macrophage
What the sources say
- Partly supportedcites [92] Cassetta L, Kitamura T. Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front Cell Developmental Biol. 2018;6:38. sourceExperimental — accuracy not yet measured
The section ‘Targeting TAM Potentiates the Efficacy of Checkpoint Inhibitors’ identifies an M2 macrophage population as immunosuppressive and describes how shifting TAMs toward immune-activating functions can improve checkpoint therapy. The Conclusion and Future Perspectives likewise contrasts immunosuppressive with tumoricidal macrophages. The paper does not identify the treatment-promoting macrophages as ‘M1 type,’ so that specific classification is not established by our copy. (LLM, conf=0.82)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Surprisingly, when interacting with apoptotic cancer cells in conditioned medium, TAMs inhibits TGFβ1-induced EMT and thus tumor invasion, which is considered the antitumor role of TAMs [95].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor-associated macrophage
What the sources say
- Supportedcites [95] Kim Y-B, Ahn Y-H, Jung J-H, Lee Y-J, Lee J-H, Kang JL. Programming of macrophages by UV-irradiated apoptotic cancer cells inhibits cancer progression and lung metastasis. Cell Mol Immunol. 2019;16:851–67. source
The Results section reports that conditioned medium from macrophages exposed to apoptotic cancer cells inhibited TGF-β1-induced EMT. The Discussion says that TAMs in contact with apoptotic cancer cells can play an antitumor role by inhibiting EMT, migration, and invasion. The wording about interaction 'in conditioned medium' is imprecise, but the attributed finding is supported. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It could be shown that TAM influences the migration rate of cancer cells by TGFβ1-induced MT1-MMP and the cancer cell migration persistence by the nuclear factor Kappa - light chain enhancer of activated B cells (NF-κB)-dependent MMP1 expression.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor-associated macrophage
What the sources say
- Supportedcites [110] Li R, Hebert JD, Lee TA, Xing H, Boussommier-Calleja A, Hynes RO, Lauffenburger DA, Kamm RD. Macrophage-secreted TNFα and TGFβ1 Influence Migration Speed and Persistence of Cancer Cells in 3D Tissue Culture via Independent Pathways. Cancer Res. 2017;77:279–20. source
The Discussion states that macrophage-released TGFβ1 increases cancer-cell migration speed through MT1-MMP expression. It also describes a TNFα- and TGFβ1-driven NF-κB pathway that increases MMP1 expression and migration persistence. (LLM, conf=0.93)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ECM forms the scaffold of tissues and organs through the production of supramolecular aggregates, such as fibrils and sheet-like networks [113, 114].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Not checked — no full text of the sourcecites [113] Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123:4195–200. source
- Partly supportedcites [114] Hynes RO. The extracellular matrix: not just pretty fibrils. Science. 2009;326:1216–9. sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says ECM provides structural support for organs and tissues and forms basement membranes beneath cell layers. The paper also discusses fibrils, but the passages in our copy do not describe ECM producing supramolecular aggregates or specify sheet-like networks as the means of support. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ECM may act as a barrier for drug delivery through increased tissue stiffness and desmoplasia or a gate for breaching the basement membrane to promote metastasis [2, 122].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Not checked — no full text of the sourcecites [2] Jahanban-Esfahlan R, Seidi K, Banimohamad-Shotorbani B, Jahanban-Esfahlan A, Yousefi B. Combination of nanotechnology with vascular targeting agents for effective cancer therapy. J Cell Physiol. 2017;233:2982–92. source
- Partly supportedcites [122] Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhibition Med Chem. 2016;31:177–83. sourceExperimental — accuracy not yet measured
The sections on MMPs and cancer and on invasion and metastasis describe ECM barriers being broken down and ECM degradation facilitating cancer-cell migration and metastasis (page unavailable). The paper does not say that stiffness or desmoplasia makes the ECM a barrier to drug delivery. Its explicit discussion of basement-membrane disruption is about angiogenesis, not metastatic breaching. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition, hypoxia, which is common in collagen-rich tumors, promotes cancer progression [124].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Supportedcites [124] Xu S, Xu H, Wang W, Li S, Li H, Li T, Zhang W, Yu X, Liu L. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019;17:309. source
The section “The reciprocity between collagen and cancer cells under hypoxic conditions” states that hypoxia is common in collagen-rich extracellular matrix and intensifies cancer progression. This directly supports the citing sentence. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the case of intravenous injection, the antibody-drug conjugate was found to bind to tenascin-C and the drug was discharged when the protease-sensitive linker between the antibody and the drug was cleaved.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Partly supportedcites [135] Dal Corso A, Gébleux R, Murer P, Soltermann A, Neri D. A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo. J Control Release. 2017;264:211–8. sourceExperimental — accuracy not yet measured
The Abstract identifies F16 as binding the A1 domain of tenascin-C, and the Therapy experiments section reports intravenous administration of F16-PNU159682 to mice (page numbers unavailable). The Abstract describes a protease-cleavable linker, but the Discussion calls extracellular protease cleavage in the tumor a conceivable mechanism rather than an established observation after injection. The claim overstates that part as a finding. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“It also derive proliferation, angiogenesis and metastasis stages of tumor progression [134].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Supportedcites [134] Lowy CM, Oskarsson T. Tenascin C in metastasis: a view from the invasive front. Cell Adhes Migr. 2015;9:112–24. source
The ‘Diverse cellular roles in metastatic progression’ section states that tenascin-C is associated with increased cancer-cell proliferation, promotes tumor angiogenesis, and supports metastatic growth. Its discussion of proliferation and angiogenesis further substantiates those roles. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Also, bi-transgenic tumor model confirmed the role of stromal collagen condensation as indication for mammary tumor initiation and progression.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Partly supportedcites [129] Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006;4:38. sourceExperimental — accuracy not yet measured
The Results section (‘Tumor-associated collagen signatures’; page unavailable) reports that dense collagen near a tumor was a reliable hallmark for locating small, pre-palpable tumors. It does not establish that collagen condensation indicates tumor initiation or progression: the authors explicitly say it is unclear whether the dense region precedes tumor formation. The Methods describe two mouse tumor models, not a bi-transgenic model that confirmed the claimed role. (LLM, conf=0.87)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Other ECM components with therapeutic value include fibronectin extra domain A and B (anti-EDB aptide) [138], laminin (IKVAV) [139], gelatin (anginex, small geletic-1 binding peptide) [140], aggrecan (a conjugate of quaternary ammonium) [141], and heparan sulfate (CGKRK peptide), among others [142].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Not checked — no full text of the sourcecites [138] Park J, Kim S, Saw PE, Lee IH, Yu MK, Kim M, Lee K, Kim YC, Jeong YY, Jon S. Fibronectin extra domain B-specific aptide conjugated nanoparticles for targeted cancer imaging. J Control Release. 2012;163:111–8. source
- Not checked — no full text of the sourcecites [139] Okur AC, Erkoc P, Kizilel S. Targeting cancer cells via tumor-homing peptide CREKA functional PEG nanoparticles. Colloids Surf B Biointerfaces. 2016;147:191–200. source
- Partly supportedcites [140] Upreti M, Jyoti A, Johnson SE, Swindell EP, Napier D, Sethi P, Chan R, Feddock JM, Weiss HL, O'Halloran TV, Evers BM. Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer. Oncotarget. 2016;7:41559–74. sourceExperimental — accuracy not yet measured
The Research Paper section describes anginex as a galectin-1-binding peptide and a ligand for targeted delivery to tumor endothelium, supporting the anginex portion attached to citation [140]. It does not identify gelatin as the target or establish anginex as a gelatin-targeting therapy. No page number is available in our copy. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“This formulation allowed drug targets to bind to the tumor stroma to exert their effects locally and gained a promising efficacy and safety profile compared to the unconjugated molecules tested in several mouse models.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Supportedcites [137] Ishihara J, Ishihara A, Sasaki K, Lee SS-Y, Williford J-M, Yasui M, Abe H, Potin L, Hosseinchi P, Fukunaga K, et al. Targeted antibody and cytokine cancer immunotherapies through collagen affinity. Sci Transl Med. 2019;11:eaau3259. source
The Abstract reports that the collagen-binding formulation targets exposed tumor-stroma collagen and that the modified drugs reduced toxicity and suppressed tumor growth compared with unmodified drugs in multiple murine cancer models. The Discussion describes the tumor stroma matrix as both a drug target and a drug reservoir. Page numbers are not provided in our copy. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Their results indicated that simultaneous administration of anti-CD274 antibody (also known as PD-L1 or B7-H1) and anti-CD47 checkpoints antibody can respectively block the signal of “don’t find me” for immune evasion and “don’t eat me” for phagocytosis on CTCs.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Supportedcites [153] Lian S, Xie R, Ye Y, Lu Y, Cheng Y, Xie X, Li S, Jia LJSr. Dual blockage of both PD-L1 and CD47 enhances immunotherapy against circulating tumor cells. Sci Rep. 2019;9:4532. source
The Abstract states that antibodies simultaneously block CD274 (PD-L1/B7-H1) and CD47 on CTCs, identifying them respectively as the “don’t find me” and “don’t eat me” signals. The Introduction gives the same signal assignments. (LLM, conf=0.94)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“They facilitate specific cell-cell interactions and stimulate several signaling pathways in their target cells, including cancer cells [173].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Supportedcites [173] Sullivan R, Maresh G, Zhang X, Salomon C, Hooper J, Margolin D, Li L. The emerging roles of extracellular vesicles as communication vehicles within the tumor microenvironment and beyond. Front Endocrinol (Lausanne). 2017;8:194. source
The figure caption in “Communication via EVs within the TME” (page not supplied) describes bidirectional communication via exosomes between tumor cells and other cells, with cargo influencing multiple pathways involved in tumor progression. The “Proliferation” section also gives examples of vesicles affecting signaling and proliferation in recipient cancer cells. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Thus, these combination shifts immune evasion to immune activation, which resulted in enhanced anti-tumor growth activity and reduced CTCs metastasis in 4 T1 tumor mouse model in vivo [153].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Supportedcites [153] Lian S, Xie R, Ye Y, Lu Y, Cheng Y, Xie X, Li S, Jia LJSr. Dual blockage of both PD-L1 and CD47 enhances immunotherapy against circulating tumor cells. Sci Rep. 2019;9:4532. source
The Results (Fig. 2F) depict dual CD47/PD-L1 blockade changing immune evasion to immune activation. The Abstract and Results report stronger inhibition of tumor growth and CTC metastasis in the in vivo 4T1 mouse model with dual blockade than with either antibody alone. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Additionally, dimeric 123B9 conjugation with paclitaxel is found to be very useful in combating CTCs and preventing the lung metastasis in breast cancer models [168].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Supportedcites [168] Salem AF, Wang S, Billet S, Chen J-F, Udompholkul P, Gambini L, Baggio C, Tseng H-R, Posadas EM, Bhowmick NA, Pellecchia M. Reduction of circulating Cancer cells and metastases in breast-Cancer models by a potent EphA2-agonistic peptide–drug conjugate. J Med Chem. 2018;61:2052–61. source
The Results section on circulating tumor cells reports significantly fewer CTCs after (123B9)2–L2–PTX treatment than after Abraxane in an orthotopic breast-cancer mouse model. The Results section on the breast-cancer metastasis model reports more than 75% fewer gross lung metastases than in the control and Abraxane groups. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thus, they can serve as valuable prognostic, diagnostic, and biosensing tools to detect cancer cells that are clinically undetectable, and to make plans for timely and precise therapeutic interventions (Fig. 2e) [9].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Partly supportedcites [9] Jahanban-Esfahlan R, Seidi K, Manjili MH, Jahanban-Esfahlan A, Javaheri T, Zare P. Tumor cell dormancy: threat or opportunity in the fight against Cancer. Cancers. 2019;11:1207. sourceExperimental — accuracy not yet measured
The Introduction identifies CTCs as detectable dormant tumor cells, and the Conclusions and Clinical Implications say that CTCs and other circulating material offer opportunities for timely detection and monitoring of treatment outcomes. The paper does not establish CTCs specifically as prognostic or biosensing tools for planning precise interventions; it cautions that their rarity makes minimal residual disease difficult to detect. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the development of liquid biopsy platforms capable of capturing this rare population of cells from the blood is highly rewarding [155].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Supportedcites [155] Jahanban-Esfahlan R, Seidi K, Jahanban-Esfahlan A, Jaymand M, Alizadeh E, Majdi H, Najjar R, Javaheri T, Zare P. Static DNA nanostructures for cancer theranostics: Recent progress in design and applications. Nannotechnol Sci Appl. 2019;12:25–46. source
The DNA Hydrogel section describes a liquid-biopsy method that captures circulating tumor cells and calls it an effective tool for live single-cell isolation. The Introduction identifies detection and analysis of rare circulating tumor cells as a use in predictive cancer diagnostics. Together, these passages support the claim that developing platforms to capture these cells is valuable. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Consequently, tumor self-seeding leads to enhanced angiogenesis, tumor growth, stromal recruitment through seed-derived factors including the chemokine CXCL1, anaplasia, tumor size, and vascularity.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Partly supportedcites [147] Kim M-Y, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH-F, Norton L, Massagué J. Tumor self-seeding by circulating cancer cells. Cell. 2009;139:1315–26. sourceExperimental — accuracy not yet measured
The Abstract and Discussion report that self-seeding can accelerate tumor growth, angiogenesis, and stromal recruitment; the Results identify seeder-derived CXCL1 as contributing to stromal recruitment. But the Discussion presents links to anaplasia, tumor size, and vascularity as possible explanations for clinical associations, not as established outcomes of self-seeding. Page numbers are not provided in our copy. (LLM, conf=0.88)
- Partly supportedcites [148] Jayatilaka H, Phillip JM. Targeting metastasis through the inhibition of interleukin 6 and 8. Future Medicine. 2019. https://doi.org/10.2217/bmt-2019-0002. sourceExperimental — accuracy not yet measured
The Abstract reports that IL-6 and IL-8 promote tumor self-seeding and co-regulate tumor-cell proliferation; it also mentions interactions with stromal cells. It does not say that self-seeding causes the listed changes in angiogenesis, stromal recruitment, anaplasia, tumor size, or vascularity, or identify CXCL1 as a seed-derived factor. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Another study, involving 6712 breast cancer patients showed a decrease in the number of CTCs only in human epidermal growth factor receptor 2 (HER2+) or HER2- patients but not in the triple-negative ones and nor in patients who underwent surgery.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Partly supportedcites [151] Yan W-T, Cui X, Chen Q, Li Y-F, Cui Y-H, Wang Y, Jiang JJSr. Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis . Sci Rep. 2017;7:43464. sourceExperimental — accuracy not yet measured
The Results describe a meta-analysis of 50 studies involving 6,712 patients. Subgroup analyses report significant decreases in CTC-positive rates for HER2-positive and HER2-negative patients, but not for triple-negative patients or after surgery. The claim calls these decreases changes in the number of CTCs, whereas the paper distinguishes CTC-positive rates from CTC counts; its initial pooled count analysis found no significant change. Page numbers were not supplied. (LLM, conf=0.89)
plainn = 6,712- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Moreover, these exosomes display differential integrin expression, and blockade of integrins αvβ5 and α6β4 dampen exosome uptake, as well as liver and lung metastasis, respectively.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Supportedcites [176] Hoshino A, Costa-Silva B, Shen T-L, Rodrigues G, Hashimoto A, Mark MT, Molina H, Kohsaka S, Di Giannatale A, Ceder SJN: Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35. source
The Abstract reports distinct exosomal integrin patterns and states that targeting α6β4 and αvβ5 decreased exosome uptake and lung and liver metastasis, respectively. The cited claim gives the same organ associations in reverse order: αvβ5 with liver and α6β4 with lung. The sections “Exosomal ITGs determine organotropism” and “Exosomal tropism requires ITGβ4 and ITGβ5” provide supporting experimental detail. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Finally, integrin-mediated uptake of exosome activates Src phosphorylation and pro-inflammatory S100 gene expression in resident cells [176].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Supportedcites [176] Hoshino A, Costa-Silva B, Shen T-L, Rodrigues G, Hashimoto A, Mark MT, Molina H, Kohsaka S, Di Giannatale A, Ceder SJN: Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35. source
In “Exosomal ITGs activate S100 genes” (page not supplied), the paper reports an exosomal integrin-dependent increase in phosphorylated Src in lung fibroblasts and upregulation of pro-inflammatory S100 genes in target cells. The Discussion links cell-type-specific exosome integrin uptake to S100 gene upregulation, while noting that the response varies by resident cell type. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In this space, tumor cells and their adjacent microenvironments are in frequent communication.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Mechanism of interaction
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The interaction of cancer cells with their microenvironment is dynamic and bidirectional and includes (i) cell-cell contacts, or cell-free contacts (involving ECM) and (ii) the mediators that enable these contacts.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Mechanism of interaction
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The consequence of such crosstalks is reflected in tumor formation and maintenance as well as deficient response to therapy and multi-drug resistance (MDR).”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Background
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Tumors develop in complex and dynamic microenvironments that influencetheir growth, invasion, and metastasis.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Mechanism of interaction
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the meantime, the detection and monitoring of other tumor-interacting components, such as CTCs, cfDNA and apoptotic bodies in the bloodstream can be beneficial to extend the knowledge of the condition of the malignant disease and improve cancer detection and diagnosis, as well as enable timely and appropriate treatment (Fig. 2).”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In fact, inhibitors of these pathways can target and block proliferation and pathological angiogenesis in vivo [53].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
What the sources say
- Not checked — no full text of the sourcecites [53] Missiaen R, Morales-Rodriguez F, Eelen G, Carmeliet P. Targeting endothelial metabolism for anti-angiogenesis therapy: a pharmacological perspective. Vasc Pharmacol. 2017;90:8–18. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Equally, 3D systems enable studying the organ-specific preference of metastatic cancer cells and the underlying molecular pathways/interactions.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Tumor endothelial cells (TECs)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In addition, pericytes have several functions in the immune system including the attraction of inborn leukocytes to exit blood vessels, regulating lymphocyte activation and eliciting direct phagocytic activity [26].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Pericytes
What the sources say
- Not checked — no full text of the sourcecites [26] Birbrair A: Pericyte biology: development, homeostasis, and disease. In Pericyte Biology-Novel Concepts Springer; 2018: 1–3. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Such liposomes were capable of regulating the tumor ECM through efficiently removing CAFs, rendering the ECM accessible for doxorubicin-loaded nanoparticles that were administered later [136].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > ECM
What the sources say
- Not checked — no full text of the sourcecites [136] Chen B, Dai W, Mei D, Liu T, Li S, He B, He B, Yuan L, Zhang H, Wang X. Comprehensively priming the tumor microenvironment by cancer-associated fibroblast-targeted liposomes for combined therapy with cancer cell-targeted chemotherapeutic drug delivery system. J Control Release. 2016;241:68–80. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This aptamer-conjugate can work properly when 108 interfering cells or blood cells that do not express EpCAM or Her2 are present, as well as in complex biological samples of patients and mice with greatly enhanced bio-stability and high capturing precision.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Not checked — no full text of the sourcecites [154] Dong H, Han L, Wu Z-S, Zhang T, Xie J, Ma J, Wang J, Li T, Gao Y, Shao J. Biostable aptamer rings conjugated for targeting two biomarkers on circulating tumor cells in vivo with great precision. Chem Mater. 2017;29:10312–25. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In this line, an interesting formulation based on DNA hydrogel is developed in which a DNA staple strand with aptamer-toehold biblocks binds to EpCAM receptor. This CTC-specific binding, initiate aptamer-triggered clamped hybridization chain reaction via toehold-initiated branch migration on CTC surface, realizing single/clusters of live CTC clocked in DNA hydrogel.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Not checked — no full text of the sourcecites [156] Song P, Ye D, Zuo X, Li J, Wang J, Liu H, Hwang MT, Chao J, Su S, Wang L, et al. DNA hydrogel with Aptamer-toehold-based recognition, cloaking, and Decloaking of circulating tumor cells for live cell analysis. Nano Lett. 2017;17:5193–8. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, despite uncertainty about the analytic validity, clinical validity, and clinical utility of CTCs, their status is a valuable indicator of the efficacy of cancer therapy, which may aid clinicians to make decisions for further personalized therapy.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In this formulation, capture arms could distinctly bind two biomarkers at the same time (EpCAM and Her2). This, induced apoptosis as a result of the arrestment of cell cycle and the inhibition of tumor progression in captured CTCs (Fig. 3) [154].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Not checked — no full text of the sourcecites [154] Dong H, Han L, Wu Z-S, Zhang T, Xie J, Ma J, Wang J, Li T, Gao Y, Shao J. Biostable aptamer rings conjugated for targeting two biomarkers on circulating tumor cells in vivo with great precision. Chem Mater. 2017;29:10312–25. source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The aptamer-conjugate impeded metastasis and displayed enhanced bio-stability against endogenous nucleases in vivo.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Circulating tumor cells
What the sources say
- Not checked — no full text of the sourcecites [154] Dong H, Han L, Wu Z-S, Zhang T, Xie J, Ma J, Wang J, Li T, Gao Y, Shao J. Biostable aptamer rings conjugated for targeting two biomarkers on circulating tumor cells in vivo with great precision. Chem Mater. 2017;29:10312–25. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Form therapeutic point of view, exosomes are applied as diagnostic biomarkers, therapeutic targets, or as anticancer drug-delivery vehicles [178].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Not checked — no full text of the sourcecites [178] Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016;30:836–48. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In addition, Nishida-Aoki and colleagues applied therapeutic antibody targeting EVs including human-specific anti-CD9 or anti-CD63 antibodies which aimed at decreasing tumor-derived exosomes generation, possibly through clearance of EVs by macrophages, resulting in a decline in breast cancer distant metastasis in a mouse model (Fig. 2f) [186].”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
What the sources say
- Not checked — no full text of the sourcecites [186] Nishida-Aoki N, Tominaga N, Takeshita F, Sonoda H, Yoshioka Y, Ochiya T. Disruption of circulating extracellular vesicles as a novel therapeutic strategy against cancer metastasis. Mol Ther. 2017;25:181–91. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Findings from preclinical animal models are predictive of therapeutic outcomes in human cancer patients.
“This formulation is found as a promising approach in treatment of a variety of cancers including breast, lung, colon and melanoma in preclinical settings [92].”
The paper relies on this without support.
In vitro 3D and microfluidic models sufficiently recapitulate the in vivo tumor microenvironment to inform therapeutic development.
“Recent advances on three dimensional (3D) platforms through the use of lab-on-chip and microfluidic devices [17] have provided an enormous opportunity to better stimulate the function and biology of TME and to bridge the translational gap between preclinical and clinical settings [18].”
The authors state this as an assumption.
Disrupting tumor cell interactions can be exploited as a novel strategy for future cancer therapy regimes.
“Together, we assume that disrupting tumor cell interactions can be exploited as a novel strategy for future cancer therapy regimes; however, further studies are still pending for clinical implementation in order to fully understand tumor cell interactions.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“With the advancement of tumor biology, it became clear that tumor cells actively reprogram surrounding fibroblasts into a modified state termed cancer-associated fibroblasts (CAFs) [5,19,35,36].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This biochemical framework imparts key biophysical properties to the tumor tissue, including stiffness, porosity, insolubility, and molecular density [5,77,78,79]. These characteristics serve as biomechanical cues that modulate diverse cellular processes, such as migration, proliferation, polarity maintenance, and lineage specification [25,80].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The dynamic interactions between tumor cells and the non-transformed cells are key in determining the progression of cancer, as these could either suppress or promote cancer initiation, growth, migration, and metastasis, as well as cancer recurrence and drug resistance (2)”
From Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis (2021) · cites this paper as [2]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It is now widely accepted that tumor initiation and progression are not governed solely by genetic mutations but are significantly influenced by the dynamic interplay between tumor cells and their surrounding microenvironment.”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“This surrounding landscape—referred to as the tumor microenvironment (TME)—comprises a complex network of cellular, acellular, and immune components [5,20,21].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [5]
In the citing paper
“Single‐cell‐based technologies have enabled a better dissection of the TME through precise monitoring of cell sub‐populations and spatial architecture, thus revealing the heterogeneous and complex nature of the TME [10, 12].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
“To increase nutrient availability, breast cancer cells secrete miR-122 -enriched vesicles to suppress glucose uptake by niche cells in vitro and in vivo.”
§ Tumor microenvironment complexity and therapeutic implications at a glance > Understanding tumor cell interactions for effective cancer theranostics > Exosomes
“Mechanistically, miR-122 downregulate the glycolytic enzyme pyruvate kinase and restores glucose uptake by lungs and brain and lessen disease progression [177].”
Citations
Cites
Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994 · cited 1×
“In view of the critical role of CAFs in the design of TME, the therapeutic options for deactivating CAF-mediated interaction are largely focused on using/reprogramming or eliminating of CAFs [76] [77] [78] .”
BackgroundThe chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534 · cited 1×
“Based on their origin and half-life, they are (i) long-living embryonically (yolk sac)-derived tissue-resident macrophages and (ii) short-lived circulating monocyte-derived macrophages derived from bone marrow and recruited to tumor tissue by growth factors and chemokines, such as, CCL2, CCL5, and macrophage colony-st…”
BackgroundTumour exosome integrins determine organotropic metastasis
Hoshino, A., Costa-Silva, B., Shen, T.-L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., Molina, H., Kohsaka, S., Di Giannatale, A., Ceder, S., et al. (2015) · Nature · doi:10.1038/nature15756 · Cited by 5,101 · cited 1×
“Finally, integrin-mediated uptake of exosome activates Src phosphorylation and pro-inflammatory S100 gene expression in resident cells [176].”
BackgroundAccessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment
Hanahan, D., & Coussens, L. M. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.022 · Cited by 4,632 · cited 1×
“The non-malignant cells in the TME are known to promote tumorigenesis in all phases of cancer development and metastasis [4, 5] .”
BackgroundThe biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366 · cited 1×
“apoptosis and improving the proliferation, migration and viability of cancer cells [58, 59].”
BackgroundThe extracellular matrix at a glance
Frantz, C., Stewart, K. M., & Weaver, V. M. (2010) · Journal of Cell Science · doi:10.1242/jcs.023820 · Cited by 4,334 · cited 1×
“ECM forms the scaffold of tissues and organs through the production of supramolecular aggregates, such as fibrils and sheet-like networks [113, 114] .”
BackgroundTumour-associated macrophages as treatment targets in oncology
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L., & Allavena, P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.217 · Cited by 4,157 · cited 1×
“TAM targeting, in turn, can be achieved by barricading the colony stimulating factor 1 receptor (CSF1R), which is essential for the recruitment, differentiation and survival of TAM [103] (Fig.”
BackgroundTumor-Associated Macrophages: From Mechanisms to Therapy
Noy, R., & Pollard, J. W. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.010 · Cited by 4,089 · cited 2×
“Accordingly, TAM-based therapeutic strategies are being developed that aim at TAM targeting, TAM reeducation, and TAM depletion [88, 96, 101, 102] .”
BackgroundThe Extracellular Matrix: Not Just Pretty Fibrils
Hynes, R. O. (2009) · Science · doi:10.1126/science.1176009 · Cited by 3,527 · cited 1×
“ECM forms the scaffold of tissues and organs through the production of supramolecular aggregates, such as fibrils and sheet-like networks [113, 114] .”
BackgroundTumour-cell invasion and migration: diversity and escape mechanisms
Friedl, P., & Wolf, K. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1075 · Cited by 3,350 · cited 1×
“And most of them only discussed a limited number of players/strategies such as anti-angiogenic therapies or targeting ECM yet fail to discuss the newly formed gadgets of cell-cell interactions such as cfDNA, apoptotic bodies, CTCs as well as exosomes [21, 22] .”
Background
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Sorted by citations
Items 601–700 of 1,790
Singh, D. D., Haque, S., Kim, Y., Han, I., & Yadav, D. K. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1455211 · Cited by 20
Chlorin e6: a promising photosensitizer of anti-tumor and anti-inflammatory effects in PDT
Yu, H., Huang, Z., Wu, J., Zhao, Z., Hua, Y., & Yang, Y. (2025) · Nanomedicine · doi:10.1080/17435889.2025.2456450 · Cited by 18
Yang, H., Wu, C., Chen, J., & Lee, T. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238993 · Cited by 15
“All the components within TME, including low pH, hypoxia, nutrient-limiting metabolic competition, and nitric oxide (NO) production work together to impair T cell function [20, 65-69].”
BackgroundMoody, A. S., Dayton, P. A., & Zamboni, W. C. (2021) · Cancer Drug Resistance · doi:10.20517/cdr.2020.94 · Cited by 18
“The tumor microenvironment (TME) is characterized by many factors including increased concentrations of extracellular matrix proteins such as collagen, hyaluronan, and fibronectins, as well as low extracellular pH, tortuous neovasculature, and hypoxia[1].”
BackgroundImmune Checkpoints in Pediatric Solid Tumors: Targetable Pathways for Advanced Therapeutic Purposes
Cocco, C., Morandi, F., & Airoldi, I. (2021) · Cells · doi:10.3390/cells10040927 · Cited by 18
“Stromal cells also contribute to the formation and remodelling of ECM, produce several tumor growth factors and promote vessel formation [1,2].”
BackgroundHarnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients
Γκουντάκος, Α., Delfino, P., Lawlor, R. T., Scarpa, A., Corbo, V., & Bria, E. (2021) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359211006947 · Cited by 16
Chen, H., Tu, W., Lu, Y., Zhang, Y., Xu, Y., Chen, X., Zhu, M., & Liu, Y. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113114 · Cited by 16
Pieniądz, P., Pięt, M., & Paduch, R. (2024) · Applied Sciences · doi:10.3390/app14072930 · Cited by 18
Old drugs, new challenges: reassigning drugs for cancer therapies
Czechowicz, P., Więch, A., Sławski, J., Collawn, J. F., & Bartoszewski, R. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-025-00710-0 · Cited by 19
Garemilla, S. S. S., Gampa, S. C., & Garimella, S. V. (2025) · Medical Oncology · doi:10.1007/s12032-025-02754-w · Cited by 19
“For instance, a study proposed a domain adaptation network for feature disentanglement to model the impact of the TME on drug response, aiming to separate the effects of the TME from other factors influencing drug response [5].”
Rajankar, N., Kumar, A., & Gulbake, A. (2025) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2025.107050 · Cited by 20
Ren, T., Sun, L., Zheng, Y., Jiang, Y., Guo, Y., & Ma, J. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000002636 · Cited by 20
Mauro, A. D., Berretta, M., Santorsola, M., Ferrara, G., Picone, C., Savarese, G., & Ottaiano, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26167723 · Cited by 19
“Technologies for in situ mutation detection and spatial genomics have improved the ability to identify subclonal niches, providing essential information for personalized therapeutic strategies [43–45].”
Fejza, A., Camicia, L., Poletto, E., Carobolante, G., Mongiat, M., & Andreuzzi, E. (2021) · Cancers · doi:10.3390/cancers13112759 · Cited by 16
Gardiner, J. C., & Cukierman, E. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2022.01.004 · Cited by 16
Yang, J.-I., Lee, H. L., Yun, J.-J., Kim, J., So, K.-H., Jeong, Y., & Kang, D.-H. (2022) · Materials · doi:10.3390/ma15113795 · Cited by 18
“Paradoxically, the abnormal status of the tumor microenvironment has been considered for targeting issues and led the development of various drug-targeting strategies for the conquest of MDR of tumors [28,47].”
BackgroundLin, N., Luo, Y., Zhang, D., & Hou, L. (2022) · Current Pharmaceutical Biotechnology · doi:10.2174/1389201023666220728150544 · Cited by 15
Organoids in lung cancer: A teenager with infinite growth potential
Xu, Y., Xin, W., Yan, C., Shi, Y., Li, Y., Hu, Y., & Ying, K. (2022) · Lung Cancer · doi:10.1016/j.lungcan.2022.08.006 · Cited by 14
Li, A., Muenst, S. E., Hoffman, J., Starck, L., Sarem, M., Fischer, A., Hütter, G., & Shastri, V. P. (2022) · Communications Biology · doi:10.1038/s42003-022-04236-5 · Cited by 19
Liu, W., Zhu, M., Li, X., Er, L., & Li, S. (2023) · Disease Markers · doi:10.1155/2023/9226712 · Cited by 15
“The TME is essential in stimulating heterogeneity among cancer cells, thus leading to cancer cell progression and metastasis [17].”
BackgroundUnraveling the Role of Adiponectin Receptors in Obesity-Related Breast Cancer
Naimo, G. D., Paolì, A., Giordano, F., Forestiero, M., Panno, M. L., Andò, S., & Mauro, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24108907 · Cited by 16
“Recent evidence has highlighted the existence of a dynamic interaction between breast cancer and the cellular components of TME that drives remodeling of extracellular matrix, neovascularization nd epithelial c ll ransition to stem cells [88].”
BackgroundShi, X., Wei, K., Wu, Y., Mao, L., Pei, W., Zhu, H., Shi, Y., Zhang, S., Tao, S., Wang, J., et al. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110884 · Cited by 18
Sun, Z., Chu, X., Adams, C., Ilina, T. V., Guerrero, M., Lin, G., Chen, C., Jelev, D. V., Ishima, R., Li, W., et al. (2023) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2023.09.002 · Cited by 16
“To address this, a more sensitive approach is needed to detect the penetration and antibody uptake by the tumor cells.(34,35) Domain drug conjugates to cytotoxic payloads (DCC) have been evaluated recently in different tumor models and could be a good way to overcome penetration and recruitment issues that CAR-T thera…”
BackgroundRahimi, A., Malakoutikhah, Z., Rahimmanesh, I., Ferns, G. A., Nedaeinia, R., Ishaghi, S. M. M., Dana, N., & Javanmard, S. H. (2023) · Cancer Cell International · doi:10.1186/s12935-023-03134-y · Cited by 15
“…that form the tis-sue’s supporting structure or stroma; blood vessels that grow in response to tumor signals; resident and infiltrating immune cells; signaling molecules provided by both cancerous and normal cells; and the extracellular matrix (ECM) comprise the tumor microenvironment [17].”
BackgroundCancer Biology and Therapeutics: Navigating Recent Advances and Charting Future Directions
Cleanclay, W. D., Zakari, S., Adigun, T. O., Ayeni, T. O., Nnaji, P. C., Amuji, D. N., Blessing, A., Adebosoye, A., Gbadebo, M., Agbetuyi-Tayo, P., et al. (2023) · Tropical Journal of Natural Product Research · doi:10.26538/tjnpr/v7i12.4 · Cited by 17
Liu, Y., Li, X., Chen, S., Zhu, C., Shi, Y., Dang, S., Zhang, W., & Li, W. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1277508 · Cited by 18
“…consists of tumor cells, tumor stromal cells including stromal fi broblasts, endothelial cells and immune cells like microglia, macrophages and lymphocytes and the non-cellular components of extracellular matrix such as collagen, fi bronectin, hyaluronan, laminin, among others (Baghban et al., 2020).”
BackgroundAdvancement in Cancer Vasculogenesis Modeling through 3D Bioprinting Technology
Shukla, A. K., Yoon, S., Oh, S., Lee, D., Ahn, M., & Kim, B. S. (2024) · Biomimetics · doi:10.3390/biomimetics9050306 · Cited by 18
“By analyzing these intricate relationships, scientists can find new therapeutic targets and create more potent treatment plans to halt the spread of cancer and overcome drug resistance [67,81].”
BackgroundMicrobiome's Universe: Impact on health, disease and cancer treatment
Réthi‐Nagy, Z., & Juhász, S. (2024) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2024.07.002 · Cited by 17
Bian, Y., Chang, X., Hu, X., Li, B., Song, Y., Hu, Z., Wang, K., Wan, X., & Lu, W. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e35727 · Cited by 19
“The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and diverse immune cells regulating tumour growth and invasion [5,6].”
BackgroundZhu, X.-Y., Liu, W., Hou, X., Zong, C., Yu, W., Shen, Z.-M., Qu, S., Tao, M., Xue, M., Zhou, D.-Y., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.12.008 · Cited by 15
“These discrete cell types release a series of signals that translate into a pathological entity, thereby maintaining the cancer cell plasticity, invasiveness, and migration abilities[11].”
Kwon, W., Seo, H. K., Song, G., Lee, M.-K., & Park, W. S. (2025) · Biomedicines · doi:10.3390/biomedicines13010086 · Cited by 15
Roda, E., Luca, F. D., Locatelli, C., Ratto, D., Iorio, C. D., Savino, E., Bottone, M. G., & Rossi, P. (2020) · Molecules · doi:10.3390/molecules25225400 · Cited by 15
“Experimental and clinical data evidence that an in-depth analysis of the bidirectional communications and interactions between tumor cells and their surrounding dynamic TME is essential to identify the existing mechanisms of tumor expansion and invasion [41].”
BackgroundEngineering stromal heterogeneity in cancer
Tang, L. J. W., Zaseela, A., Toh, C. C. M., Adine, C., Aydar, A. O., Iyer, N. G., & Fong, E. L. S. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.027 · Cited by 15
Si, C., Chen, C., Guo, Y., Kang, Q., & Sun, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.711815 · Cited by 14
Trout, R. M., Gnanatheepam, E., Gado, A., Reik, C., Ramella‐Roman, J. C., Hunter, M., Schnelldorfer, T., & Georgakoudi, I. (2021) · Biomedical Optics Express · doi:10.1364/boe.443926 · Cited by 17
A Novel Microwave Resonant Sensor for Measuring Cancer Cell Line Aggressiveness
D’Alvia, L., Carraro, S., Peruzzi, B., Urciuoli, E., Palla, L., Prete, Z. D., & Rizzuto, E. (2022) · Sensors · doi:10.3390/s22124383 · Cited by 16
“However, due to the complex and various signaling pathways involved in cancer development, there is currently a lack of knowledge on tumor behavior [23–25].”
Primary cancer-associated fibroblasts exhibit high heterogeneity among breast cancer subtypes
Piwócka, O., Musielak, M., Piotrowski, I., Kulcenty, K. I., Adamczyk, B., Fundowicz, M., Suchorska, W. M., & Malicki, J. (2023) · Reports of Practical Oncology & Radiotherapy · doi:10.5603/rpor.a2023.0026 · Cited by 17
“Key words: primary culture; breast cancer; cells isolation; cancer-associated fibroblasts; tumour heterogeneity Rep Pract Oncol Radiother 2023;28(2):159–171 https://journals.viamedica.pl/rpor160 participates in the cross-talk between cancer cells and components of TME.”
BackgroundInfluentialMuraoka, S., Baba, T., Akazawa, T., et al. (2024) · International Journal of Cancer · doi:10.1002/ijc.35229 · Cited by 14
The endocannabinoid system in cancer biology: a mini-review of mechanisms and therapeutic potential
Salum, K. C. R., Miranda, G. B. A., Dias, A. L., Carneiro, J. R. I., Bozza, P. T., da Fonseca, A. C. P., & Silva, T. (2025) · Oncology Reviews · doi:10.3389/or.2025.1573797 · Cited by 15
Akbariqomi, M., Zarandi, P. K., Abedi, A., Moghaddam, M. M., & Fooladi, A. A. I. (2025) · Microbial Cell Factories · doi:10.1186/s12934-025-02838-2 · Cited by 16
“The non-malignant cells inside the TME are recognized for facilitating carcinogenesis across all stages of cancer progression and metastasis [83, 85].”
The Role of MYC in Tumor Immune Microenvironment Regulation: Insights and Future Directions
Nirala, B. K., & Yustein, J. T. (2025) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl37304 · Cited by 19
“These components collectively shape tumor progression, immune evasion, and therapeutic response [21].”
Jolasun, Y., Song, K., Zheng, Y., Wang, J., Fonseca, G. J., Eidelman, D. H., & Ding, J. (2025) · Nature Communications · doi:10.1038/s41467-025-66162-4 · Cited by 17
“These fi ndings underscore the cellular diversity between tumors and highlight the necessity of patient-speci fi c therapeutic strategies 122,123 .”
Cancer‑associated fibroblasts as cellular vehicles in endometrial cancer cell migration
Voon, Y., Omar, I. S., Wu, M., Said, N. A. B. M., & Chung, I. (2021) · Oncology Letters · doi:10.3892/ol.2021.13121 · Cited by 13
“It has long been recognized that crosstalk between tumor cells and their microenvironment alters the mecha‐ nistic property of tumor cells in proliferation, motility and metastasis (20).”
BackgroundTumor-Associated Macrophages: Reasons to Be Cheerful, Reasons to Be Fearful
Szulc-Kiełbik, I., & Kiełbik, M. (2022) · Experientia supplementum · doi:10.1007/978-3-030-91311-3_4 · Cited by 14
Li, X., & Li, M. (2022) · Medicinal Research Reviews · doi:10.1002/med.21924 · Cited by 15
Obesity as a Risk Factor for Breast Cancer—The Role of miRNA
Hanusek, K., Karczmarski, J., Litwiniuk, A., Urbańska, K., Ambrożkiewicz, F., Kwiatkowski, A., Martyńska, L., Domańska, A., Bik, W., & Paziewska, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232415683 · Cited by 18
“This complex influences the inflammation processes and the development of tumors [107,108].”
BackgroundEpithelial-mesenchymal plasticity: Implications for ferroptosis vulnerability and cancer therapy
Lee, J., & Roh, J. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.103964 · Cited by 19
Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment
Lv, J., Jiang, Z., Yuan, J., Zhuang, M., Guan, X., Liu, H., Yin, Y., Ma, Y., Liu, Z., Wang, H., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1093716 · Cited by 14
Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment
Szymanowska, A., Rodriguez‐Aguayo, C., Lopez‐Berestein, G., & Amero, P. (2023) · Non-Coding RNA · doi:10.3390/ncrna9050052 · Cited by 15
“The communication among the TME cell types is in part mediated by secreted proteins, cytokines, and non-coding RNAs transported by exosomes [42].”
BackgroundGorini, F., & Tonacci, A. (2023) · Antioxidants · doi:10.3390/antiox12101898 · Cited by 16
“…a pivotal player in tumorigenesis, consists of both proliferating malignant cells and non-malignant components, including tumor stromal cells (stromal fibroblasts and immune cells, such as microglia, macrophages, and lymphocytes), elements of the extracellular matrix, and endothelial cells [28,85].”
BackgroundJia, L., Gao, F., Hu, G., Fang, Y., Tang, L., Wen, Q., Gao, N., Xu, H., & Qiao, H. (2023) · Advanced Science · doi:10.1002/advs.202303975 · Cited by 17
Dynamic interplay of intratumoral microbiota within the colorectal cancer microenvironment
Wu, Y., Wang, P., Zhao, X., Liu, T., Situ, B., & Zheng, L. (2023) · Open Research (University of Surrey) · doi:10.1002/viw.20230100 · Cited by 14
Antoniraj, M. G., Dhayanandamoorthy, Y., Ponnuchamy, K., Kandasamy, R., & Devi, K. P. (2024) · Carbohydrate Research · doi:10.1016/j.carres.2024.109049 · Cited by 14
Gao, K., Li, X., Luo, S., & Zhao, L. (2024) · International Journal of Oncology · doi:10.3892/ijo.2024.5639 · Cited by 14
“The tumor microenvironment (TME) refers to the unique environment around the tumor consisting of blood vessels, immune cells, fibroblasts and an extracellular matrix, which is more conducive for tumor cells than normal cells (1).”
BackgroundInfluence of tumor microenvironment on the different breast cancer subtypes and applied therapies
Almeida, C. F., Correia‐da‐Silva, G., Teixeira, N. A. A., & Amaral, C. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116178 · Cited by 16
The Role of TAMs in the Regulation of Tumor Cell Resistance to Chemotherapy
McWhorter, R., & Bonavida, B. (2024) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2024053667 · Cited by 14
Targeted drug delivery in cancer using nanomaterials: advances and challenges
Sharma, T., Gorivale, S., & Bhandari, P. (2024) · Journal of Nanoparticle Research · doi:10.1007/s11051-024-06023-1 · Cited by 14
“It is widely recognised that under certain conditions, such as inflammation or hypoxia, frequently observed in tumours, the endothelium of blood vessels demonstrates heightened permeability in comparison to its normal state [46].”
Dalpati, N., Rai, S. K., Sharma, P., & Sarangi, P. P. (2024) · Matrix Biology · doi:10.1016/j.matbio.2024.12.003 · Cited by 20
Non-Coding RNAs in the Crosstalk between Breast Cancer Cells and Tumor-Associated Macrophages
Benedetti, A., Turco, C., Fontemaggi, G., & Fazi, F. (2022) · Non-Coding RNA · doi:10.3390/ncrna8010016 · Cited by 16
Matricellular proteins in intrahepatic cholangiocarcinoma
Sirica, A. E. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2022.01.010 · Cited by 14
Role of Base Excision Repair in Innate Immune Cells and Its Relevance for Cancer Therapy
Zhao, S., Habib, S. L., Senejani, A. G., Sebastian, M. M., & Kidane, D. (2022) · Biomedicines · doi:10.3390/biomedicines10030557 · Cited by 14
The interface stiffness and topographic feature dictate interfacial invasiveness of cancer spheroids
Mao, B.-H., Thi, K. M. N., Tang, M., et al. (2022) · Biofabrication · doi:10.1088/1758-5090/acaa00 · Cited by 14
“During cancer progression, dysregulated ECM remodeling, which is under the influence of cancer cells and tumor stroma, can not only alter the mechanical properties of the ECM, characteristically increasing stiffness of the tumor tissue, but also contribute to spatial and temporal heterogeneity of the ECM networks [11].”
BackgroundA Novel Fibromodulin Antagonist Peptide RP4 Exerts Antitumor Effects on Colorectal Cancer
Deng, T., Hou, Y., Lin, G., Feng, C., Liu, K., Chen, W., Wei, W., Huang, L., & Dai, X. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15030944 · Cited by 16
“The TME generally comprises immune cells, stromal cells, blood vessels, and extracellular matrix [4,5].”
BackgroundSynthesis strategies and cancer therapy applications of PEDOT nanoparticles
Dias, D., Resina, L., Ferreira, F. C., Sanjuan‐Alberte, P., & Esteves, T. (2024) · Materials Advances · doi:10.1039/d4ma00260a · Cited by 14
Tumor Microenvironment Role in Pancreatic Cancer Stem Cells
Galindo-Vega, A., Maldonado, V., Mitre-Aguilar, I. B., & Meléndez-Zajgla, J. (2023) · Cells · doi:10.3390/cells12121560 · Cited by 14
“The interactions between cellular and acellular components are also crucial to the generation of tumor heterogeneity and clonal evolution [50].”
BackgroundSherapura, A., Siddesh, B. M., Malojirao, V. H., Thirusangu, P., Avin, B. R. V., Kumari, S., Ramachandra, Y. L., & Prabhakar, B. T. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154981 · Cited by 12
Shadmani, N., Gohari, S., Kadkhodamanesh, A., Ghaderinia, P., Hassani, M., & Sharifyrad, M. (2023) · RSC Advances · doi:10.1039/d3ra03660j · Cited by 13
Javanmard, S. H., Rafiee, L., Najafi, M. B., Khorsandi, D., Hasan, A., Vaseghi, G., & Makvandi, P. (2023) · Environmental Research · doi:10.1016/j.envres.2023.117083 · Cited by 13
Chalcones as Potential Cyclooxygenase-2 Inhibitors: A Review
Mahboubi‐Rabbani, M., Zarei, R., Baradaran, M., et al. (2023) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/0118715206267309231103053808 · Cited by 13
Improving targeted small molecule drugs to overcome chemotherapy resistance
Rismanbaf, A. (2023) · Cancer Reports · doi:10.1002/cnr2.1945 · Cited by 14
“6,19,98 Although many tumor cells and diverse types of stromal cells can produce ECM proteins, CAFs have a main and significant role in the organization and composition of ECM.”
BackgroundPong, A., Mah, C. K., Yeo, G. W.-M., & Lewis, N. E. (2023) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2023.103048 · Cited by 13
PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases
Ferrucci, V., Lomada, S. K., Wieland, T., & Zollo, M. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10165-4 · Cited by 12
“The TME consists of tumor cells, stromal fibroblasts, endothelial cells, immune cells, secreted factors, and extra-cellular matrix (ECM) components [121–123].”
BackgroundTherapeutic biomarkers in acute myeloid leukemia: functional and genomic approaches
Bhatia, K. S., Sandhu, V., Wong, M. H., Iyer, P., & Bhatt, S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1275251 · Cited by 13
Qiao, L., Dong, C., Jia, W., & Sun, G. (2024) · Endocrine Related Cancer · doi:10.1530/erc-23-0257 · Cited by 13
Macrophage-Induced Carboxypeptidase A4 Promotes the Progression of Anaplastic Thyroid Cancer
Choi, Y., Jeon, M. J., Lee, W. K., et al. (2024) · Thyroid · doi:10.1089/thy.2023.0427 · Cited by 13
“8,12,19 However, the role of in fi ltrating macrophages in cancer is poorly understood.”
Liu, X., Qu, C., Liu, C., Zhu, N., Huang, H., Teng, F., Huang, C., Luo, B., Liu, X., Xie, M., et al. (2024) · GigaScience · doi:10.1093/gigascience/giae078 · Cited by 12
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Metadata
- Authors
- Baghban, R., Roshangar, L., Jahanban-Esfahlan, R., Seidi, K., Ebrahimi-Kalan, A., Jaymand, M., Kolahian, S., Javaheri, T., & Zare, P.
- Affiliations
- Tabriz University of Medical Sciences (IR)
- Kermanshah University of Medical Sciences (IR)
- Universitätsklinikum Tübingen (DE)
- Boston University (US)
- Corresponding author
- Javaheri, Tahereh
- Venue
- Cell Communication and Signaling
- Published
- 2020-04-07
- Volume
- 18
- Issue
- 1
- Pages
- 59-59
- ISSN
- 1478-811X (ISSN-L)
- PMC
- PMC7140346
- OpenAlex
- W3014913757
- Cited by
- 1,784
- References
- 236
- Citations by year
- 2026: 149 · 2025: 328 · 2024: 373 · 2023: 410 · 2022: 318 · 2021: 171 · 2020: 30
- FWCI
- 25.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Communication and Signaling (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Instytut Biologii Doswiadczalnej im. M. Nenckiego PAN
- Uniwersytet Kardynała Stefana Wyszyńskiego w Warszawie
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- tumor microenvironment, tumor stroma, extracellular matrix, tumor heterogeneity, clonal evolution, multidrug resistance, metastasis, tumor invasion, cancer diagnosis, 3D tumor models, lab-on-a-chip
- MeSH terms
- Animals, Cell Communication, Extracellular Matrix, Humans, Neoplasms, Stromal Cells, Tumor Microenvironment, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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