{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T12:41:35Z","timestamp":1779108095936,"version":"3.51.4"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Metastasis to mediastinal lymph nodes signifies an advanced stage of non-small cell lung cancer (NSCLC) and presents significant clinical challenges. Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) play a crucial role in tumor progression by promoting growth and invasion. However, the specific contributions of lung CAFs to mediastinal lymph node metastasis in NSCLC remain poorly understood. Moreover, no therapeutics currently target CAFs to combat mediastinal lymph node metastasis in NSCLC. This study aims to elucidate the precise roles of CAFs in these complex processes and to investigate innovative therapeutic strategies that target CAFs to suppress metastasis to mediastinal lymph nodes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Normal human lung fibroblasts (MRC-5) were directly co-cultured with NSCLC cell lines (H358 and HCC827) to generate lung CAFs. These activated CAFs were identified using immunofluorescence, flow cytometry, and Western blotting. To model human mediastinal lymph node metastasis, orthotopic xenograft (OX) models were established by intrathoracically injecting NSCLC cells into the left lung of mice, either alone or in combination with lung CAFs. The viability of cancer cells and lung CAFs post-treatment with ABT-199, a Bcl-2 inhibitor, was evaluated using MTT assays. The therapeutic efficacy of ABT-199 was further assessed through oral gavage in OX models, focusing on its potential to prevent metastasis to mediastinal lymph nodes. Tumor growth was monitored longitudinally using micro-computed tomography (CT), and treatment response was evaluated in accordance with RECIST 1.1 criteria. Primary tumors and mediastinal lymph node metastases were analyzed using hematoxylin and eosin (H&amp;amp;E) staining for general morphology, supplemented by immunohistochemistry\/immunofluorescence to detect specific protein markers. Fibrillar collagen deposition within the TME was quantified using picrosirius red staining (PRS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Activation of \u03b1-SMA, accompanied by a significant increase in Col 1A1 expression in MRC-5 cells, was successfully induced through a direct 14-day co-culture with NSCLC cell lines. Histological analysis revealed increased fibrotic tissue formation, enhanced fibrillar collagen deposition, peritumoral lymphangiogenesis, and mediastinal lymph node metastasis in CAFs-enriched orthotopic xenograft (OX) tumors compared to CAFs-devoid OX tumors. The viability of lung CAFs was dose-dependently inhibited by ABT-199 <jats:italic>in vitro<\/jats:italic>. A two-week treatment with ABT-199 (100mg\/kg) led to a significant reduction in lung CAFs and lymphangiogenesis in the CAFs-enriched OX model. Furthermore, an eight-week treatment with ABT-199 (100mg\/kg) significantly reduced fibrillar collagen deposition and inhibited the number of metastases to mediastinal lymph nodes in both CAFs-devoid and CAFs-enriched OX models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In NSCLC, cancer cells induce the differentiation of resident normal lung fibroblasts into lung CAFs. These CAFs secrete excessive collagens within the TME, thereby promoting tumor lymphangiogenesis and facilitating metastasis to mediastinal lymph nodes. Our findings, based on modified OX models, suggest that targeting lung CAFs could effectively attenuate lymphatic dissemination in NSCLC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2025.1597585","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T05:21:14Z","timestamp":1749705674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Lung cancer-associated fibroblasts-mediated collagen deposition drives mediastinal lymph node metastasis in non-small cell lung cancer"],"prefix":"10.3389","volume":"15","author":[{"given":"Caoyang","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqian","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frankie Chi Fat","family":"Ko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sze Kwan","family":"Lam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James Chung Man","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e31827457db","article-title":"Mediastinal lymph node examination and survival in resected early-stage non-small-cell lung cancer in the surveillance, epidemiology, and end results database","volume":"7","author":"Osarogiagbon","year":"2012","journal-title":"J Thorac Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.04.016","article-title":"Prognostic impact of the number of metastatic lymph nodes on the eighth edition of the TNM classification of NSCLC","volume":"14","author":"Katsumata","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B3","first-page":"98","article-title":"The distribution of secondary growths in cancer of the breast","volume":"8","author":"Paget","year":"1989","journal-title":"Cancer Metast Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1172\/JCI72589","article-title":"Multifocal epithelial tumors and field cancerization: stroma as a primary determinant","volume":"124","author":"Dotto","year":"2014","journal-title":"J Clin Invest"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.016","article-title":"Fibroblasts in cancer: Unity in heterogeneity","volume":"186","author":"Chhabra","year":"2023","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.addr.2020.08.001","article-title":"Stromal regulation of tumor-associated lymphatics","author":"Munir","year":"2020","journal-title":"Adv Drug Delivery Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0096-5","article-title":"Phenotype molding of stromal cells in the lung tumor microenvironment","volume":"24","author":"Lambrechts","year":"2018","journal-title":"Nat Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2285","DOI":"10.1038\/s41467-020-16164-1","article-title":"Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma","volume":"11","author":"Kim","year":"2020","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.12.021","article-title":"Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer","author":"Cords","year":"2024","journal-title":"Cancer Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-1097","article-title":"Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo","volume":"72","author":"Vicent","year":"2012","journal-title":"Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31953","article-title":"Cancer-associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma","volume":"144","author":"Kashima","year":"2019","journal-title":"Int J Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-3158","article-title":"NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors","volume":"80","author":"Ford","year":"2020","journal-title":"Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2013.02.007","article-title":"Mouse models for studying angiogenesis and lymphangiogenesis in cancer","volume":"7","author":"Eklund","year":"2013","journal-title":"Mol Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"14 27 11","DOI":"10.1002\/0471141755.ph1427s62","article-title":"Utility and applications of orthotopic models of human non-small cell lung cancer (NSCLC) for the evaluation of novel and emerging cancer therapeutics","volume":"62","author":"Justilien","year":"2013","journal-title":"Curr Protoc Pharmacol"},{"key":"B16","article-title":"Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice","volume":"9","author":"Onn","year":"2003","journal-title":"Clin Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1097\/JTO.0000000000000367","article-title":"In the hunt for therapeutic targets: mimicking the growth, metastasis, and stromal associations of early-stage lung cancer using a novel orthotopic animal model","volume":"10","author":"Weiss","year":"2015","journal-title":"J Thorac Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/jcb.240560103","article-title":"Metastatic models of human cancer xenografted in the nude mouse: the importance of orthotopic transplantation","volume":"56","author":"Kubota","year":"1994","journal-title":"J Cell Biochem"},{"key":"B19","article-title":"SCID mouse lymphogenous metastatic model of human lung cancer constructed using orthotopic inoculation of cancer cells","volume":"20","author":"Miyoshi","year":"2000","journal-title":"Anticancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/jnci\/djac178","article-title":"Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features","volume":"115","author":"Pellinen","year":"2023","journal-title":"J Natl Cancer Inst"},{"key":"B22","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1038\/s41571-021-00546-5","article-title":"Clinical and therapeutic relevance of cancer-associated fibroblasts","volume":"18","author":"Chen","year":"2021","journal-title":"Nat Rev Clin Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20140692","article-title":"Fibroblast heterogeneity in the cancer wound","volume":"211","author":"Ohlund","year":"2014","journal-title":"J Exp Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/s43018-022-00411-z","article-title":"Cancer-associated fibroblasts in the single-cell era","volume":"3","author":"Lavie","year":"2022","journal-title":"Nat Cancer"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.7150\/jca.11187","article-title":"The effect of tumor microenvironment on autophagy and sensitivity to targeted therapy in EGFR-mutated lung adenocarcinoma","volume":"6","author":"Li","year":"2015","journal-title":"J Cancer"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.3892\/or.2018.6598","article-title":"Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models","volume":"40","author":"Lam","year":"2018","journal-title":"Oncol Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3791\/53904","article-title":"Using micro-computed tomography for the assessment of tumor development and follow-up of response to treatment in a mouse model of lung cancer","author":"Hegab","year":"2016","journal-title":"J Vis Exp"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur J Cancer"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2004.019174","article-title":"LYVE-1 immunohistochemical assessment of lymphangiogenesis in endometrial and lung cancer","volume":"58","author":"Koukourakis","year":"2005","journal-title":"J Clin Pathol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jtho.2018.12.005","article-title":"Best practices recommendations for diagnostic immunohistochemistry in lung cancer","volume":"14","author":"Yatabe","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2021.100916","article-title":"A simple method for quantitating confocal fluorescent images","volume":"25","author":"Shihan","year":"2021","journal-title":"Biochem Biophys Rep"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4753","DOI":"10.1016\/j.cell.2021.07.020","article-title":"Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy","volume":"184","author":"Koikawa","year":"2021","journal-title":"Cell"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3048","article-title":"ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets","volume":"19","author":"Souers","year":"2013","journal-title":"Nat Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.645846","article-title":"Therapeutic effects of the bcl-2 inhibitor on bleomycin-induced pulmonary fibrosis in mice","volume":"8","author":"He","year":"2021","journal-title":"Front Mol Biosci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/84643","article-title":"Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis","volume":"7","author":"Skobe","year":"2001","journal-title":"Nat Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.12.026","article-title":"VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium","volume":"21","author":"Karnezis","year":"2012","journal-title":"Cancer Cell"},{"key":"B37","doi-asserted-by":"publisher","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"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-15-0307","article-title":"Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma","volume":"14","author":"Pankova","year":"2016","journal-title":"Mol Cancer Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00329-7","article-title":"The matrix in cancer","volume":"21","author":"Cox","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2019.07.020","article-title":"Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer","volume":"135","author":"Alcaraz","year":"2019","journal-title":"Lung Cancer"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0727","article-title":"Maintaining tumor heterogeneity in patient-derived tumor xenografts","volume":"75","author":"Cassidy","year":"2015","journal-title":"Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2019.03.009","article-title":"Characterization of distinct populations of carcinoma-associated fibroblasts from non-small cell lung carcinoma reveals a role for ST8SIA2 in cancer cell invasion","volume":"21","author":"Hao","year":"2019","journal-title":"Neoplasia"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01488","article-title":"Reciprocal interplay between fibrillar collagens and collagen-binding integrins: implications in cancer progression and metastasis","volume":"10","author":"Bourgot","year":"2020","journal-title":"Front Oncol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3677","article-title":"Lymphangiogenesis and lymphatic vessel remodelling in cancer","volume":"14","author":"Stacker","year":"2014","journal-title":"Nat Rev Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2010.08.001","article-title":"Interaction between the extracellular matrix and lymphatics: consequences for lymphangiogenesis and lymphatic function","volume":"29","author":"Wiig","year":"2010","journal-title":"Matrix Biol"},{"key":"B46","doi-asserted-by":"publisher","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":"B47","doi-asserted-by":"publisher","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 U.S.A"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal3765","article-title":"Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis","volume":"9","author":"Lagares","year":"2017","journal-title":"Sci Transl Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.03.027","article-title":"Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members","volume":"9","author":"Certo","year":"2006","journal-title":"Cancer Cell"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.307","article-title":"Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases","volume":"30","author":"Strasser","year":"2011","journal-title":"EMBO J"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.563064","article-title":"Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis","volume":"289","author":"Rizvi","year":"2014","journal-title":"J Biol Chem"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-019-02587-9","article-title":"Prognostic significance of combining immunohistochemical markers for cancer-associated fibroblasts in lung adenocarcinoma tissue","volume":"475","author":"Inoue","year":"2019","journal-title":"Virchows Arch"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014506108","article-title":"Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer","volume":"108","author":"Navab","year":"2011","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2286","article-title":"Modeling and predicting clinical efficacy for drugs targeting the tumor milieu","volume":"30","author":"Singh","year":"2012","journal-title":"Nat Biotechnol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41421-020-00200-x","article-title":"Single-cell transcriptome atlas of lung adenocarcinoma featured with ground glass nodules","volume":"6","author":"Lu","year":"2020","journal-title":"Cell Discov"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-019-09966-1","article-title":"The extracellular matrix in tumor progression and metastasis","volume":"36","author":"Eble","year":"2019","journal-title":"Clin Exp Metast"},{"key":"B58","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/s41571-018-0134-8","article-title":"A framework for the development of effective anti-metastatic agents","volume":"16","author":"Anderson","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1126\/science.1067100","article-title":"Matrix metalloproteinase inhibitors and cancer: trials and tribulations","volume":"295","author":"Coussens","year":"2002","journal-title":"Science"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.62.8719","article-title":"Randomized phase ib\/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer","volume":"33","author":"Catenacci","year":"2015","journal-title":"J Clin Oncol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1269","article-title":"Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma","volume":"20","author":"Kim","year":"2014","journal-title":"Clin Cancer Res"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1411679111","article-title":"Stromal response to Hedgehog signaling restrains pancreatic cancer progression","volume":"111","author":"Lee","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.09.010","article-title":"Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling","volume":"9","author":"Mathew","year":"2014","journal-title":"Cell Rep"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.04.021","article-title":"Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma","volume":"25","author":"Rhim","year":"2014","journal-title":"Cancer Cell"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.04.005","article-title":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","volume":"25","author":"Ozdemir","year":"2014","journal-title":"Cancer Cell"},{"key":"B66","doi-asserted-by":"publisher","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":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2022.166403","article-title":"Identifying and targeting the molecular signature of smooth muscle cells undergoing early vascular ageing","volume":"1868","author":"Riches-Suman","year":"2022","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B68","doi-asserted-by":"publisher","first-page":"6619","DOI":"10.1038\/s41467-022-34395-2","article-title":"Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment","volume":"13","author":"Luo","year":"2022","journal-title":"Nat Commun"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0495-5","article-title":"The role of mouse tumour models in the discovery and development of anticancer drugs","volume":"121","author":"Ireson","year":"2019","journal-title":"Br J Cancer"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.015","article-title":"Activated fibroblasts in cancer: Perspectives and challenges","volume":"41","author":"Caligiuri","year":"2023","journal-title":"Cancer Cell"},{"key":"B71","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12943-021-01428-1","article-title":"Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives","volume":"20","author":"Mao","year":"2021","journal-title":"Mol Cancer"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1597585\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T05:21:15Z","timestamp":1749705675000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1597585\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":71,"alternative-id":["10.3389\/fonc.2025.1597585"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1597585","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,12]]},"article-number":"1597585"}}