Tumor microenvironment complexity and therapeutic implications at a glance

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].”

What the sources say

• Disputed

  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.

  cites [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

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].”

What the sources say

• Disputed

  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.

  cites [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

In the paper

“LOX enzymes are widely used to block collagen crosslinking in various preclinical settings [130, 131].”

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
• Disputed

  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.

  cites [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

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].”

What the sources say

• ?Could not verify

  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)

  cites [6] Denisenko TV, Budkevich IN, Zhivotovsky BJCd, disease: Cell death-based treatment of lung adenocarcinoma. 2018, 9:117. sourceExperimental — accuracy not yet measured
• ?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

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].”

What the sources say

• ?Could not verify

  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)

  cites [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

In the paper

“Along with endothelial cells, pericytes are involved in the basement membrane remodeling during angiogenesis [24] and tumorigenesis [25].”

What the sources say

• Supported

  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)

  cites [24] Kloc M, Kubiak JZ, Li XC, Ghobrial RM. Pericytes, microvasular dysfunction and chronic rejection. Transplantation. 2015;99:658. source
• Supported

  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)

  cites [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

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].”

What the sources say

• ?Could not verify

  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)

  cites [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

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].”

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
• Supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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
• ?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

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”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

In the paper

“The non-malignant cells in the TME are known to promote tumorigenesis in all phases of cancer development and metastasis [4, 5].”

What the sources say

• ?Not checked — no full text of the sourcecites [4] Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22. source
• Partly supported

  Section 2, The Tumor Microenvironment (TME), says nonmalignant cells often adopt a tumor-promoting phenotype and that interactions involving them can promote cancer growth and metastasis. It lists initiation, promotion, progression, and metastasis as phases of carcinogenesis, but does not establish that nonmalignant TME cells promote tumorigenesis in every phase. Page numbers are not available in our copy. (LLM, conf=0.86)

  cites [5] Frisch J, Angenendt A, Hoth M, Prates Roma L, Lis AJC: STIM-Orai Channels and Reactive Oxygen Species in the Tumor Microenvironment 2019, 11:457. sourceExperimental — accuracy not yet measured

In the paper

“Using a genetically engineered mouse model of PDGF-induced gliomas, it has been shown that this interaction was mediated through perivascular nitric oxide, which activates notch signaling to promotes stem-like character [48].”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [48] Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, Holland EC. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell. 2010;6:141–52. source

In the paper

“analysis of human specimens has revealed that glioblastoma stem cells (GSCs) are responsible for producing the majority of vascular pericytes to reshape the perivascular niche to support vascular function and tumor growth.”

What the sources say

• Partly supported

  The Results section on primary human GBMs reports that most pericytes carried cancer-cell genetic alterations, supporting a neoplastic origin, but that analysis does not establish that they came specifically from GSCs. The Results on GBM xenografts and the Discussion support the GSC-origin and vessel-function claims; the citing sentence overattributes that conclusion to analysis of human specimens alone (page numbers unavailable). (LLM, conf=0.86)

  cites [35] Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153:139–52. sourceExperimental — accuracy not yet measured

In the paper

“Compared to normal ECs, tumor-derived endothelial cells (TECs) have a disturbed morphology and phenotypes at the cellular and molecular levels, similar to the tumor itself [40–42].”

What the sources say

• Supported

  The Introduction states that, compared with normal endothelial cells, tumor endothelial cells become morphologically and phenotypically dysregulated at the cellular and molecular level, much like the tumor itself. (LLM, conf=0.95)

  cites [40] Salazar N, Zabel BA. Support of tumor endothelial cells by chemokine receptors. Front Immunol. 2019;10. source
• Partly supported

  The “Defective Endothelial Monolayer” section contrasts normal endothelial cells with TECs of irregular shape and size, while “Studies of Isolated Tumor Endothelial Cells” describes altered molecular signatures. The copy does not establish that TEC morphology and phenotypes are similar to those of the tumor itself. Page numbers were not available in the indexed passages. (LLM, conf=0.82)

  cites [41] Dudley AC. Tumor endothelial cells. Cold Spring Harbor perspectives in medicine. 2012;2:a006536. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Aird WC. Molecular heterogeneity of tumor endothelium. Cell Tissue Res. 2009;335:271–81. source

In the paper

“Due to their role in tumor angiogenesis, strategies targeting pericytes have been proposed as antiangiogenic therapies for cancer [27].”

What the sources say

• Supported

  The Introduction describes pericytes as regulators of tumor angiogenesis and reports experiments targeting them. The Discussion explicitly calls early-stage pericyte depletion an anti-vascular therapy and reports that it suppressed tumor angiogenesis, supporting the claim that pericyte targeting has been proposed as an antiangiogenic cancer strategy. (LLM, conf=0.92)

  cites [27] Keskin D, Kim J, Cooke VG, Wu C-C, Sugimoto H, Gu C, De Palma M, Kalluri R, LeBleu VS. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 2015;10:1066–81. source

In the paper

“Moreover, TEC can be used for cancer vaccine development.”

What the sources say

• Supported

  The Discussion describes a cancer vaccine made by pulsing dendritic cells with TEC lysates. The section on suppressive effects reports that this vaccination significantly reduced lung metastasis in a mouse model. The paper therefore supports using TECs in cancer vaccine development, though it does not establish clinical effectiveness. (LLM, conf=0.93)

  cites [54] Nomura T, Yamakawa M, Shimaoka T, Hirai T, Koizumi N, Maruyama K, Utoguchi N. Development of dendritic cell-based immunotherapy targeting tumor blood vessels in a mouse model of lung metastasis. Biol Pharm Bull. 2019;42:645–8. source

In the paper

“Prophylactic vaccination with DCs pulsed with lysates of TECs (positive for angiotensin-converting enzyme (ACE) activity) isolated from the lung with metastases was shown to significantly suppress lung metastasis in the B16/BL6 mouse melanoma model.”

What the sources say

• Supported

  The Abstract states that the TEC-rich fraction from metastasis-bearing lungs was identified using ACE activity and that prophylactic vaccination with TEC-lysate-pulsed DCs significantly suppressed lung metastasis in the B16/BL6 model. The results section reports significant suppression versus untreated mice (p < 0.01). Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [54] Nomura T, Yamakawa M, Shimaoka T, Hirai T, Koizumi N, Maruyama K, Utoguchi N. Development of dendritic cell-based immunotherapy targeting tumor blood vessels in a mouse model of lung metastasis. Biol Pharm Bull. 2019;42:645–8. source

In the paper

“A better understanding of the molecular mechanisms of tumor progression involving pericytes may reveal specific targets within pericyte subpopulations and thus contributes to cancer treatments [36].”

What the sources say

• Supported

  The Discussion (page not provided) says that targeting perivascular cell behavior, rather than depleting pericytes, limits metastasis and identifies KLF4 as a mediator of that behavior. The Results identify NG2-expressing pericytes as a population involved in the pre-metastatic niche. Together, these passages support the claim's cautious suggestion that understanding pericyte-related mechanisms may reveal targets for cancer treatment. (LLM, conf=0.88)

  cites [36] Murgai M, Ju W, Eason M, Kline J, Beury DW, Kaczanowska S, Miettinen MM, Kruhlak M, Lei H, Shern JF. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat Med. 2017;23:1176. source

In the paper

“For example, a 3D self-organized microvascular model of the human blood-brain barrier (BBB) with endothelial cells, pericytes, and astrocytes resembles the characteristic of a physiologic BBB similar to those of the rat brain, with perfusable and selective microvascularization and lower permeability than the conventional in vitro model [37].”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [37] Campisi M, Shin Y, Osaki T, Hajal C, Chiono V, Kamm RD. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials. 2018;180:117–29. source

In the paper

“Cancer-associated fibroblasts (CAFs) in the immediate vicinity of cancer cells play an important role in tumorigenesis in various physicochemical ways by reducing apoptosis and improving the proliferation, migration and viability of cancer cells [58, 59].”

What the sources say

• Supported

  The Results section’s Figure 1 caption states that CAFs in contact with cancer cells enhance their viability, proliferation, and migration and reduce apoptosis. It also describes these interactions as critical to tumourigenesis through physicochemical cues. (LLM, conf=0.95)

  cites [58] Lee SW, Kwak HS, Kang M-H, Park Y-Y, Jeong GSJSr. Fibroblast-associated tumour microenvironment induces vascular structure-networked tumouroid. Sci Rep. 2018;8:2365. source
• ?Not checked — no full text of the sourcecites [59] Kalluri RJNRC. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98. source

In the paper

“GSCs migrate along the SDF-1/CXCR4 axis toward the ECs, where they are transformed into pericytes mainly by the action of the transforming growth factor β (TGFβ) [35].”

What the sources say

• Supported

  In Results, “GSCs Are Recruited toward ECs via the SDF-1/CXCR4 Axis,” CXCR4 knockdown and SDF-1 blockade reduced GSC recruitment to endothelial cells. In Results, “TGF-β Induces Differentiation of GSCs into Pericytes,” TGF-β was the dominant inducer among the factors tested, although the authors say it accounts for pericyte specification at least in part. Page numbers were not supplied in the passages. (LLM, conf=0.92)

  cites [35] Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153:139–52. source

In the paper

“others indicated that therapeutic targets involving pericytes may exacerbate the process of tumor metastasis [31–34].”

What the sources say

• Partly supported

  The Abstract and Discussion (page unavailable) report that pericyte dysfunction increased tumor-cell dissemination in a genetic mouse model, supporting the concern that disrupting pericytes could worsen metastasis. The paper does not report that a therapeutic intervention targeting pericytes exacerbated metastasis; that part is an inference from its findings. (LLM, conf=0.82)

  cites [31] Xian X, Håkansson J, Ståhlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H. Pericytes limit tumor cell metastasis. J Clin Invest. 2006;116:642–51. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [32] Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, Tachibana T, Imamura M. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology. 2005;69:159–66. source
• Partly supported

  The Results (page not provided) report more circulating malignant cells in pericyte-deficient mice bearing B16 tumors, supporting concern that loss of pericytes could aid tumor-cell dissemination. The study used genetic pericyte deficiency, not a pericyte-targeting therapy, and did not establish increased metastasis; the claim extends beyond those findings. (LLM, conf=0.85)

  cites [33] Hong J, Tobin NP, Rundqvist H, Li T, Lavergne M, García-Ibáñez Y, Qin H, Paulsson J, Zeitelhofer M, Adzemovic MZ. Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J National Cancer Institute. 2015;107:djv209. sourceExperimental — accuracy not yet measured
• Supported

  The Discussion (page not provided) states that targeting pericytes, alone or with endothelial cells, leads to enhanced metastasis. The Results section (page not provided) also reports increased metastatic effects after pharmacological pericyte targeting. This supports the claim's cautious wording that such therapeutic targeting may exacerbate metastasis. (LLM, conf=0.94)

  cites [34] Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21:66–81. source

In the paper

“However, clinical trials have not yielded consistent conclusions [28, 29].”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Hainsworth JD, Spigel DR, Sosman JA, Burris HA III, Farley C, Cucullu H, Yost K, Hart LL, Sylvester L, Waterhouse DM. Treatment of advanced renal cell carcinoma with the combination bevacizumab/erlotinib/imatinib: a phase I/II trial. Clinical Genitourinary Cancer. 2007;5:427–32. source
• Partly supported

  The Results and Discussion reports one clinical trial in which combined anti-VEGF and anti-PDGF treatment did not improve on VEGF inhibition alone and was toxic. It does not report differing conclusions across clinical trials; the contrasting evidence in the Introduction concerns experimental models. (LLM, conf=0.84)

  cites [29] Nisancioglu MH, Betsholtz C, Genové G. The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-a blockade. Cancer Res. 2010;70:5109–15. sourceExperimental — accuracy not yet measured

In the paper

“In addition to the findings from the regular cancer models, the 3D cancer models showed an obvious case of selective control of CAF function by TCs.”

What the sources say

• Supported

  The Results section reports that, in tumor-organoid co-cultures, removing IL-1α from tumor organoids reduced inflammatory CAF markers and increased a myofibroblastic marker. The Discussion describes tumor-secreted IL-1 and TGF-β as cues that shape distinct CAF states. Together, these passages support the claim that the 3D model showed tumor-cell control of CAF phenotype. (LLM, conf=0.90)

  cites [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

In the paper

“Such polyclonal antibodies have been shown to delay tumor growth in mice bearing murine CT26 colon carcinoma [85].”

What the sources say

• Supported

  The Introduction states that the polyclonal rabbit anti-CAF antibodies were produced by immunizing rabbits with bFGF-activated fibroblasts. The Abstract reports that intravenous injections inhibited tumor growth in mice bearing murine CT26 colon carcinoma; the Xenograft mouse model section describes the CT26-bearing mice and antibody treatment. (LLM, conf=0.94)

  cites [85] Li X, Huang F, Xu X, Hu S. Polyclonal rabbit anti-Cancer-associated fibroblasts globulins induce Cancer cells apoptosis and inhibit tumor growth. Int J Biol Sci. 2018;14:1621–9. source

In the paper

“In this 3D model, CAFs were shown to enhance invasion and migration speed by inducing expression of a new candidate gene, glycoprotein nonmetastatic B (GPNMB) in breast cancer cells [75].”

What the sources say

• Supported

  The Discussion states that, in the 3D microfluidic model, CAFs induced GPNMB expression in breast cancer cells and increased invasion speed. It also reports that knocking down GPNMB blunted the CAF-associated increase in invasion. The effect varied among the patient-derived CAFs: two of three showed clear tumor-promoting behavior. (LLM, conf=0.94)

  cites [75] Truong DD, Kratz A, Park JG, Barrientos ES, Saini H, Nguyen T, Pockaj B, Mouneimne G, LaBaer J, Nikkhah M. A human Organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast Cancer cells. Cancer Res. 2019;79:3139–51. source

In the paper

“PFD also suppressed metastasis in the lung and progression of the tumor in combination with doxorubicin in in vivo models [84].”

What the sources say

• Supported

  The Results section (page not provided) reports that pirfenidone combined with doxorubicin inhibited primary tumor growth and significantly reduced lung metastasis in a TNBC mouse model. This supports the claim about in vivo tumor progression and lung metastasis. (LLM, conf=0.94)

  cites [84] Takai K, Le A, Weaver VM, Werb Z. Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget. 2016;7:82889. source

In the paper

“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 [76–78].”

What the sources say

• ?Not checked — no full text of the sourcecites [76] Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein–α. Science. 2010;330:827–30. source
• Partly supported

  The section “Therapeutic strategies for re-educating the TME” discusses depleting stromal cells and proposes manipulating or re-educating the tumor microenvironment instead. The CAF section establishes that CAFs are tumor-microenvironment cells, but the paper does not say that therapeutic options for CAF-mediated interactions are largely focused on using, reprogramming, or eliminating CAFs specifically. No page number is available in our copy. (LLM, conf=0.82)

  cites [77] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423. sourceExperimental — accuracy not yet measured
• Partly supported

  The section on rapamycin treatment (page unavailable in our copy) reports reduced tumor growth and decreased tumor-associated fibroblasts in Cav-1 knockout mice, supporting an example of a treatment associated with fewer CAFs. It does not discuss using or reprogramming CAFs, or establish that therapeutic options are largely focused on those approaches. (LLM, conf=0.83)

  cites [78] Mercier I, Camacho J, Titchen K, Gonzales DM, Quann K, Bryant KG, Molchansky A, Milliman JN, Whitaker-Menezes D, Sotgia F. Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. Am J Pathol. 2012;181:278–93. sourceExperimental — accuracy not yet measured

In the paper

“Moreover, CAFs positively influence the proliferation and metabolism of cancer cells through oxidative stress, which induces the autophagy pathway [69].”

What the sources say

• Partly supported

  The Abstract and Discussion report that colorectal cancer cells induce oxidative stress and autophagy in fibroblasts, which then support colorectal cancer-cell metabolism and proliferation. The claim omits the study’s colorectal-cancer setting and could imply that CAFs, rather than the cancer cells, initiate the oxidative stress. (LLM, conf=0.86)

  cites [69] Zhou W, Xu G, Wang Y, Xu Z, Liu X, Xu X, Ren G, Tian K. Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells. Cell Cycle. 2017;16:73–81. sourceExperimental — accuracy not yet measured

In the paper

“Thus the use of NP to modify CAFs can be an effective strategy to treat desmoplastic cancers (Fig. 2b) [83].”

What the sources say

• Supported

  The Abstract explicitly describes the results as proof of concept for using nanoparticles to modify tumor-associated fibroblasts to treat desmoplastic cancers. It reports efficacy in murine models of bladder and pancreatic cancer; the claim’s 'can be' wording is consistent with that scope. (LLM, conf=0.95)

  cites [83] Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L, Yin W, Hu S, Kim WY, Huang L. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Res. 2017;77:719–31. source

In the paper

“Furthermore, the ECM of distant organs can be remotely shaped into permissive/restrictive soils by soluble factors/CTCs/exosomes from primary tumors to facilitate the seeding of metastasizing cancer cells (See for review [9]).”

What the sources say

• Partly supported

  The Introduction and §9 describe distant sites as permissive or restrictive soils for metastatic cells, while §5 links ECM conditions to dormancy and metastatic outgrowth. The paper does not say that primary-tumor soluble factors, CTCs, or exosomes remotely shape the ECM of those sites to facilitate seeding; its discussion of exosomes in §8 concerns mesenchymal stem cell-derived exosomes and breast cancer dormancy. (LLM, conf=0.85)

  cites [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

In the paper

“TAM is another key element of the TME which significantly affects cancer cell behavior [87].”

What the sources say

• Supported

  The Introduction describes TAMs as a dominant cell type in the tumor milieu and says macrophages with TAM-like properties promote tumor progression. The Results section reports that CAFs promoted colorectal cancer progression partly by increasing TAM infiltration, supporting the claim that TAMs affect cancer cell behavior. (LLM, conf=0.90)

  cites [87] Zhang R, Qi F, Zhao F, Li G, Shao S, Zhang X, Yuan L, Feng Y. Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer. Cell Death Dis. 2019;10:273. source

In the paper

“Besides its biochemical composition, such as intermolecular covalent cross-linkages, the ECM biophysical characteristics include its topography, stiffness/rigidity, molecular density, and tension [118].”

What the sources say

• Partly supported

  In “Properties and features of the ECM” (page unavailable), the paper identifies topography and rigidity as physical properties and discusses stiff, dense cross-linked fibers. It also discusses tensile strength and mechanical forces, but does not explicitly list tension or molecular density as ECM biophysical characteristics. It distinguishes changes in ECM composition from changes in how components are covalently cross-linked, rather than treating cross-linkages as an example of biochemical composition. (LLM, conf=0.85)

  cites [118] Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406. sourceExperimental — accuracy not yet measured

In the paper

“Clinical studies and experimental animal models suggest that TAM commonly plays a pro-tumoral role in various ways [89, 96, 97].”

What the sources say

• Supported

  The ‘Macrophages and tumor progression’ section says experimental models and clinical observations show a supportive role for macrophages in cancer development. It lists several pro-tumoral actions of TAMs, while noting that their effects can vary by tumor type. (LLM, conf=0.94)

  cites [89] Larionova I, Cherdyntseva N, Liu T, Patysheva M, Rakina M, Kzhyshkowska J. Interaction of tumor-associated macrophages and cancer chemotherapy. OncoImmunol. 2019;8:e1596004. source
• Supported

  The Overview section describes several ways TAMs support tumor growth and metastasis. The section on TAM-facilitated intravasation reports both experimental imaging evidence and clinical observations linking TAM-containing tumor structures to metastasis and poor prognosis. The Conclusions note that TAM roles are heterogeneous, which is consistent with the claim’s qualifier “commonly.” Page numbers are unavailable in our copy. (LLM, conf=0.92)

  cites [96] Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019;12:76. source
• Supported

  The Discussion (page not specified in our copy) describes clinical correlations between macrophage infiltration and poor prognosis, alongside mouse models in which macrophage ablation inhibits tumor progression. It also describes several tumor-promoting mechanisms, including angiogenesis, motility, invasion and intravasation. (LLM, conf=0.93)

  cites [97] Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One. 2009;4:e6562. source

In the paper

“In this line, a study in human colorectal cancer (CRC) specimens and in vitro co-culture, revealed that TAMs induce EMT program to enhance CRC invasion, migration, and CTC-mediated metastasis by producing IL6 to activate JAK2/STAT3 axis and inhibit the suppressive role of miR-506-3p on FoxQ1 expression.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [94] Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, Liu Q, Dou R, Xiong B. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18:64. source

In the paper

“Accordingly, TAM-based therapeutic strategies are being developed that aim at TAM targeting, TAM re-education, and TAM depletion [88, 96, 101, 102].”

What the sources say

• Supported

  The “Macrophages as Therapeutic Targets” section describes TAM targeting through ablation or re-polarization, corresponding to depletion and re-education. It also reports CSF1R inhibitors that deplete some TAM populations or cause them to re-polarize. Page numbers were not provided in the copy. (LLM, conf=0.93)

  cites [88] Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61. source
• Supported

  The “Potential strategies targeting macrophages” section describes approaches to eliminate TAMs, inhibit their recruitment, and suppress M2 polarization. The “Conclusions and perspectives” section likewise identifies agents that modulate TAM survival, polarization, and recruitment, supporting the three strategy types in the claim. (LLM, conf=0.94)

  cites [96] Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019;12:76. source
• Supported

  The “Strategies to deplete or re-educate TAMs” section describes TAMs as therapeutic targets and discusses both depletion and re-education approaches. The Conclusions also refer to TAM-targeted therapies and re-education as a promising strategy. The supplied passages have no page numbers. (LLM, conf=0.93)

  cites [101] Kowal J, Kornete M, Joyce JA. Re-education of macrophages as a therapeutic strategy in cancer. Immunotherapy. 2019;11:677–89. source
• ?Not checked — no full text of the sourcecites [102] Zhan X, Jia L, Niu Y, Qi H, Chen X, Zhang Q, Zhang J, Wang Y, Dong L, Wang C. Targeted depletion of tumour-associated macrophages by an alendronate-glucomannan conjugate for cancer immunotherapy. Biomaterials. 2014;35:10046–57. source

In the paper

“Combined administration of tranilast (anti-fibrotic drugs) and doxorubicin significantly diminished tumor growth and invasion, as validated by reduced stiffness of the stromal matrix, disrupted fibronectin assembly and reduced collagen fiber density [128].”

What the sources say

• Supported

  The Methods describe MDA-MB-231 cells in microwells surrounded by CAFs in collagen I hydrogel. The Results report significant decreases in MDA-MB-231 proliferation (Fig. 5b) and tumor-cell invasion (Fig. 6) with combined tranilast and doxorubicin versus control. They also report reduced stromal stiffness, disrupted fibronectin assembly, and lower collagen fiber density. Page numbers were not available in our copy. (LLM, conf=0.94)

  cites [128] Saini H, Eliato K, Silva C, Allam M, Mouneimne G, Ros R, Nikkhah M. The role of Desmoplasia and stromal fibroblasts on anti-cancer drug resistance in a microengineered tumor model. Cell Mol Bioeng. 2018;11:419–33. source

In the paper

“Dal Corso et al. introduced a study in which a non-internalizing antibody against tenascin-C was exploited to transport anthracycline (PNU159682), a chemotherapeutic agent, into the ECM of cancer cells (Fig. 2d).”

What the sources say

• Supported

  The Introduction states that the authors coupled PNU159682 to the non-internalizing F16 antibody, which targets tenascin-C in tumor stroma. The Results (Therapy experiments) report that the conjugate localized around tumor blood vessels, supporting its delivery to the tumor extracellular environment. (LLM, conf=0.92)

  cites [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. source

In the paper

“The implication of CTCs is well established in tumor cell dormancy, as a major cause of metastatic outgrowth, multi drug resistance (MDR) and cancer relapse [144].”

What the sources say

• Partly supported

  The Discussion (page unavailable) says that identifying CTC subpopulations may help identify cells driving metastasis and chemotherapeutic resistance. It does not establish CTC involvement in tumor-cell dormancy or cancer relapse, or describe dormancy as a major cause of the listed outcomes. (LLM, conf=0.85)

  cites [144] Shishido SN, Carlsson A, Nieva J, Bethel K, Hicks JB, Bazhenova L, Kuhn P. Circulating tumor cells as a response monitor in stage IV non-small cell lung cancer. J Transl Med. 2019;17:294. sourceExperimental — accuracy not yet measured

In the paper

“Collagen in turn influences tumor cell behavior through integrins, tyrosine kinase receptors, discoidin domain receptors, and some signaling pathways [124].”

What the sources say

• Supported

  In “The influence of collagen on cancer cell behavior” (page not provided), the review describes collagen binding to integrins and discoidin domain receptors (DDRs), activating signaling pathways that affect cancer-cell behavior. It identifies DDRs as tyrosine kinase receptors, supporting the cited paraphrase. (LLM, conf=0.90)

  cites [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

In the paper

“immune checkpoint inhibitors (antibodies) including anti-CTLA4 and anti-PD-L1 plus IL-2 were conjugated to the collagen-binding domain of the blood protein von willebrand factor (VWF) A3 domain to reduce side effects.”

What the sources say

• Partly supported

  The Results section (page unavailable) reports reduced toxicity for the collagen-binding-domain-modified checkpoint antibodies and IL-2 in mice. However, the paper specifies that the antibodies were conjugated to the domain, whereas IL-2 was joined by recombinant fusion—not conjugation as the citing sentence states. (LLM, conf=0.88)

  cites [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

In the paper

“Moreover, collagen interaction with other ECM molecules including fibronectin, laminin, hyaluronic acid, and MMPs influences cancer cell activity [127].”

What the sources say

• Partly supported

  The Discussion (page unavailable) says collagen deposition and remodeling can promote tumor proliferation and invasion, supporting the broad point that collagen influences cancer-cell activity. The paper does not say that interactions between collagen and fibronectin, laminin, hyaluronic acid, or MMPs produce those effects; its results instead examine collagen remodeling involving LOX. (LLM, conf=0.87)

  cites [127] Natarajan S, Foreman KM, Soriano MI, Rossen NS, Shehade H, Fregoso DR, Eggold JT, Krishnan V, Dorigo O, Krieg AJ. Collagen remodeling in the hypoxic tumor-mesothelial niche promotes ovarian cancer metastasis. Cancer Res. 2019. https://doi.org/10.1158/0008-5472.CAN-18-2616. sourceExperimental — accuracy not yet measured

In the paper

“This in turn resulted in significant tumor growth inhibition of epidermoid carcinoma mouse xenografts [135].”

What the sources say

• Supported

  The Results (Therapy experiments; page unavailable) identify the model as mice bearing A431 human epidermoid carcinoma xenografts. They report that F16-PNU159682 produced complete responses in the higher-dose experiment and significant tumor-volume stabilization for more than 30 days in the lower-dose experiment, supporting the claimed tumor-growth inhibition. (LLM, conf=0.93)

  cites [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. source

In the paper

“Synthesis of collagen can be regulated by cancer cells, mutated genes, signaling pathways/receptors, and transcription factors [123].”

What the sources say

• ?Could not verify

  The Results section on increased collagen I expression reports COL1A1 overexpression in HCC tissue but does not identify what regulates its synthesis. The ERK-dependent activation results describe collagen I acting on cancer cells, not a pathway regulating collagen synthesis. Searches for collagen synthesis and its regulators found related titles in the References, but no passage in the paper making the attributed claim. (LLM, conf=0.73)

  cites [123] Zhang R, Ma M, Lin X-H, Liu H-H, Chen J, Chen J, Gao D-M, Cui J-F, Ren Z-G, Chen R-X. Extracellular matrix collagen I promotes the tumor progression of residual hepatocellular carcinoma after heat treatment. BMC Cancer. 2018;18:901. sourceExperimental — accuracy not yet measured

In the paper

“Other partners in close contact with collagen involvement in cancer are microRNAs (miRNAs) [125] and exosomes [126].”

What the sources say

• Supported

  Citation [125] is attached to microRNAs, not exosomes, which have a separate citation. The Discussion reports that miR-143 regulates collagen type III expression in stromal fibroblasts of scirrhous-type gastric cancer. (LLM, conf=0.93)

  cites [125] Naito Y, Sakamoto N, Oue N, Yashiro M, Sentani K, Yanagihara K, Hirakawa K, Yasui W. MicroRNA-143 regulates collagen type III expression in stromal fibroblasts of scirrhous type gastric cancer. Cancer Sci. 2014;105:228–35. sourceExperimental — accuracy not yet measured
• Supported

  Citation [126] is attached to exosomes, not miRNAs. The “Host Matrix Modulation by TEX” section reports that tumor exosomes degrade collagen I and II, supporting their involvement with collagen in cancer. (LLM, conf=0.93)

  cites [126] Mu W, Rana S, Zoller M. Host matrix modulation by tumor exosomes promotes motility and invasiveness. Neoplasia. 2013;15:875–87. sourceExperimental — accuracy not yet measured

In the paper

“Alternatively, ECM components can be used to ensure a precise tumor drug delivery [132].”

What the sources say

• Partly supported

  Section 4.2 says tumor ECM components can serve as drug-delivery targets, supporting the proposed approach. But it says specific delivery requires a target expressed specifically in tumor ECM, while the Future outlook warns that expression in healthy tissue may cause off-targeting. The paper therefore does not support the claim that using ECM components ensures precise delivery. (LLM, conf=0.85)

  cites [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

In the paper

“studying epithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in 3D culture revealed the role of collagen reorganization at the tumor-stromal interface to facilitate local invasion [129].”

What the sources say

• Supported

  The Abstract Methods section says the study examined epithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in three-dimensional culture. The Abstract Results section reports that tumor explants realigned collagen fibers and that invading cells migrated along the aligned fibers, supporting the claimed role in local invasion. (LLM, conf=0.94)

  cites [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. source

In the paper

“In a recent study, Wang et al. developed a peptide–drug conjugate (PDCs) using EphA2 agonists, YSA peptide or its enhanced version, 123B9.”

What the sources say

• Partly supported

  The Introduction and Results describe YSA as an EphA2-activating peptide and report the development of a YSA–paclitaxel conjugate. Our copy does not identify 123B9 or report a conjugate made with that enhanced peptide, so that part of the attribution is unsupported. (LLM, conf=0.88)

  cites [166] Wang S, Placzek WJ, Stebbins JL, Mitra S, Noberini R, Koolpe M, Zhang Z, Dahl R, Pasquale EB, Pellecchia M. Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. J Med Chem. 2012;55:2427–36. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that this study synthesized gemcitabine conjugates using YNH and 123B9, not YSA. The Introduction describes 123B9 as more stable than YSA, while the Discussion identifies YSA conjugates as work from previous studies. Thus the paper supports development of a 123B9 peptide–drug conjugate, but not the claim that this study developed one using YSA. (LLM, conf=0.88)

  cites [167] Quinn BA, Wang S, Barile E, Das SK, Emdad L, Sarkar D, De SK, Kharagh SM, Stebbins JL, Pandol SJ. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. Oncotarget. 2016;7:17103. sourceExperimental — accuracy not yet measured

In the paper

“CTC-targeted therapies may provide a new approach to improve the prognosis of cancer therapy [152].”

What the sources say

• Supported

  The paper’s opening section explicitly says CTC-targeted therapies may provide a promising new approach to improve cancer prognosis. Its Abstract also concludes that eliminating CTCs may improve cancer-patient survival. The citing sentence preserves that tentative framing. (LLM, conf=0.94)

  cites [152] Kim YR, Yoo JK, Jeong CW, Choi JW. Selective killing of circulating tumor cells prevents metastasis and extends survival. J Hematol Oncol. 2018;11:114. source

In the paper

“In this way, aggressive CTCs preferentially mediate self-seeding of breast, melanoma, and colon cancers in mice, including those with bone, brain, or lung -metastatic tropism.”

What the sources say

• Supported

  The Abstract states this claim directly. The Results section ('Seeding of established tumors by CTCs') also reports seeding in mouse models of breast, colon, and melanoma cancers using cells with bone, lung, or brain metastatic tropism. (LLM, conf=0.95)

  cites [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. source
• Partly supported

  The Abstract (page unavailable) says IL-6 and IL-8 attract CTCs and promote self-seeding of breast, colon, and melanoma tumors. It does not say that aggressive CTCs preferentially self-seed, that these findings were in mice, or that the cells had bone, brain, or lung metastatic tropism. (LLM, conf=0.88)

  cites [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

In the paper

“Upregulation of EphA2 occurs in several cancers such as melanoma [157], ovarian [158, 159], prostate [160, 161], lung [162, 163], and breast [164, 165] cancer.”

What the sources say

• Supported

  The citation to this paper is attached to melanoma, not to the other cancers in the sentence. The Discussion states that EPHA2 is reported to be overexpressed in cancers including melanoma; the Results also report EPHA2 staining in the melanoma cases. Page numbers were not supplied in our copy. (LLM, conf=0.93)

  cites [157] Straume O, Akslen L. Strong expression of ID1 protein is associated with decreased survival, increased expression of ephrin-A1/EPHA2, and reduced thrombospondin-1 in malignant melanoma. Br J Cancer. 2005;93:933. source
• ?Not checked — no full text of the sourcecites [158] Thaker PH, Deavers M, Celestino J, Thornton A, Fletcher MS, Landen CN, Kinch MS, Kiener PA, Sood AK. EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res. 2004;10:5145–50. source
• ?Not checked — no full text of the sourcecites [159] Han L, Dong Z, Qiao Y, Kristensen GB, Holm R, Nesland JM, Suo Z. The clinical significance of EphA2 and Ephrin A-1 in epithelial ovarian carcinomas. Gynecol Oncol. 2005;99:278–86. source
• ?Not checked — no full text of the sourcecites [160] Walker-Daniels J, Coffman K, Azimi M, Rhim J, Bostwick D, Snyder P, Kerns B, Waters D, Kinch M. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate. 1999;41:275–80. source
• Supported

  This source is cited for the prostate-cancer part of a sentence that assigns separate citations to the other cancers. The Introduction says EphA2 expression is higher in prostate carcinoma tissue than in normal tissue, and the Results report high EphA2 levels in prostate cancer. (LLM, conf=0.93)

  cites [161] Chen P, Huang Y, Zhang B, Wang Q, Bai P. EphA2 enhances the proliferation and invasion ability of LNCaP prostate cancer cells. Oncol Lett. 2014;8:41–6. source

In the paper

“Given that CTCs can be used as diagnostic tools providing molecular information on the primary tumor state”

What the sources say

• Partly supported

  The Introduction table lists detection and analysis of rare circulating tumor cells (CTCs) as a predictive cancer diagnostic application. The DNA Hydrogel section describes capturing CTCs for subsequent live-cell analysis, but neither passage says they provide molecular information about the primary tumor’s state. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites [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. sourceExperimental — accuracy not yet measured

In the paper

“Even more interesting is that, in contrast to the traditional view that tumor cell metastases occur unidirectional, the reverse process is also possible through CTC-mediated “self-seeding”.”

What the sources say

• Supported

  The Introduction contrasts the conventional model of dissemination to distant organs with the possibility that CTCs re-enter their tumors of origin, calling this process “tumor self-seeding.” The Discussion reports experimental evidence of CTC self-seeding in mouse tumor models. (LLM, conf=0.94)

  cites [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. source
• Supported

  The Abstract says tumor cells attract circulating tumor cells (CTCs) and promote tumor self-seeding. This supports the claimed reverse process; the paper does not need to use the citing sentence’s contrast with the traditional view verbatim. (LLM, conf=0.90)

  cites [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. source

In the paper

“These nanoparticles called exosomes are key to maintain homeostasis of their releasing (originating) cells [169–172].”

What the sources say

• ?Not checked — no full text of the sourcecites [169] Valcz G, Galamb O, Krenács T, Spisák S, Kalmár A, Patai ÁV, Wichmann B, Dede K, Tulassay Z, Molnár BJMP. Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass. Modern Pathology. 2016;29:928. source
• Supported

  The Abstract states that exosome secretion plays a crucial role in maintaining homeostasis in exosome-secreting cells. The Results section, “Exosome secretion maintains cellular homeostasis,” reports this effect in certain types of normal human cells. (LLM, conf=0.94)

  cites [170] Takahashi A, Okada R, Nagao K, Kawamata Y, Hanyu A, Yoshimoto S, Takasugi M, Watanabe S, Kanemaki MT, Obuse CJNc. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells.Nat Commun. 2017;8:15287. source
• ?Could not verify

  The Introduction describes exosomes as mediators of communication that can alter recipient cells, and the Discussion suggests that exosomes released under stress may have an immunomodulatory function. Neither passage says exosomes are key to maintaining homeostasis in the cells that release them; a search for that role found no supporting passage in our copy. (LLM, conf=0.76)

  cites [171] Németh A, Orgovan N, Sódar BW, Osteikoetxea X, Pálóczi K, Szabó-Taylor KÉ, Vukman KV, Kittel Á, Turiák L, Wiener ZJSr. Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA. Sci Rep. 2017;7:8202. sourceExperimental — accuracy not yet measured
• Supported

  The section “Exosomes in the breast cancer niche” explicitly says exosomes play an important role in maintaining homeostasis of the releasing cells. This directly supports the attributed paraphrase. (LLM, conf=0.94)

  cites [172] Valcz G, Buzás EI, Szállási Z, Kalmár A, Krenács T, Tulassay Z, Igaz P. Molnár BJNbc. Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation. 2018;4:18. source

In the paper

“Finally, there is the prognosis for local recurrence by seeding of disseminated cells after apparently complete tumor ablation [147, 148].”

What the sources say

• Supported

  The Abstract proposes that tumor self-seeding could explain local recurrence after ostensibly complete tumor excision. The Discussion likewise describes reseeding after excision as a potential cause of eventual local recurrence; the citing sentence is consistent with that proposed possibility. (LLM, conf=0.90)

  cites [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. source
• Partly supported

  The paper’s Abstract (page not provided) says circulating tumor cells can self-seed breast, colon and melanoma tumors. It does not say that this causes local recurrence after apparently complete tumor ablation or offer a prognosis for that setting. (LLM, conf=0.85)

  cites [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

In the paper

“These cells are precise representations of primary and metastatic tumors that convey information for the detection, diagnosis (monitoring) and the treatment of cancer [145].”

What the sources say

• Partly supported

  The Introduction (page unavailable) says CTC analysis may monitor tumour evolution and potentially guide treatment, and describes CTCs as prognostic markers in metastatic breast cancer. It does not establish that CTCs are precise representations of both primary and metastatic tumours or that they provide diagnostic information; those parts overstate the source. (LLM, conf=0.86)

  cites [145] Yap Y-S, Leong MC, Chua YW, Loh KWJ, Lee GE, Lim EH, Dent R, Ng RCH, Lim JH-C, Singh G, et al. Detection and prognostic relevance of circulating tumour cells (CTCs) in Asian breast cancers using a label-free microfluidic platform. PLoS One. 2019;14:e0221305. sourceExperimental — accuracy not yet measured

In the paper

“Since an increase in the number of CTCs is associated with a poor prognosis”

What the sources say

• Supported

  The paper’s introductory passage states that an increased number of CTCs is associated with poor prognosis. This directly matches the attributed claim. (LLM, conf=0.95)

  cites [152] Kim YR, Yoo JK, Jeong CW, Choi JW. Selective killing of circulating tumor cells prevents metastasis and extends survival. J Hematol Oncol. 2018;11:114. source

In the paper

“Therapeutic regimes including metastatic treatment, adjuvant treatment, neoadjuvant treatment, or combination therapy were equally effective in reducing CTC positivity and the chance of disease progression [151].”

What the sources say

• Partly supported

  The Results section (Fig. 5) reports lower CTC-positive rates after the four treatment settings, but the reductions differ in size and the adjuvant result is not statistically significant; it does not establish that the treatments were equally effective. The disease-progression subgroup analysis (Fig. 8) finds a significant association with CTC reduction in the metastatic setting, but not in the adjuvant or neoadjuvant settings, and does not report a combination-therapy subgroup. (LLM, conf=0.90)

  cites [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

In the paper

“Furthermore, a dimeric 123B9 was able to perform receptor activation at concentrations in the nanomolar range.”

What the sources say

• Supported

  The Results section (“EphA2-Receptor Activation by Dimeric 123B9”) reports that 10 nM of the dimeric (123B9)2 motif induced EphA2 receptor activation in transfected HEK293T cells. The Discussion and Conclusions likewise describes receptor activation in the nanomolar range. (LLM, conf=0.95)

  cites [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

In the paper

“Their studies suggested that YSA– and 123B9– drug conjugates could selectively transport cytotoxic drugs to cancer cells in vivo [166, 167].”

What the sources say

• Partly supported

  The Results section (‘YSA-PTX targets tumors in vivo’) reports greater paclitaxel delivery to mouse tumor xenografts with YSA-PTX than with free paclitaxel, supporting the YSA portion. This paper does not address 123B9 conjugates, so it does not support that part of the sentence. (LLM, conf=0.87)

  cites [166] Wang S, Placzek WJ, Stebbins JL, Mitra S, Noberini R, Koolpe M, Zhang Z, Dahl R, Pasquale EB, Pellecchia M. Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. J Med Chem. 2012;55:2427–36. sourceExperimental — accuracy not yet measured
• Supported

  The Introduction (page unavailable) says EphA2-targeting peptides, including YSA and 123B9, can deliver attached drugs selectively to EphA2-expressing cancer cells. The Discussion (page unavailable) reports tumor accumulation for a YSA–paclitaxel conjugate and in vivo tumor targeting with a 123B9-linked imaging agent; the Results report improved antitumor efficacy for 123B9–gemcitabine in mice. Together, these support the citing sentence’s cautious 'could' claim. (LLM, conf=0.90)

  cites [167] Quinn BA, Wang S, Barile E, Das SK, Emdad L, Sarkar D, De SK, Kharagh SM, Stebbins JL, Pandol SJ. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. Oncotarget. 2016;7:17103. source

In the paper

“That, bidirectional transport of exosomes containing different species of RNA (e.g. miRNA) and proteins between cancer stem cells and the fibroblast-rich microenvironment is shown to promote the growth of the tumor and the metastatic outbreak in breast carcinoma models [172].”

What the sources say

• Supported

  The Abstract says cancer-cell- and fibroblast-derived exosomes carry proteins and different RNA species that support metastatic spread, and explicitly links their interactions to tumor growth and metastatic expansion in breast carcinoma models. The Clinical perspectives and future directions section describes exosomal crosstalk between breast cancer stem cells and fibroblastic cells as important from niche formation through metastatic growth. (LLM, conf=0.91)

  cites [172] Valcz G, Buzás EI, Szállási Z, Kalmár A, Krenács T, Tulassay Z, Igaz P. Molnár BJNbc. Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation. 2018;4:18. source

In the paper

“Lian et al. described a unique set of checkpoints, CD274 and CD47, on CTCs which camouflaged these cells from being detected by immune cells and corresponding apoptosis.”

What the sources say

• Supported

  The Introduction identifies CD274 (PD-L1) and CD47 as immune checkpoints that signal “don’t find me” and “don’t eat me,” respectively. The Discussion links their expression to CTC immune escape, and the Results report the greatest areas of apoptosis and necrosis after dual blockade in a mouse model. (LLM, conf=0.88)

  cites [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

In the paper

“Notably, even confined tumors without metastasis can produce CTCs [146].”

What the sources say

• Partly supported

  The Background describes a study of 36 patients with metastatic breast cancer, and the Results report CTCs in 83% of patient samples. Those findings establish CTCs in metastatic disease, but do not show that confined tumors without metastasis can produce them. No page numbers are available in our copy. (LLM, conf=0.83)

  cites [146] Adams DL, Adams DK, Stefansson S, Haudenschild C, Martin SS, Charpentier M, Chumsri S, Cristofanilli M, Tang C-M, Alpaugh RK. Mitosis in circulating tumor cells stratifies highly aggressive breast carcinomas. Breast Cancer Res. 2016;18:44. sourceExperimental — accuracy not yet measured

In the paper

“Rack B. et al. piloted a larger prospective study with 2026 breast cancer patients and discovered that the detection rate of CTCs after chemotherapy (22.1%) increased slightly in comparison to the baseline condition (21.5%) [150].”

What the sources say

• Partly supported

  The Results (Prevalence of CTCs in Early Breast Cancer) report 21.5% CTC-positive among 2026 patients before chemotherapy and 22.1% after chemotherapy, but the post-chemotherapy measurement was available only for a subgroup of about 1492 patients. The percentages are correct, but describing them as an increase in the 2026 patients implies a like-for-like change that the paper does not establish; it reports no difference in CTC counts before and after chemotherapy. (LLM, conf=0.87)

  cites [150] Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;106:dju066. sourceExperimental — accuracy not yet measured

In the paper

“Martin M. et al. assessed the variations in CTCs in 117 breast cancer patients and observed a considerable decline in CTC-positive rate after chemotherapy [149].”

What the sources say

• Partly supported

  The CTC Enumeration results show a decline in patients with at least five CTCs after the first chemotherapy cycle: 47 at baseline versus 28 on day 21. However, the Results (p. 918) say 117 patients were initially registered, while only 99 had evaluable CTC measurements; the decline was not assessed in all 117. (LLM, conf=0.91)

  cites [149] Martín M, Custodio S, de las Casas M-LM, García-Sáenz J-Á, de la Torre J-C, Bellón-Cano J-M, López-Tarruella S, Vidaurreta-Lazaro M, de la Orden V, Jerez YJTo. Circulating tumor cells following first chemotherapy cycle: an early and strong predictor of outcome in patients with metastatic breast cancer. Oncologist. 2013;18:917–23. sourceExperimental — accuracy not yet measured

In the paper

“while CTC infiltration into mammary tumors is mediated by MMP1/collagenase-1 and the actin cytoskeleton component fascin-1.”

What the sources say

• Supported

  The Abstract states that MMP1/collagenase-1 and fascin-1 mediate CTC infiltration into mammary tumors. The Results section, “Mediators of cancer cell infiltration of tumors,” reports that FSCN1 knockdown reduced infiltration from the circulation and combined MMP1/FSCN1 knockdown reduced it further. (LLM, conf=0.95)

  cites [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. source
• Partly supported

  The Abstract (page not provided) says IL-6 and IL-8 attract circulating tumor cells and promote self-seeding of breast tumors. It does not say that CTC infiltration is mediated by MMP1/collagenase-1 or fascin-1; the mechanism it describes instead involves IL-6/IL-8 signaling, WASF3, and the Arp2/3 complex. (LLM, conf=0.85)

  cites [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

In the paper

“CTCs usually express simultaneously over one immune checkpoint [153]”

What the sources say

• Supported

  The Introduction explicitly states that CTCs usually express more than one immune checkpoint simultaneously. This directly supports the citing sentence. (LLM, conf=0.95)

  cites [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

In the paper

“Mechanistically, tumors secrete IL-6 and IL-8 cytokines to attract CTC”

What the sources say

• Supported

  The Results section on tumor-derived mediators of cancer cell attraction reports that tumor cells secreted IL-6 or IL-8 and that these cytokines promoted cancer-cell migration and self-seeding. The Discussion identifies them as attractants of circulating tumor cells in the breast carcinoma and melanoma models studied; it does not suggest the same cytokines operate in every tumor type. (LLM, conf=0.91)

  cites [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
• Supported

  The Abstract states that tumor cells produce IL-6 and IL-8, which together attract circulating tumor cells (CTCs). This directly supports the attributed mechanism. (LLM, conf=0.95)

  cites [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

In the paper

“Another interesting role of the exosome as mediators of cancer cell interaction with non-malignant cells is the observation that cancer cells can systemically reprogram energy metabolism by recipient premetastatic niche cells to promote metastasis.”

What the sources say

• Supported

  The Abstract states that cancer-secreted vesicles carrying miR-122 suppress glucose uptake by non-tumour cells in the pre-metastatic niche and facilitate metastasis. The Results likewise describe glucose reallocation in the niche that facilitates metastatic growth. (LLM, conf=0.95)

  cites [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. source

In the paper

“In this perspective, exosomes from mouse and human lung-, brain- and liver-tropic tumor cells fuse preferentially with resident cells namely lung fibroblasts and epithelial cells, brain endothelial cells and liver Kupffer cells at their predicted destination.”

What the sources say

• Partly supported

  The 'Distinct cells uptake tropic exosomes' section identifies the claimed lung, liver and brain resident-cell targets for exosomes from human tumour cell lines. It describes fusion with Kupffer cells, but only co-localization with lung cells and interaction with brain endothelial cells. The 'Future metastatic sites uptake exosomes' section reports organ-specific uptake for mouse exosomes, not preferential fusion with those particular resident cells. (LLM, conf=0.86)

  cites [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. sourceExperimental — accuracy not yet measured

In the paper

“To increase nutrient availability, breast cancer cells secrete miR-122 -enriched vesicles to suppress glucose uptake by niche cells in vitro and in vivo.”

What the sources say

• Supported

  The Results section on cancer-secreted miR-122 reports that miR-122-bearing vesicles reduced glucose uptake by niche cells in vitro. The Results section on systemic intervention and the Discussion describe corresponding effects in pre-metastatic tissues in vivo, with increased glucose availability to cancer cells. (LLM, conf=0.93)

  cites [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

In the paper

“Furthermore, uptake of tumor-derived exosomes prepares organ-specific cells to serve as pre-metastatic niche.”

What the sources say

• Supported

  The Abstract describes tumour exosomes reaching target cells in an organ-specific manner and initiating pre-metastatic niche formation. The sections “Future metastatic sites uptake exosomes” and “Distinct cells uptake tropic exosomes” report organ-specific uptake by resident cells in metastatic target organs. No page numbers are available in our copy. (LLM, conf=0.92)

  cites [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. sourceExperimental — accuracy not yet measured

In the paper

“Sento et al. reported that heparin may suppress metastasis by lessening the uptake of exosomes, derived from cancer cells in oral squamous cell carcinoma [185].”

What the sources say

• Partly supported

  The Results section reports that repeated heparin treatment reduced uptake of OSCC-derived exosomes and inhibited exosome-induced cell migration and invasion. It does not report a reduction in metastasis itself; that part of the claim extrapolates from the measured effects. The indexed copy provides no page numbers for these passages. (LLM, conf=0.86)

  cites [185] Sento S, Sasabe E, Yamamoto T. Application of a persistent heparin treatment inhibits the malignant potential of oral squamous carcinoma cells induced by tumor cell-derived exosomes. PLoS One. 2016;11:e0148454. sourceExperimental — accuracy not yet measured

In the paper

“A number of preclinical and clinical findings have reported that targeting pathways and molecules involved in the formation of exosome can inhibit tumor progression, such as heparanase/syndecan-1 axis [182, 183] or syndecan heparan sulfate proteoglycans [179, 184].”

What the sources say

• Partly supported

  The section on exosome biogenesis says heparanase and syndecan-1 help regulate exosome formation, while the therapeutic-strategies section reports that targeting these molecules or related proteoglycans can inhibit tumor growth. The paper does not show that the reported tumor inhibition results from suppressing exosome formation; it describes that connection as a subject for further study. Page numbers were not available in our copy. (LLM, conf=0.86)

  cites [182] Ramani VC, Purushothaman A, Stewart MD, Thompson CA, Vlodavsky I, Au JLS, Sanderson RD. The heparanase/syndecan-1 axis in cancer: mechanisms and therapies. FEBS J. 2013;280:2294–306. sourceExperimental — accuracy not yet measured
• Partly supported

  The Background section, under “Implications of exosomes in metastatic cancer therapy,” says that targeting the heparanase/syndecan-1 axis or syndecan heparan sulfate proteoglycans may partly alleviate metastatic cancers; it also links these molecules to exosome formation. That supports the proposed approach to inhibiting metastasis, but the citing sentence broadens the outcome to tumor progression generally. (LLM, conf=0.85)

  cites [183] Wu M, Wang G, Hu W, Yao Y, Yu X-F. Emerging roles and therapeutic value of exosomes in cancer metastasis. Mol Cancer. 2019;18:53. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [179] Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E. Syndecan–syntenin–ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012;14:677. source
• Partly supported

  The paper reports that heparanase regulates exosome secretion and discusses a possible role for syndecan-1 in exosome formation (Discussion, p. 5). It says therapeutic inhibition of heparanase may decrease exosome secretion and slow tumor progression (p. 1), but does not report that targeting this axis inhibited tumor progression in a preclinical or clinical study. (LLM, conf=0.87)

  cites [184] Thompson CA, Purushothaman A, Ramani VC, Vlodavsky I, Sanderson RD. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J Biol Chem. 2013;288:10093–9. sourceExperimental — accuracy not yet measured

In the paper

“Communications mediated by exosomes in cancer can be disrupted by inhibition of the exosome production, secretion, cell-to-cell communication as well as removal of exosomal-specific loads [179, 180].”

What the sources say

• ?Not checked — no full text of the sourcecites [179] Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E. Syndecan–syntenin–ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012;14:677. source
• Supported

  The “Tumor exosomes as therapeutic targets” section proposes blocking exosome production, secretion, and exosome-mediated cell-to-cell communication, as well as ablating specific active exosomal cargoes, as cancer interventions. This directly supports the cited paraphrase; the source frames these approaches as proposed strategies. (LLM, conf=0.94)

  cites [180] Tai YL, Chen KC, Hsieh JT, Shen TL. Exosomes in cancer development and clinical applications. Cancer Sci. 2018;109:2364–74. source

In the paper

“Notably, the injection of exosomes from lung-tropic models can redirect the metastasis of bone-tropic tumor cells.”

What the sources say

• Supported

  In “Exosomes redirect metastatic distribution,” mice given lung-tropic 4175-LuT exosomes before injection of bone-tropic 1833-BoT tumour cells showed a significant increase in the cells’ lung metastatic capacity compared with mice given bone-tropic exosomes or PBS. This supports the claim that lung-tropic exosomes can redirect where bone-tropic tumour cells metastasize. (LLM, conf=0.94)

  cites [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 the paper

“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.”

In the paper

“As the heart of TME, tumor cells control the function of cellular and non-cellular components through complex signaling networks to use the non-malignant cells to work for their own benefit.”

In the paper

“Understanding the interaction between cancer cells can be used to develop therapeutic strategies to predict and neutralize tactics deployed by cancer cells to survive and resist anti-cancer modalities.”

In the paper

“Recent advances in tumor biology have shown that a comprehensive analysis of the multiple exchanges between tumor cells and their neighboring microenvironment is essential to understand the different underlying mechanisms of tumor growth and metastasis [8].”

What the sources say

• ?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

In the paper

“Current strategies may lack sufficient specificity due to targeting of whole population of pericytes.”

In the paper

“Recent progress in 3D platforms have provided more insight into the critical roles of TECs and their collaboration with different TME components.”

In the paper

“Since, disorganized TECs are essential for the characteristics of a tumor characterized by a leaking vascular system, high interstitial fluid pressure, reduced blood flow, tumor hypoxia and acidosis [45].”

What the sources say

• ?Not checked — no full text of the sourcecites [45] Dianat-Moghadam H, Heydarifard M, Jahanban-Esfahlan R, Panahi Y, Hamishehkar H, Pouremamali F, Rahbarghazi R, Nouri M. Cancer stem cells-emanated therapy resistance: implications for liposomal drug delivery systems. J Control Release. 2018;288:62–83. source

In the paper

“Given the numerous supporting functions for TCs, TECs represents an indispensable target in cancer therapy.”

In the paper

“Tumor hypoxia induces angiogenesis by activating the expression of vascular endothelial growth factor (VEGF) [3].”

What the sources say

• ?Not checked — no full text of the sourcecites [3] Jahanban-Esfahlan R, Seidi K, Zarghami N. Tumor vascular infarction: prospects and challenges. Int J Hematol. 2017;105:244–56. source

In the paper

“This can be achieved in part by using microfluidic systems that can recapitulate more complex biological interfaces that would otherwise be unattainable by two-dimensional (2D) systems to study the dynamic interaction of pericytes with different TME components under normal or pathological conditions.”

In the paper

“To this end, most primary strategies are directed at inhibiting tumor angiogenesis by blocking either growth factors or factors involved in endothelial cell migration, survival, and proliferation (Fig. 2a) [50] (see for review [3, 51]).”

What the sources say

• ?Not checked — no full text of the sourcecites [50] Daei Farshchi Adli A, Jahanban-Esfahlan R, Seidi K, Samandari-Rad S, Zarghami N. An overview on vadimezan (dmxaa), the vascular disrupting agent. Chem Biol Drug Des. 2017;91(5):996–1006. source
• ?Not checked — no full text of the sourcecites [3] Jahanban-Esfahlan R, Seidi K, Zarghami N. Tumor vascular infarction: prospects and challenges. Int J Hematol. 2017;105:244–56. source
• ?Not checked — no full text of the sourcecites [51] Seidi K, Jahanban-Esfahlan R, Zarghami N. Tumor rim cells: from resistance to vascular targeting agents to complete tumor ablation. Tumour Biol. 2017;39:1010428317691001. source

In the paper

“A deep understanding of the contribution of collagen to tumor progression can be achieved using 3D models.”

In the paper

“Tenascin-C, a300 kDa large glycoprotein, is overexpressed within the ECM of numerous cancer cells such as breast, colon, lung, and ovarian.”

What the sources say

• ?Not checked — no full text of the sourcecites [133] Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244:143–63. source

In the paper

“Each component of ECM plays an important role in the cancer progression.”

In the paper

“Among them, the role of collagen stands out.”

In the paper

“Its concentration in healthy ECM is almost low-to-none [133].”

What the sources say

• ?Not checked — no full text of the sourcecites [133] Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244:143–63. source

In the paper

“The hydrogel is ATP-responsive which allows further stimuli-responsive shifting of gel to sol state, to decloak and release CTC for live cell analysis (Fig. 4) [156].”

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

In the paper

“The production and release of exosomes from the tumor cells transmits a great deal of information with regards to the molecular and genetics properties, from the tumor cells to healthy ones or other abnormal cells residing nearby or at distant sites specifically designed to promote tumor invasion, metastasis and drug resistance [174].”

What the sources say

• ?Not checked — no full text of the sourcecites [174] Wendler F, Stamp GW, Giamas G. Tumor–stromal cell communication: small vesicles signal big changes. Trends Cancer. 2016;2:326–9. source

In the paper

“hence the blockage of multiple immune checkpoints can immediately confine more biomarkers among CTCs with higher immune recognition avidity.”

In the paper

“Dong et al. reported on the design, synthesis, and description of the new dual double-stranded (ds) aptamer ring conjugate (cCAP1-G4.5-cCAP2) capable of simultaneously targeting EpCAM and Her2 epitopes on CTCs.”

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

In the paper

“Also given their stability in systemic circulation and tumor-based specificity, exosomes are studied for their abilities to deliver anti-cancer agents [181].”

What the sources say

• ?Not checked — no full text of the sourcecites [181] Bastos N, Ruivo CF, da Silva S, Melo SA. Exosomes in cancer: Use them or target them? Semin Cell Dev Biol. 2018;78:13–21. source