{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:25:23Z","timestamp":1787729123476,"version":"build-2784847793"},"reference-count":167,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In tumor cells\u2019 struggle for survival following therapy, they resist treatment. Resistance to therapy is the outcome of well-planned, highly efficient adaptive strategies initiated and utilized by these transformed tumor cells. Cancer cells undergo several reprogramming events towards adapting this opportunistic behavior, leading them to gain specific survival advantages. The strategy involves changes within the transformed tumors cells as well as in their neighboring non-transformed extra-tumoral support system, the tumor microenvironment (TME). Cancer-Associated Fibroblasts (CAFs) are one of the components of the TME that is used by tumor cells to achieve resistance to therapy. CAFs are diverse in origin and are the most abundant non-transformed element of the microenvironment in solid tumors. Cells of an established tumor initially play a direct role in the establishment of the CAF population for its own microenvironment. Like their origin, CAFs are also diverse in their functions in catering to the pro-tumor microenvironment. Once instituted, CAFs interact in unison with both tumor cells and all other components of the TME towards the progression of the disease and the worst outcome. One of the many functions of CAFs in influencing the outcome of the disease is their participation in the development of resistance to treatment. CAFs resist therapy in solid tumors. A tumor\u2013CAF relationship is initiated by tumor cells to exploit host stroma in favor of tumor progression. CAFs in concert with tumor cells and other components of the TME are abettors of resistance to treatment. Thus, this liaison between CAFs and tumor cells is a b\u00eate noire of therapy. Here, we portray a comprehensive picture of the modes and functions of CAFs in conjunction with their role in orchestrating the development of resistance to different chemotherapies and targeted therapies in solid tumors. We investigate the various functions of CAFs in various solid tumors in light of their dialogue with tumor cells and the two components of the TME, the immune component, and the vascular component. Acknowledgment of the irrefutable role of CAFs in the development of treatment resistance will impact our future strategies and ability to design improved therapies inclusive of CAFs. Finally, we discuss the future implications of this understanding from a therapeutic standpoint and in light of currently ongoing and completed CAF-based NIH clinical trials.<\/jats:p>","DOI":"10.3390\/cancers14061519","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T22:09:58Z","timestamp":1647468598000},"page":"1519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["B\u00eate Noire of Chemotherapy and Targeted Therapy: CAF-Mediated Resistance"],"prefix":"10.3390","volume":"14","author":[{"given":"Pradip","family":"De","sequence":"first","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9405-5464","authenticated-orcid":false,"given":"Jennifer","family":"Aske","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raed","family":"Sulaiman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Avera McKennan Hospital, Sioux Falls, SD 57105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5533-8784","authenticated-orcid":false,"given":"Nandini","family":"Dey","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Avera Cancer Institute, Sioux Falls, SD 57105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1152\/physrev.00048.2019","article-title":"Diversity and Biology of Cancer-Associated Fibroblasts","volume":"101","author":"Biffi","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.cell.2020.03.013","article-title":"SnapShot: Cancer-Associated Fibroblasts","volume":"181","author":"Park","year":"2020","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"De, P., Aske, J., and Dey, N. (2021). Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy. Cancers, 13.","DOI":"10.3390\/cancers13205246"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"De, P., Aske, J., and Dey, N. (2021). Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179121"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1158\/0008-5472.CAN-15-2973","article-title":"FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling","volume":"76","author":"Yang","year":"2016","journal-title":"Cancer Res."},{"key":"ref_6","first-page":"21","article-title":"Cancer Metabolic and immune reprogramming: The intimate interaction between cancer cells and microenviroment","volume":"1","year":"2014","journal-title":"Cancer Prev. Curr. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.4161\/cc.8.23.10238","article-title":"The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma","volume":"8","author":"Pavlides","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.4161\/cc.10.11.15659","article-title":"Evidence for a stromal-epithelial \"lactate shuttle\" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts","volume":"10","author":"Lin","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.semcancer.2013.12.007","article-title":"The role of reactive oxygen species and metabolism on cancer cells and their microenvironment","volume":"25","author":"Costa","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.ccell.2018.01.011","article-title":"Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer","volume":"33","author":"Costa","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1158\/2159-8290.CD-19-0094","article-title":"Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts","volume":"9","author":"Elyada","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.3389\/fimmu.2019.01835","article-title":"The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment","volume":"10","author":"Monteran","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4820","DOI":"10.1158\/1078-0432.CCR-18-0205","article-title":"Cancer-Associated Fibroblasts Affect Intratumoral CD8(+) and FoxP3(+) T Cells Via IL6 in the Tumor Microenvironment","volume":"24","author":"Kato","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"684505","DOI":"10.3389\/fcell.2021.684505","article-title":"Cancer-Associated Fibroblast-Derived Interleukin-8 Promotes Ovarian Cancer Cell Stemness and Malignancy Through the Notch3-Mediated Signaling","volume":"9","author":"Ji","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.cell.2018.01.009","article-title":"CD10(+)GPR77(+) Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness","volume":"172","author":"Su","year":"2018","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.canlet.2011.01.011","article-title":"Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion","volume":"303","author":"Zhang","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/bjc.2013.768","article-title":"Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling","volume":"110","author":"Yu","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.semcdb.2019.10.016","article-title":"A centralized communication network: Recent insights into the role of the cancer associated fibroblast in the development of drug resistance in tumors","volume":"101","author":"Leask","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.2174\/1389450119666180219124439","article-title":"Versatility of Cancer Associated Fibroblasts: Commendable Targets for Anti-tumor Therapy","volume":"19","author":"Khan","year":"2018","journal-title":"Curr. Drug Targets"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1089\/omi.2020.0023","article-title":"Architecture of Cancer-Associated Fibroblasts in Tumor Microenvironment: Mapping Their Origins, Heterogeneity, and Role in Cancer Therapy Resistance","volume":"24","author":"Dzobo","year":"2020","journal-title":"Omics. J. Integr. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4686","DOI":"10.1038\/s41388-021-01870-x","article-title":"Cell-type deconvolution analysis identifies cancer-associated myofibroblast component as a poor prognostic factor in multiple cancer types","volume":"40","author":"Li","year":"2021","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vaish, U., Jain, T., Are, A.C., and Dudeja, V. (2021). Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413408"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2268","DOI":"10.1002\/2211-5463.12976","article-title":"Adipose-derived mesenchymal stem cells differentiate into pancreatic cancer-associated fibroblasts In Vitro","volume":"10","author":"Miyazaki","year":"2020","journal-title":"FEBS Open Bio"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.ccell.2021.03.012","article-title":"Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations","volume":"39","author":"Affo","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1158\/2159-8290.CD-19-1384","article-title":"Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer","volume":"10","author":"Kieffer","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1002\/stem.3455","article-title":"ELF3 mediates IL-1alpha induced differentiation of mesenchymal stem cells to inflammatory iCAFs","volume":"39","author":"Tran","year":"2021","journal-title":"Stem Cells"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Goulet, C.R., Champagne, A., Bernard, G., Vandal, D., Chabaud, S., Pouliot, F., and Bolduc, S. (2019). Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5353-6"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13045-021-01203-1","article-title":"Cancer-associated fibroblast heterogeneity is associated with organ-specific metastasis in pancreatic ductal adenocarcinoma","volume":"14","author":"Pan","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1158\/1078-0432.CCR-20-3715","article-title":"Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer","volume":"27","author":"Steele","year":"2021","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1158\/0008-5472.CAN-20-0263","article-title":"A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer","volume":"80","author":"Mosa","year":"2020","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zeltz, C., Alam, J., Liu, H., Erusappan, P.M., Hoschuetzky, H., Molven, A., Parajuli, H., Cukierman, E., Costea, D.E., and Lu, N. (2019). Alpha11beta1 Integrin is Induced in a Subset of Cancer-Associated Fibroblasts in Desmoplastic Tumor Stroma and Mediates In Vitro Cell Migration. Cancers, 11.","DOI":"10.3390\/cancers11060765"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Diaz-Maroto, N.G., Garcia-Vicien, G., Polcaro, G., Banuls, M., Albert, N., Villanueva, A., and Mollevi, D.G. (2021). The Blockade of Tumoral IL1beta-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094960"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s10549-010-0855-6","article-title":"Tumor-stroma ratio in the primary tumor is a prognostic factor in early breast cancer patients, especially in triple-negative carcinoma patients","volume":"125","author":"Putter","year":"2011","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.surg.2015.02.013","article-title":"Tumor-stroma ratio is a prognostic factor for survival in hepatocellular carcinoma patients after liver resection or transplantation","volume":"158","author":"Lv","year":"2015","journal-title":"Surgery"},{"key":"ref_36","first-page":"387","article-title":"The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage","volume":"29","author":"Mesker","year":"2007","journal-title":"Cell. Oncol. Off. J. Int. Soc. Cell. Oncol."},{"key":"ref_37","first-page":"1457","article-title":"Tumor-stroma ratio is an independent predictor for survival in esophageal squamous cell carcinoma","volume":"7","author":"Wang","year":"2012","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_38","first-page":"11348","article-title":"Tumor-stroma ratio is an independent predictor for survival in NSCLC","volume":"8","author":"Zhang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1136\/gutjnl-2011-301373","article-title":"Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer","volume":"62","author":"Wu","year":"2013","journal-title":"Gut"},{"key":"ref_40","first-page":"591","article-title":"Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas","volume":"20","author":"Lee","year":"2017","journal-title":"Gastric Cancer Off. J. Int. Gastric Cancer Assoc. Jpn. Gastric Cancer Assoc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.4143\/crt.2018.031","article-title":"Cancer-Associated Fibroblasts Promote the Chemo-resistance in Gastric Cancer through Secreting IL-11 Targeting JAK\/STAT3\/Bcl2 Pathway","volume":"51","author":"Ma","year":"2019","journal-title":"Cancer Res. Treat."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s12943-019-0972-8","article-title":"Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer","volume":"18","author":"Ham","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6270784","DOI":"10.1155\/2019\/6270784","article-title":"Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments","volume":"2019","author":"Ham","year":"2019","journal-title":"J. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1158\/0008-5472.CAN-19-3803","article-title":"Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing beta1 Integrin, Enhancing Drug Resistance","volume":"80","author":"Uchihara","year":"2020","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1111\/cas.13998","article-title":"Cancer-associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells","volume":"110","author":"Wang","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1111\/jcmm.14205","article-title":"Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts","volume":"23","author":"Masuda","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.canlet.2019.04.002","article-title":"Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer","volume":"454","author":"Zhai","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41419-019-1581-6","article-title":"Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1\/ERbeta\/Bcl-2 signalling","volume":"10","author":"Long","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1186\/s12935-019-1051-3","article-title":"Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A","volume":"19","author":"Guo","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13059-018-1604-0","article-title":"Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5","volume":"20","author":"Qin","year":"2019","journal-title":"Genome Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2002518","DOI":"10.1002\/advs.202002518","article-title":"CD63(+) Cancer-Associated Fibroblasts Confer Tamoxifen Resistance to Breast Cancer Cells through Exosomal miR-22","volume":"7","author":"Gao","year":"2020","journal-title":"Adv. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s13046-019-1507-2","article-title":"Exosome-mediated transfer of miR-93-5p from cancer-associated fibroblasts confer radioresistance in colorectal cancer cells by downregulating FOXA1 and upregulating TGFB3","volume":"39","author":"Chen","year":"2020","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.omtn.2020.11.003","article-title":"Exosomal miR-590-3p derived from cancer-associated fibroblasts confers radioresistance in colorectal cancer","volume":"24","author":"Chen","year":"2021","journal-title":"Mol. Therapy Nucleic Acids"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1158\/1078-0432.CCR-18-0773","article-title":"Cancer-associated Fibroblast-promoted LncRNA DNM3OS Confers Radioresistance by Regulating DNA Damage Response in Esophageal Squamous Cell Carcinoma","volume":"25","author":"Zhang","year":"2019","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12964-021-00711-4","article-title":"Acquired radioresistance in cancer associated fibroblasts is concomitant with enhanced antioxidant potential and DNA repair capacity","volume":"19","author":"Domogauer","year":"2021","journal-title":"Cell Commun. Signal. CCS"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ragunathan, K., Upfold, N.L.E., and Oksenych, V. (2020). Interaction between Fibroblasts and Immune Cells Following DNA Damage Induced by Ionizing Radiation. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202011.0339.v2"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3154","DOI":"10.3389\/fimmu.2018.03154","article-title":"Overcoming Resistance to Combination Radiation-Immunotherapy: A Focus on Contributing Pathways Within the Tumor Microenvironment","volume":"9","author":"Darragh","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1172\/JCI95200","article-title":"Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance","volume":"128","author":"Leung","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12943-020-01168-8","article-title":"CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer","volume":"19","author":"Zhang","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1002\/ijc.32608","article-title":"Long noncoding RNA CCAL transferred from fibroblasts by exosomes promotes chemoresistance of colorectal cancer cells","volume":"146","author":"Deng","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12943-019-1019-x","article-title":"CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer","volume":"18","author":"Hu","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41419-021-03420-5","article-title":"Correction: Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1\/SATB-1 pathway in pancreatic cancer","volume":"12","author":"Wei","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3414","DOI":"10.2174\/0929867325666180309120746","article-title":"Involvement of Breast Cancer-Associated Fibroblasts in Tumor Development, Therapy Resistance and Evaluation of Potential Therapeutic Strategies","volume":"25","author":"Ruocco","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.ccell.2020.06.005","article-title":"Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer","volume":"38","author":"Zhang","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s13046-020-01611-0","article-title":"Regulation of heterogeneous cancer-associated fibroblasts: The molecular pathology of activated signaling pathways","volume":"39","author":"Yoshida","year":"2020","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.cmet.2018.08.006","article-title":"Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies","volume":"28","author":"Apicella","year":"2018","journal-title":"Cell Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1111\/pin.12838","article-title":"Secretion of high amounts of hepatocyte growth factor is a characteristic feature of cancer-associated fibroblasts with EGFR-TKI resistance-promoting phenotype: A study of 18 cases of cancer-associated fibroblasts","volume":"69","author":"Suzuki","year":"2019","journal-title":"Pathol. Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13046-015-0221-y","article-title":"Metabolic reprogramming: The emerging concept and associated therapeutic strategies","volume":"34","author":"Yoshida","year":"2015","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5339","DOI":"10.1038\/s41388-019-0805-7","article-title":"Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer","volume":"38","author":"Ippolito","year":"2019","journal-title":"Oncogene"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41419-020-2434-z","article-title":"Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells","volume":"11","author":"Gong","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"107451","DOI":"10.1016\/j.pharmthera.2019.107451","article-title":"Lactate\/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon","volume":"206","author":"Brown","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"24267","DOI":"10.1074\/jbc.M115.657270","article-title":"Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma","volume":"290","author":"Capparelli","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1158\/1078-0432.CCR-19-0353","article-title":"Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation","volume":"26","author":"Mancino","year":"2020","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_74","first-page":"3151","article-title":"The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides","volume":"62","author":"Motoyama","year":"2002","journal-title":"Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1002\/cam4.1995","article-title":"Targeting of the HER2\/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer","volume":"8","author":"Watanabe","year":"2019","journal-title":"Cancer Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"R85","DOI":"10.1186\/bcr3480","article-title":"An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models","volume":"15","author":"Xia","year":"2013","journal-title":"Breast Cancer Res. BCR"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1158\/1078-0432.CCR-13-0358","article-title":"Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: Critical role for neuregulin blockade in antitumor response to combination therapy","volume":"20","author":"Phillips","year":"2014","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5096","DOI":"10.1158\/1078-0432.CCR-20-2915","article-title":"Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer","volume":"27","author":"Guardia","year":"2021","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/ijc.32859","article-title":"Reactive stroma and trastuzumab resistance in HER2-positive early breast cancer","volume":"147","author":"Sonnenblick","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1158\/0008-5472.CAN-21-0614","article-title":"BRAF Inhibitors Reprogram Cancer-Associated Fibroblasts to Drive Matrix Remodeling and Therapeutic Escape in Melanoma","volume":"82","author":"Liu","year":"2022","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.jcmgh.2020.09.003","article-title":"Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance","volume":"11","author":"Liu","year":"2021","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/j.ccell.2021.09.003","article-title":"Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms","volume":"11","author":"Hu","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1111\/cas.14537","article-title":"Heterogeneity of cancer-associated fibroblasts: Opportunities for precision medicine","volume":"111","author":"Kanzaki","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Laplagne, C., Domagala, M., Le Naour, A., Quemerais, C., Hamel, D., Fournie, J.J., Couderc, B., Bousquet, C., Ferrand, A., and Poupot, M. (2019). Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194719"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1158\/2326-6066.CIR-16-0011","article-title":"Can Targeting Stroma Pave the Way to Enhanced Antitumor Immunity and Immunotherapy of Solid Tumors?","volume":"4","author":"Pure","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s41181-019-0069-0","article-title":"Targeting of activated fibroblasts for imaging and therapy","volume":"4","author":"Lindner","year":"2019","journal-title":"EJNMMI Radiopharm. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4343","DOI":"10.1038\/s41388-018-0275-3","article-title":"Pro-tumorigenic roles of fibroblast activation protein in cancer: Back to the basics","volume":"37","author":"Pure","year":"2018","journal-title":"Oncogene"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4584","DOI":"10.1158\/1078-0432.CCR-07-5211","article-title":"Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts","volume":"14","author":"Ostermann","year":"2008","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1200\/JCO.1994.12.6.1193","article-title":"Antibody targeting in metastatic colon cancer: A phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts","volume":"12","author":"Welt","year":"1994","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"20212","DOI":"10.1073\/pnas.1320318110","article-title":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer","volume":"110","author":"Feig","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1158\/2326-6066.CIR-13-0150","article-title":"Tumoral immune suppression by macrophages expressing fibroblast activation protein-alpha and heme oxygenase-1","volume":"2","author":"Arnold","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.1195300","article-title":"Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha","volume":"330","author":"Kraman","year":"2010","journal-title":"Science"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1158\/0008-5472.CAN-14-3041","article-title":"Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells","volume":"75","author":"Lo","year":"2015","journal-title":"Cancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1158\/2326-6066.CIR-13-0027","article-title":"Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity","volume":"2","author":"Wang","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1158\/1535-7163.MCT-15-0647","article-title":"RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis","volume":"15","author":"Brunker","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"15003","DOI":"10.1038\/mto.2015.3","article-title":"Expression of anti-VEGF antibody together with anti-EGFR or anti-FAP enhances tumor regression as a result of vaccinia virotherapy","volume":"2","author":"Huang","year":"2015","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"23282","DOI":"10.18632\/oncotarget.7818","article-title":"Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_98","first-page":"1639","article-title":"A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer","volume":"9","author":"Scott","year":"2003","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Kaps, L., and Schuppan, D. (2020). Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers. Cells, 9.","DOI":"10.3390\/cells9092027"},{"key":"ref_100","first-page":"326","article-title":"Gold nanoparticles inhibit activation of cancer-associated fibroblasts by disrupting communication from tumor and microenvironmental cells","volume":"6","author":"Zhang","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1021\/acs.molpharmaceut.0c00014","article-title":"Emerging Nano Drug Delivery Systems Targeting Cancer-Associated Fibroblasts for Improved Antitumor Effect and Tumor Drug Penetration","volume":"17","author":"Guo","year":"2020","journal-title":"Mol. Pharm."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Truffi, M., Mazzucchelli, S., Bonizzi, A., Sorrentino, L., Allevi, R., Vanna, R., Morasso, C., and Corsi, F. (2019). Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061263"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"374","DOI":"10.2174\/1874471013666201224114148","article-title":"Theranostic radiopharmaceuticals targeting cancer-associated fibroblasts","volume":"14","author":"Zhuravlev","year":"2020","journal-title":"Curr. Radiopharm."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Koustoulidou, S., Hoorens, M.W.H., Dalm, S.U., Mahajan, S., Debets, R., Seimbille, Y., and de Jong, M. (2021). Cancer-Associated Fibroblasts as Players in Cancer Development and Progression and Their Role in Targeted Radionuclide Imaging and Therapy. Cancers, 13.","DOI":"10.3390\/cancers13051100"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrgastro.2011.222","article-title":"The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma","volume":"9","author":"Sirica","year":"2011","journal-title":"Nat. Reviews. Gastroenterol. Hepatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1097\/MOG.0000000000000609","article-title":"Cancer-associated fibroblasts in cholangiocarcinoma","volume":"36","author":"Vaquero","year":"2020","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.trecan.2018.01.007","article-title":"Desmoplastic Tumor Microenvironment and Immunotherapy in Cholangiocarcinoma","volume":"4","author":"Hogdall","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1158\/0008-5472.CAN-12-2130","article-title":"Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma","volume":"73","author":"Mertens","year":"2013","journal-title":"Cancer Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5738","DOI":"10.1021\/acsnano.0c00417","article-title":"Photothermal Depletion of Cancer-Associated Fibroblasts Normalizes Tumor Stiffness in Desmoplastic Cholangiocarcinoma","volume":"14","author":"Vaquero","year":"2020","journal-title":"ACS Nano"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1038\/s41598-021-81465-4","article-title":"Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer","volume":"11","author":"Katsube","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Gorchs, L., and Kaipe, H. (2021). Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines. Cancers, 13.","DOI":"10.3390\/cancers13122995"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"7243","DOI":"10.7554\/eLife.57243","article-title":"Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy","volume":"9","author":"Barrett","year":"2020","journal-title":"Elife"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"36","DOI":"10.14715\/cmb\/2020.66.2.5","article-title":"Cancer-associated fibroblasts induce immunotherapy resistance in hepatocellular carcinoma animal model","volume":"66","author":"Yu","year":"2020","journal-title":"Cell. Mol. Biol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13045-019-0770-1","article-title":"Cancer-associated fibroblasts: An emerging target of anti-cancer immunotherapy","volume":"12","author":"Liu","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Freeman, P., and Mielgo, A. (2020). Cancer-Associated Fibroblast Mediated Inhibition of CD8+ Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities. Cancers, 12.","DOI":"10.3390\/cancers12092687"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Valcz, G., Buzas, E.I., Sebestyen, A., Krenacs, T., Szallasi, Z., Igaz, P., and Molnar, B. (2020). Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy. Cancers, 12.","DOI":"10.3390\/cancers12082324"},{"key":"ref_117","first-page":"1889","article-title":"Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells","volume":"9","author":"Huang","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1021\/mp200421k","article-title":"Fibroblasts contribute to melanoma tumor growth and drug resistance","volume":"8","author":"Flach","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/stem.1556","article-title":"CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment","volume":"32","author":"Kinugasa","year":"2014","journal-title":"Stem Cells"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Bellei, B., Migliano, E., and Picardo, M. (2020). A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue. Cancers, 12.","DOI":"10.3390\/cancers12113400"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.neo.2016.07.007","article-title":"DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis","volume":"18","author":"Lee","year":"2016","journal-title":"Neoplasia"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"5551","DOI":"10.1038\/onc.2017.159","article-title":"DNA methylation variations are required for epithelial-to-mesenchymal transition induced by cancer-associated fibroblasts in prostate cancer cells","volume":"36","author":"Pistore","year":"2017","journal-title":"Oncogene"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.freeradbiomed.2018.10.450","article-title":"Cancer-associated fibroblasts modify lung cancer metabolism involving ROS and TGF-beta signaling","volume":"130","author":"Coronado","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1158\/2159-8290.CD-18-0710","article-title":"IL1-Induced JAK\/STAT Signaling Is Antagonized by TGFbeta to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Biffi","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"4692","DOI":"10.1038\/s41467-018-06654-8","article-title":"TGF-beta-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure","volume":"9","author":"Chakravarthy","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1053\/j.gastro.2017.03.046","article-title":"Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells","volume":"153","author":"Ishimoto","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.4161\/15592294.2014.971608","article-title":"TGF-beta induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells","volume":"9","author":"Cardenas","year":"2014","journal-title":"Epigenetics"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"16618","DOI":"10.1073\/pnas.1117610109","article-title":"TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma","volume":"109","author":"Liu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/nm.2890","article-title":"Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B","volume":"18","author":"Sun","year":"2012","journal-title":"Nat. Med."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1038\/onc.2015.494","article-title":"SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment","volume":"35","author":"Sun","year":"2016","journal-title":"Oncogene"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1084\/jem.20131195","article-title":"Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A","volume":"210","author":"Lotti","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.4161\/cc.25695","article-title":"Oncogenes induce the cancer-associated fibroblast phenotype: Metabolic symbiosis and \"fibroblast addiction\" are new therapeutic targets for drug discovery","volume":"12","author":"Lisanti","year":"2013","journal-title":"Cell Cycle"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.semcancer.2014.01.005","article-title":"Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth","volume":"25","author":"Lisanti","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/978-3-030-65768-0_15","article-title":"Targeting Metabolic Cross Talk Between Cancer Cells and Cancer-Associated Fibroblasts","volume":"1311","author":"Jung","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1634\/theoncologist.9-90005-31","article-title":"Hypoxia and anemia: Factors in decreased sensitivity to radiation therapy and chemotherapy?","volume":"9","author":"Harrison","year":"2004","journal-title":"Oncologist"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1038\/bjc.1997.201","article-title":"Influence of low pH on cytotoxicity of paclitaxel, mitoxantrone and topotecan","volume":"75","author":"Vukovic","year":"1997","journal-title":"Br. J. Cancer"},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Simon, M.C. (2010). Diverse Effects of Hypoxia on Tumor Progression, Springer.","DOI":"10.1007\/978-3-642-13329-9"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/nrc2540","article-title":"The impact of O2 availability on human cancer","volume":"8","author":"Bertout","year":"2008","journal-title":"Nat. Reviews Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.cell.2007.04.019","article-title":"Hypoxia-inducible factors, stem cells, and cancer","volume":"129","author":"Keith","year":"2007","journal-title":"Cell"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"8247","DOI":"10.1126\/scisignal.aan8247","article-title":"Hypoxic cancer-associated fibroblasts increase NCBP2-AS2\/HIAR to promote endothelial sprouting through enhanced VEGF signaling","volume":"12","author":"Kugeratski","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_141","first-page":"31","article-title":"Role of carcinoma-associated fibroblasts and hypoxia in tumor progression","volume":"345","author":"Giaccia","year":"2010","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1950953","DOI":"10.1080\/2162402X.2021.1950953","article-title":"Hypoxia increases melanoma-associated fibroblasts immunosuppressive potential and inhibitory effect on T cell-mediated cytotoxicity","volume":"10","author":"Ziani","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1152\/ajpgi.90356.2008","article-title":"Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer","volume":"295","author":"Masamune","year":"2008","journal-title":"Am. J. Physiology Gastrointest. Liver Physiol."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Kugeratski, F.G., Hernandez, J.R., Kalna, G., and Zanivan, S. (2016). Abstract A34: Hypoxic cancer-associated fibroblasts secrete regulators of angiogenesis: Novel potenital players revealed by MS. Cancer Res., 76.","DOI":"10.1158\/1538-7445.TME16-A34"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Ganguly, D., Chandra, R., Karalis, J., Teke, M., Aguilera, T., Maddipati, R., Wachsmann, M.B., Ghersi, D., Siravegna, G., and Zeh, H.J. (2020). Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment. Cancers, 12.","DOI":"10.3390\/cancers12092652"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"11156","DOI":"10.1158\/0008-5472.CAN-05-2805","article-title":"Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts","volume":"65","author":"Lee","year":"2005","journal-title":"Cancer Res."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Sunami, Y., Boker, V., and Kleeff, J. (2021). Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer. Cancers, 13.","DOI":"10.3390\/cancers13040697"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1002\/jcb.27681","article-title":"Extracellular matrix (ECM) stiffness and degradation as cancer drivers","volume":"120","author":"Najafi","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13046-019-1110-6","article-title":"Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology","volume":"38","author":"Nissen","year":"2019","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3389\/fcell.2018.00048","article-title":"Hyaluronan, Cancer-Associated Fibroblasts and the Tumor Microenvironment in Malignant Progression","volume":"6","author":"McCarthy","year":"2018","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1186\/s13046-016-0458-0","article-title":"Hyaluronan synthase 2 expressed by cancer-associated fibroblasts promotes oral cancer invasion","volume":"35","author":"Zhang","year":"2016","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Bellei, B., Caputo, S., Migliano, E., Lopez, G., Marcaccini, V., Cota, C., and Picardo, M. (2021). Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060597"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s42003-018-0180-x","article-title":"Mesothelial to mesenchyme transition as a major developmental and pathological player in trunk organs and their cavities","volume":"1","author":"Koopmans","year":"2018","journal-title":"Commun. Biol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/path.4281","article-title":"Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis","volume":"231","author":"Sandoval","year":"2013","journal-title":"J. Pathol."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Gordillo, C.H., Sandoval, P., Munoz-Hernandez, P., Pascual-Anton, L., Lopez-Cabrera, M., and Jimenez-Heffernan, J.A. (2020). Mesothelial-to-Mesenchymal Transition Contributes to the Generation of Carcinoma-Associated Fibroblasts in Locally Advanced Primary Colorectal Carcinomas. Cancers, 12.","DOI":"10.3390\/cancers12020499"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1002\/ijc.32193","article-title":"In search of definitions: Cancer-associated fibroblasts and their markers","volume":"146","author":"Nurmik","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1002\/cyto.a.23101","article-title":"The fibroblast surface markers FAP, anti-fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial-to-mesenchymal transition","volume":"93","author":"Kahounova","year":"2018","journal-title":"Cytometry. Part A J. Int. Soc. Anal. Cytol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/jnci\/djx121","article-title":"Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4","volume":"110","author":"Hanley","year":"2018","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1177\/1933719117734319","article-title":"Composition of the Stroma in the Human Endometrium and Endometriosis","volume":"25","author":"Konrad","year":"2018","journal-title":"Reprod. Sci."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/S0002-9440(10)61768-3","article-title":"Fibroblast heterogeneity: Existence of functionally distinct Thy 1(+) and Thy 1(-) human female reproductive tract fibroblasts","volume":"159","author":"Koumas","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Panayiotou, H., Orsi, N.M., Thygesen, H.H., Wright, A.I., Winder, M., Hutson, R., and Cummings, M. (2015). The prognostic significance of tumour-stroma ratio in endometrial carcinoma. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1981-7"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/modpathol.2013.131","article-title":"Stromal signatures in endometrioid endometrial carcinomas","volume":"27","author":"Espinosa","year":"2014","journal-title":"Mod. Pathol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"103269","DOI":"10.1016\/j.ebiom.2021.103269","article-title":"The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types","volume":"65","author":"Micke","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41573-018-0004-1","article-title":"Turning foes to friends: Targeting cancer-associated fibroblasts","volume":"18","author":"Chen","year":"2019","journal-title":"Nat. Reviews. Drug Discov."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41416-019-0509-3","article-title":"Cancer-associated fibroblasts-heroes or villains?","volume":"121","author":"Gieniec","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"Krisnawan, V.E., Stanley, J.A., Schwarz, J.K., and DeNardo, D.G. (2020). Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance. Cancers, 12.","DOI":"10.3390\/cancers12102916"},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Bhattacharjee, S., Hamberger, F., Ravichandra, A., Miller, M., Nair, A., Affo, S., Filliol, A., Chin, L., Savage, T.M., and Yin, D. (2021). Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J. Clin. Investig., 131.","DOI":"10.1172\/JCI146987"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/6\/1519\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:37:20Z","timestamp":1760135840000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/6\/1519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,16]]},"references-count":167,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cancers14061519"],"URL":"https:\/\/doi.org\/10.3390\/cancers14061519","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,16]]}}}