Tumor microenvironment complexity and therapeutic implications at a glance

Chemotherapeutic agents can be targeted to ECM of tumor cells through membrane-bound receptors such as tenascin-C.

“Chemotherapeutic agents can also be targeted to ECM of the tumor cells through the membrane-bound receptors such as tenascin-C [132].”

• cites [132] Raavé R, van Kuppevelt TH, Daamen WF. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting. J Control Release. 2018;274:1–8. sourceDisputed

  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.

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Combination treatment with CPI and IL-2 resulted in complete elimination of tumors in 9 of 13 animals bearing orthotopic breast cancer.

“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].”

• 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. sourceDisputed

  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)

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LOX enzymes are widely used to block collagen crosslinking in various preclinical settings.

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

• cites [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. sourceNot checked — no full text of the source
• 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. sourceDisputed

  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)

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Circulating tumor cells, exosomes, cell-free DNA, and apoptotic bodies act as novel horizontal gene transfer mediators derived from tumor cells that deliver information to distant target cells, including tumor and normal cells.

“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].”

• cites [6] Denisenko TV, Budkevich IN, Zhivotovsky BJCd, disease: Cell death-based treatment of lung adenocarcinoma. 2018, 9:117. sourceCould 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)

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• cites [7] Balkwill FR, Capasso M, Hagemann T: The tumor microenvironment at a glance. The Company of Biologists Ltd; 2012. sourceNot checked — no full text of the source

Pericytes are vital multifunctional cells in the TME that envelop the surface of endothelial cells using cytoplasmic processes extending along the abluminal surface of the endothelium.

“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].”

• 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. sourceCould 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)

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Pericytes, along with endothelial cells, are involved in basement membrane remodeling during angiogenesis and tumorigenesis.

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

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

Tumor formation and progression are influenced by genetic and epigenetic changes in tumor cells and by rearrangement of tumor microenvironment components through mutual dynamic crosstalk.

“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].”

• 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. sourceCould 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)

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Recent advances in 3D platforms using lab-on-chip and microfluidic devices provide an opportunity to better simulate the function and biology of the TME and to bridge the translational gap between preclinical and clinical settings.

“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].”

• cites [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. sourceNot checked — no full text of the source
• 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. sourceSupported

• AssumptionRests on an assumption: In vitro 3D and microfluidic models sufficiently recapitulate the in vivo tumor microenvironment to inform therapeutic development.

Loss of tissue integrity, carcinogenesis, and further progression occur as a consequence of reciprocal interactions between tumor cells and the non-cellular ECM and cellular components of the TME.

“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].”

• 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. sourcePartly 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)

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• cites [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. sourceNot checked — no full text of the source

Interactions among reactive non-neoplastic cells, genetically altered tumor cells, and ECM control the majority of stages of tumorigenesis, including clonal evolution, cancer heterogeneity, epithelial-mesenchymal transition, migration, invasion, metastasis, neovascularization, apoptosis, and chemotherapeutic drug resistance.

“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”

• cites [11] Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R. Interaction of tumor cells with the microenvironment. Cell CommunSignaling. 2011;9:18. sourcePartly 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)

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• 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. sourcePartly 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)

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• 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. sourcePartly 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)

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• cites [14] Cova TF, Bento DJ, Nunes SC. Computational approaches in Theranostics: mining and predicting Cancer data. Pharmaceutics. 2019;11:119. sourcePartly 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)

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Non-malignant cells in the TME promote tumorigenesis in all phases of cancer development and metastasis.

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

• cites [4] Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

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In a genetically engineered mouse model of PDGF-induced gliomas, the interaction between glioma-initiating cells and the perivascular microenvironment is mediated through perivascular nitric oxide, which activates notch signaling to promote stem-like character.

“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].”

• 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. sourceSupported

Glioblastoma stem cells are responsible for producing the majority of vascular pericytes to reshape the perivascular niche to support vascular function and tumor growth.

“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.”

• 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. sourcePartly 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)

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Compared to normal endothelial cells, tumor-derived endothelial cells have disturbed morphology and phenotypes at the cellular and molecular levels, similar to the tumor itself.

“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].”

• cites [40] Salazar N, Zabel BA. Support of tumor endothelial cells by chemokine receptors. Front Immunol. 2019;10. sourceSupported
• cites [41] Dudley AC. Tumor endothelial cells. Cold Spring Harbor perspectives in medicine. 2012;2:a006536. sourcePartly 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)

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• cites [42] Aird WC. Molecular heterogeneity of tumor endothelium. Cell Tissue Res. 2009;335:271–81. sourceNot checked — no full text of the source

Strategies targeting pericytes have been proposed as antiangiogenic therapies for cancer due to their role in tumor angiogenesis.

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

• 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. sourceSupported

TECs can be used for cancer vaccine development.

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

• 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. sourceSupported

Prophylactic vaccination with dendritic cells pulsed with lysates of TECs positive for angiotensin-converting enzyme activity, isolated from lung with metastases, significantly suppresses lung metastasis in the B16/BL6 mouse melanoma model.

“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.”

• 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. sourceSupported

A better understanding of the molecular mechanisms of tumor progression involving pericytes may reveal specific targets within pericyte subpopulations and thus contribute to cancer treatments.

“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].”

• 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. sourceSupported

A 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes, and astrocytes resembles the characteristics of a physiologic BBB similar to the rat brain, with perfusable and selective microvascularization and lower permeability than the conventional in vitro model.

“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].”

• 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. sourceSupported

CAFs in the immediate vicinity of cancer cells play an important role in tumorigenesis by reducing apoptosis and improving proliferation, migration, and viability of cancer cells.

“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].”

• 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. sourceSupported
• cites [59] Kalluri RJNRC. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98. sourceNot checked — no full text of the source

GSCs migrate along the SDF-1/CXCR4 axis toward endothelial cells, where they are transformed into pericytes mainly by the action of TGFβ.

“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].”

• 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. sourceSupported

Therapeutic targets involving pericytes may exacerbate tumor metastasis.

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

• 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. sourcePartly 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)

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• cites [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. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

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• 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. sourceSupported

Clinical trials of pericyte-targeting therapies have not yielded consistent conclusions.

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

• cites [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. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

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3D cancer models show selective control of CAF function by tumor cells.

“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.”

• 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. sourceSupported

Polyclonal rabbit anti-CAF antibodies, achieved by immunizing rabbits with bFGF-activated fibroblasts, delay tumor growth in mice bearing murine CT26 colon carcinoma.

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

• 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. sourceSupported

In a 3D organotypic microfluidic chip, CAFs enhance invasion and migration speed by inducing expression of glycoprotein nonmetastatic B in breast cancer cells.

“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].”

• 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. sourceSupported

Pirfenidone suppresses lung metastasis and tumor progression in combination with doxorubicin in in vivo models.

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

• 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. sourceSupported

Therapeutic options for deactivating CAF-mediated interaction are largely focused on using, reprogramming, or eliminating CAFs.

“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].”

• cites [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. sourceNot checked — no full text of the source
• cites [77] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423. sourcePartly 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)

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• 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. sourcePartly 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)

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CAFs positively influence the proliferation and metabolism of cancer cells through oxidative stress, which induces the autophagy pathway.

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

• 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. sourcePartly 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)

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Use of nanoparticles to modify CAFs can be an effective strategy to treat desmoplastic cancers.

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

• 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. sourceSupported

The ECM of distant organs can be remotely shaped into permissive or restrictive soils by soluble factors, CTCs, or exosomes from primary tumors to facilitate the seeding of metastasizing cancer cells.

“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]).”

• 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. sourcePartly 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)

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TAMs are a key element of the TME that significantly affects cancer cell behavior.

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

• 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. sourceSupported

Besides biochemical composition such as intermolecular covalent cross-linkages, ECM biophysical characteristics include topography, stiffness/rigidity, molecular density, and tension.

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

• cites [118] Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406. sourcePartly 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)

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Clinical studies and experimental animal models suggest that TAMs commonly play a pro-tumoral role in various ways.

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

• 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. sourceSupported
• 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. sourceSupported
• 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. sourceSupported

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

“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.”

• 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. sourceSupported

TAM-based therapeutic strategies are being developed that aim at TAM targeting, TAM re-education, and TAM depletion.

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

• cites [88] Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61. sourceSupported
• 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. sourceSupported
• cites [101] Kowal J, Kornete M, Joyce JA. Re-education of macrophages as a therapeutic strategy in cancer. Immunotherapy. 2019;11:677–89. sourceSupported
• cites [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. sourceNot checked — no full text of the source

Combined tranilast and doxorubicin significantly diminished tumor growth and invasion in MDA-MB-231 breast cancer cells embedded in microwells surrounded by CAFs in collagen I hydrogel.

“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].”

• 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. sourceSupported

A non-internalizing antibody against tenascin-C transported anthracycline PNU159682 into the ECM of cancer cells.

“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).”

• 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. sourceSupported

CTCs are implicated in tumor cell dormancy as a major cause of metastatic outgrowth, multi drug resistance, and cancer relapse.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Collagen influences tumor cell behavior through integrins, tyrosine kinase receptors, discoidin domain receptors, and some signaling pathways.

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

• 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. sourceSupported

Conjugating immune checkpoint inhibitors anti-CTLA4 and anti-PD-L1 plus IL-2 to the collagen-binding domain of VWF A3 domain reduced side effects.

“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.”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Collagen interaction with fibronectin, laminin, hyaluronic acid, and MMPs influences cancer cell activity.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

This antibody-drug conjugate resulted in significant tumor growth inhibition of epidermoid carcinoma mouse xenografts.

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

• 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. sourceSupported

Collagen synthesis can be regulated by cancer cells, mutated genes, signaling pathways or receptors, and transcription factors.

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

• 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. sourceCould 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)

  Experimental — accuracy not yet measured

miRNAs and exosomes are partners in close contact with collagen in cancer.

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

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

ECM components can be used to ensure precise tumor drug delivery.

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

• cites [132] Raavé R, van Kuppevelt TH, Daamen WF. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting. J Control Release. 2018;274:1–8. sourcePartly 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)

  Experimental — accuracy not yet measured

Collagen reorganization at the tumor-stromal interface facilitates local invasion, as revealed by 3D culture of normal mammary glands, mammary tumors, and tumor explants.

“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].”

• 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. sourceSupported

Wang et al. developed a peptide-drug conjugate using EphA2 agonists, YSA peptide or its enhanced version 123B9.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

CTC-targeted therapies may provide a new approach to improve the prognosis of cancer therapy.

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

• 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. sourceSupported

Aggressive CTCs preferentially mediate self-seeding of breast, melanoma, and colon cancers in mice, including those with bone, brain, or lung metastatic tropism.

“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.”

• 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. sourceSupported
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Upregulation of EphA2 occurs in several cancers such as melanoma, ovarian, prostate, lung, and breast cancer.

“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.”

• 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. sourceSupported
• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source
• 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. sourceSupported

CTCs can be used as diagnostic tools providing molecular information on the primary tumor state.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

In contrast to the traditional view that tumor cell metastases occur unidirectionally, the reverse process is also possible through CTC-mediated self-seeding.

“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”.”

• 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. sourceSupported
• 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. sourceSupported

Exosomes are key to maintaining homeostasis of their releasing cells.

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

• cites [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. sourceNot checked — no full text of the source
• 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. sourceSupported
• 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. sourceCould 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)

  Experimental — accuracy not yet measured
• 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. sourceSupported

There is a prognosis for local recurrence by seeding of disseminated cells after apparently complete tumor ablation.

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

• 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. sourceSupported
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

CTCs are precise representations of primary and metastatic tumors that convey information for detection, diagnosis, and treatment of cancer.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

An increase in the number of CTCs is associated with a poor prognosis.

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

• 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. sourceSupported

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.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

A dimeric 123B9 was able to perform receptor activation at concentrations in the nanomolar range.

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

• 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. sourceSupported

YSA- and 123B9-drug conjugates could selectively transport cytotoxic drugs to cancer cells in vivo.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourceSupported

Bidirectional transport of exosomes containing different RNA species and proteins between cancer stem cells and the fibroblast-rich microenvironment promotes tumor growth and metastatic outbreak in breast carcinoma models.

“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].”

• 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. sourceSupported

Lian et al. described a unique set of checkpoints, CD274 and CD47, on CTCs which camouflaged these cells from immune detection and apoptosis.

“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.”

• 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. sourceSupported

Even confined tumors without metastasis can produce CTCs.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Rack B. et al. discovered that the detection rate of CTCs after chemotherapy (22.1%) increased slightly compared to baseline (21.5%) in 2026 breast cancer patients.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Martin M. et al. observed a considerable decline in CTC-positive rate after chemotherapy in 117 breast cancer patients.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

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

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

• 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. sourceSupported
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

CTCs usually express simultaneously more than one immune checkpoint.

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

• 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. sourceSupported

Tumors secrete IL-6 and IL-8 cytokines to attract CTCs.

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

• 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. sourceSupported
  Experimental — accuracy not yet measured
• 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. sourceSupported
  Experimental — accuracy not yet measured

Cancer cells can systemically reprogram energy metabolism by recipient premetastatic niche cells to promote metastasis.

“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.”

• 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. sourceSupported

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.

“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.”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Breast cancer cells secrete miR-122-enriched vesicles to suppress glucose uptake by niche cells in vitro and in vivo.

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

• 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. sourceSupported
  Experimental — accuracy not yet measured

Uptake of tumor-derived exosomes prepares organ-specific cells to serve as a pre-metastatic niche.

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

• 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. sourceSupported
  Experimental — accuracy not yet measured

Heparin may suppress metastasis by lessening the uptake of exosomes derived from cancer cells in oral squamous cell carcinoma.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Targeting pathways and molecules involved in exosome formation can inhibit tumor progression, such as the heparanase/syndecan-1 axis or syndecan heparan sulfate proteoglycans.

“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].”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

Exosome-mediated communications in cancer can be disrupted by inhibition of exosome production, secretion, cell-to-cell communication, and removal of exosomal-specific loads.

“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].”

• cites [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. sourceNot checked — no full text of the source
• cites [180] Tai YL, Chen KC, Hsieh JT, Shen TL. Exosomes in cancer development and clinical applications. Cancer Sci. 2018;109:2364–74. sourceSupported

Injection of exosomes from lung-tropic models can redirect the metastasis of bone-tropic tumor cells.

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

• 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. sourceSupported

Reciprocal cell-cell and cell-ECM interactions, and tumor cell hijacking of non-malignant cells, force stromal cells to lose their function and acquire new phenotypes that promote tumor development and invasion.

“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.”

Tumor cells, as the heart of the TME, control the function of cellular and non-cellular components through complex signaling networks to use non-malignant cells for their own benefit.

“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.”

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.

“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.”

A comprehensive analysis of the multiple exchanges between tumor cells and their neighboring microenvironment is essential to understand the mechanisms of tumor growth and metastasis.

“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].”

• cites [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. sourceNot checked — no full text of the source

Current strategies targeting pericytes may lack sufficient specificity because they target the whole population of pericytes.

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

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

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

• AssumptionRests on an assumption: In vitro 3D and microfluidic models sufficiently recapitulate the in vivo tumor microenvironment to inform therapeutic development.

Disorganized TECs are essential for tumor characteristics including a leaking vascular system, high interstitial fluid pressure, reduced blood flow, tumor hypoxia, and acidosis.

“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].”

• cites [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. sourceNot checked — no full text of the source

TECs represent an indispensable target in cancer therapy given their numerous supporting functions.

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

Tumor hypoxia induces angiogenesis by activating the expression of vascular endothelial growth factor.

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

• cites [3] Jahanban-Esfahlan R, Seidi K, Zarghami N. Tumor vascular infarction: prospects and challenges. Int J Hematol. 2017;105:244–56. sourceNot checked — no full text of the source

Microfluidic systems can recapitulate more complex biological interfaces than 2D systems to study the dynamic interaction of pericytes with different TME components under normal or pathological conditions.

“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.”

• AssumptionRests on an assumption: In vitro 3D and microfluidic models sufficiently recapitulate the in vivo tumor microenvironment to inform therapeutic development.

Most primary strategies for cancer therapy directed at TECs inhibit tumor angiogenesis by blocking either growth factors or factors involved in endothelial cell migration, survival, and proliferation.

“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]).”

• cites [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. sourceNot checked — no full text of the source
• cites [3] Jahanban-Esfahlan R, Seidi K, Zarghami N. Tumor vascular infarction: prospects and challenges. Int J Hematol. 2017;105:244–56. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

3D models can provide a deep understanding of collagen's contribution to tumor progression.

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

Tenascin-C is overexpressed within the ECM of numerous cancer cells such as breast, colon, lung, and ovarian.

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

• cites [133] Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244:143–63. sourceNot checked — no full text of the source

Every ECM component has an important role in cancer progression.

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

Collagen has a particularly prominent role among ECM components in cancer.

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

Tenascin-C concentration in healthy ECM is almost low-to-none.

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

• cites [133] Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244:143–63. sourceNot checked — no full text of the source

The hydrogel is ATP-responsive, allowing stimuli-responsive shifting from gel to sol state to decloak and release CTCs for live cell analysis.

“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].”

• cites [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. sourceNot checked — no full text of the source

Production and release of exosomes from tumor cells transmits molecular and genetic information from tumor cells to healthy or other abnormal cells nearby or at distant sites to promote tumor invasion, metastasis, and drug resistance.

“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].”

• cites [174] Wendler F, Stamp GW, Giamas G. Tumor–stromal cell communication: small vesicles signal big changes. Trends Cancer. 2016;2:326–9. sourceNot checked — no full text of the source

Blockage of multiple immune checkpoints can confine more biomarkers among CTCs with higher immune recognition avidity.

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

Dong et al. reported a new dual double-stranded aptamer ring conjugate (cCAP1-G4.5-cCAP2) capable of simultaneously targeting EpCAM and Her2 epitopes on CTCs.

“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.”

• cites [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. sourceNot checked — no full text of the source

Given their stability in systemic circulation and tumor-based specificity, exosomes are studied for their ability to deliver anti-cancer agents.

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

• cites [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. sourceNot checked — no full text of the source