Tumor microenvironment complexity and therapeutic implications at a glance

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].”

What the sources say

• Disputed

  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.

  cites [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

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].”

What the sources say

• Disputed

  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.

  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

“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.”

What the sources say

• ?Could not verify

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

  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

“While several studies have shown that greater pericytes coverage corresponds to a better diagnosis [30]”

What the sources say

• Partly supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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

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].”

What the sources say

• Supported

  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)

  cites [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

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].”

What the sources say

• ?Could not verify

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  cites [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

In the paper

“These properties promote the tumor cell heterogeneity, cancer resistance and impair efficient drug delivery [2, 8, 46].”

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 supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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
• Supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [41] Dudley AC. Tumor endothelial cells. Cold Spring Harbor perspectives in medicine. 2012;2:a006536. sourceExperimental — accuracy not yet measured

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].”

What the sources say

• Supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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].”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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
• Supported

  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)

  cites [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

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].”

What the sources say

• Supported

  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)

  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

“It has been recognized that TAMs may have both promoting (M1 type) and impairing roles (M2 type) when interfering with cancer treatments [92].”

What the sources say

• Partly supported

  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)

  cites [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

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].”

What the sources say

• Supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  cites [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

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].”

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 supported

  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)

  cites [114] Hynes RO. The extracellular matrix: not just pretty fibrils. Science. 2009;326:1216–9. sourceExperimental — accuracy not yet measured

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].”

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 supported

  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)

  cites [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

In the paper

“In addition, hypoxia, which is common in collagen-rich tumors, promotes cancer progression [124].”

What the sources say

• Supported

  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)

  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

“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.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

In the paper

“It also derive proliferation, angiogenesis and metastasis stages of tumor progression [134].”

What the sources say

• Supported

  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)

  cites [134] Lowy CM, Oskarsson T. Tenascin C in metastasis: a view from the invasive front. Cell Adhes Migr. 2015;9:112–24. source

In the paper

“Also, bi-transgenic tumor model confirmed the role of stromal collagen condensation as indication for mammary tumor initiation and progression.”

What the sources say

• Partly supported

  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)

  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. sourceExperimental — accuracy not yet measured

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].”

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 supported

  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)

  cites [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

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.”

What the sources say

• Supported

  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)

  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. source

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.”

What the sources say

• Supported

  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)

  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

“They facilitate specific cell-cell interactions and stimulate several signaling pathways in their target cells, including cancer cells [173].”

What the sources say

• Supported

  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)

  cites [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

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].”

What the sources say

• Supported

  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)

  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

“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].”

What the sources say

• Supported

  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)

  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

“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].”

What the sources say

• Partly supported

  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)

  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

“the development of liquid biopsy platforms capable of capturing this rare population of cells from the blood is highly rewarding [155].”

What the sources say

• Supported

  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)

  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. source

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.”

What the sources say

• Partly supported

  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)

  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
• Partly supported

  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)

  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 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.”

What the sources say

• Partly supported

  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)

  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

“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.”

What the sources say

• Supported

  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)

  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

“Finally, integrin-mediated uptake of exosome activates Src phosphorylation and pro-inflammatory S100 gene expression in resident cells [176].”

What the sources say

• Supported

  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)

  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

“In this space, tumor cells and their adjacent microenvironments are in frequent communication.”

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.”

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).”

In the paper

“Tumors develop in complex and dynamic microenvironments that influencetheir growth, invasion, and metastasis.”

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).”

In the paper

“In fact, inhibitors of these pathways can target and block proliferation and pathological angiogenesis in vivo [53].”

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

In the paper

“Equally, 3D systems enable studying the organ-specific preference of metastatic cancer cells and the underlying molecular pathways/interactions.”

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].”

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

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].”

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

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.”

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

“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.”

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

“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.”

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].”

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

“The aptamer-conjugate impeded metastasis and displayed enhanced bio-stability against endogenous nucleases in vivo.”

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

“Form therapeutic point of view, exosomes are applied as diagnostic biomarkers, therapeutic targets, or as anticancer drug-delivery vehicles [178].”

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

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].”

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