Role of cancer‑associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non‑small cell lung cancer (Review)

Molina JR, Yang P, Cassivi SD, Schild SE and Adjei AA: Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 83:584–594. 2008. View Article : Google Scholar : PubMed/NCBI

Rotow J and Bivona TG: Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer. 17:637–658. 2017. View Article : Google Scholar : PubMed/NCBI

Arbour KC and Riely GJ: Systemic therapy for locally advanced and metastatic non-small cell lung cancer: A review. JAMA. 322:764–774. 2019. View Article : Google Scholar : PubMed/NCBI

Holohan C, Schaeybroeck SV, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI

Salem A, Asselin MC, Reymen B, Jackson A, Lambin P, West CM, OConnor JP and Faivre-Finn C: Targeting hypoxia to improve non-small cell lung cancer outcome. J Natl Cancer Inst. 110:2018. View Article : Google Scholar : PubMed/NCBI

Fischer C, Leithner K, Wohlkoenig C, Quehenberger F, Bertsch A, Olschewski A, Olschewski H and Hrzenjak A: Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization. Mol Cancer. 14:42015. View Article : Google Scholar : PubMed/NCBI

Navab R, Strumpf D, To C, Pasko E, Kim KS, Park CJ, Hai J, Liu J, Jonkman J, Barczyk M, et al: Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer. Oncogene. 35:1899–1908. 2016. View Article : Google Scholar : PubMed/NCBI

Su S, Chen J, Yao H, Liu J, Yu S, Lao L, Wang M, Luo M, Xing Y, Chen F, et al: CD10⁺GPR77⁺ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell. 172:841–856.e16. 2018. View Article : Google Scholar : PubMed/NCBI

Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, Watanabe G, Kayano Y, Nishioka Y, Sone S and Yano S: Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res. 15:6630–6638. 2009. View Article : Google Scholar : PubMed/NCBI

Radisky DC: Fibroblasts act as co-conspirators for chemotherapy resistance. Cancer Biol Ther. 7:1348–1349. 2008. View Article : Google Scholar : PubMed/NCBI

Ishii G, Ochiai A and Neri S: Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev. 99:186–196. 2016. View Article : Google Scholar : PubMed/NCBI

Chen WJ, Ho CC, Chang YL, Chen HY, Lin CA, Ling TY, Yu SL, Yuan SS, Chen YJ, Lin CY, et al: Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun. 5:34722014. View Article : Google Scholar : PubMed/NCBI

Leung CS, Yeung TL, Yip KP, Wong KK, Ho SY, Mangala LS, Sood AK, Lopez-Berestein G, Sheng J, Wong ST, et al: Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance. J Clin Invest. 128:589–606. 2017. View Article : Google Scholar : PubMed/NCBI

New J, Arnold L, Ananth M, Alvi S, Thornton M, Werner L, Tawfik O, Dai H, Shnayder Y, Kakarala K, et al: Secretory autophagy in cancer-associated fibroblasts promotes head and neck cancer progression and offers a novel therapeutic target. Cancer Res. 77:6679–6691. 2017. View Article : Google Scholar : PubMed/NCBI

Allaoui R, Bergenfelz C, Mohlin S, Hagerling C, Salari K, Werb Z, Anderson RL, Ethier SP, Jirström K, Påhlman S, et al: Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat Commun. 7:130502016. View Article : Google Scholar : PubMed/NCBI

Sun Y, Wang R, Qiao M, Xu Y, Guan W and Wang L: Cancer associated fibroblasts tailored tumor microenvironment of therapy resistance in gastrointestinal cancers. J Cell Physiol. 233:6359–6369. 2018. View Article : Google Scholar : PubMed/NCBI

von Ahrens D, Bhagat TD, Nagrath D, Maitra A and Verma A: The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol. 10:762017. View Article : Google Scholar : PubMed/NCBI

Ren J, Ding L, Zhang D, Shi G, Xu Q, Shen S, Wang Y, Wang T and Hou Y: Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics. 8:3932–3948. 2018. View Article : Google Scholar : PubMed/NCBI

Ying L, Zhu Z, Xu Z, He T, Li E, Guo Z, Liu F, Jiang C and Wang Q: Cancer associated fibroblast-derived hepatocyte growth factor inhibits the paclitaxel-induced apoptosis of lung cancer A549 cells by up-regulating the PI3K/Akt and GRP78 signaling on a microfluidic platform. PLoS One. 10:e01295932015. View Article : Google Scholar : PubMed/NCBI

Shan T, Chen S, Chen X, Lin WR, Li W, Ma J, Wu T, Ji H, Li Y, Cui X and Kang Y: Prometastatic mechanisms of CAF-mediated EMT regulation in pancreatic cancer cells. Int J Oncol. 50:121–128. 2017. View Article : Google Scholar : PubMed/NCBI

Lai D, Ma L and Wang F: Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells. Int J Oncol. 41:541–550. 2012. View Article : Google Scholar : PubMed/NCBI

Foster DS, Jones RE, Ransom RC, Longaker MT and Norton JA: The evolving relationship of wound healing and tumor stroma. JCI Insight. 3:e999112018. View Article : Google Scholar

Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, Onder TT, Wang ZC, Richardson AL, Weinberg RA and Orimo A: Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA. 107:20009–20014. 2010. View Article : Google Scholar : PubMed/NCBI

Louault K, Li R and DeClerck YA: Cancer-associated fibroblasts: Understanding their heterogeneity. Cancers (Basel). 12:31082020. View Article : Google Scholar

An Y, Liu F, Chen Y and Yang Q: Crosstalk between cancer-associated fibroblasts and immune cells in cancer. J Cell Mol Med. 24:13–24. 2020. View Article : Google Scholar : PubMed/NCBI

Borriello L, Nakata R, Sheard MA, Fernandez GE, Sposto R, Malvar J, Blavier L, Shimada H, Asgharzadeh S, Seeger RC and DeClerck YA: Cancer-associated fibroblasts share characteristics and protumorigenic activity with mesenchymal stromal cells. Cancer Res. 77:5142–5157. 2017. View Article : Google Scholar : PubMed/NCBI

Koliaraki V, Pallangyo CK, Greten FR and Kollias G: Mesenchymal cells in colon cancer. Gastroenterology. 152:964–979. 2017. View Article : Google Scholar : PubMed/NCBI

Nair N, Calle AS, Zahra MH, Prieto-Vila M, Oo AKK, Hurley L, Vaidyanath A, Seno A, Masuda J, Iwasaki Y, et al: A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Sci Rep. 7:68382017. View Article : Google Scholar : PubMed/NCBI

Zeisberg EM, Potenta S, Xie L, Zeisberg M and Kalluri R: Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67:10123–10128. 2007. View Article : Google Scholar : PubMed/NCBI

Iwano M, Plieth D, Danoff TM, Xue C, Okada H and Neilson EG: Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 110:341–350. 2002. View Article : Google Scholar : PubMed/NCBI

McDonald LT, Russell DL, Kelly RR, Xiong Y, Motamarry A, Patel RK, Jones JA, Watson PM, Turner DP, Watson DK, et al: Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. Neoplasia. 17:434–448. 2015. View Article : Google Scholar : PubMed/NCBI

Gascard P and Tlsty TD: Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy. Genes Dev. 30:1002–1019. 2016. View Article : Google Scholar : PubMed/NCBI

Hoshino A, Ishii G, Ito T, Aoyagi K, Ohtaki Y, Nagai K, Sasaki H and Ochiai A: Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: Podoplanin in fibroblast functions for tumor progression. Cancer Res. 71:4769–4779. 2011. View Article : Google Scholar : PubMed/NCBI

Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, Hishida T, Nishimura M, Yoshida J, Suzuki K and Ochiai A: Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 123:1053–1059. 2008. View Article : Google Scholar : PubMed/NCBI

Schoppmann SF, Berghoff A, Dinhof C, Jakesz R, Gnant M, Dubsky P, Jesch B, Heinzl H and Birner P: Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer. Breast Cancer Res Treat. 134:237–244. 2012. View Article : Google Scholar : PubMed/NCBI

Ono S, Ishii G, Nagai K, Takuwa T, Yoshida J, Nishimura M, Hishida T, Aokage K, Fujii S, Ikeda N, Ochiai A, et al: Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: Usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest. 143:963–970. 2013. View Article : Google Scholar : PubMed/NCBI

Heldin CH: Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 11:972013. View Article : Google Scholar : PubMed/NCBI

Hsia LT, Ashley N, Ouaret D, Wang LM, Wilding J and Bodmer WF: Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers. Proc Natl Acad Sci USA. 113:E2162–E2171. 2016. View Article : Google Scholar : PubMed/NCBI

Herrera M, Islam AB, Herrera A, Martín P, García V, Silva J, Garcia JM, Salas C, Casal I, de Herreros AG, et al: Functional heterogeneity of cancer-associated fibroblasts from human colon tumors shows specific prognostic gene expression signature. Clin Cancer Res. 19:5914–5926. 2013. View Article : Google Scholar : PubMed/NCBI

Nurmik M, Ullmann P, Rodriguez F, Haan S and Letellier E: In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer. 146:895–905. 2020. View Article : Google Scholar : PubMed/NCBI

Park SY, Kim HM and Koo JS: Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Res Treat. 149:727–741. 2015. View Article : Google Scholar : PubMed/NCBI

Patel AK, Vipparthi K, Thatikonda V, Arun I, Bhattacharjee S, Sharan R, Arun P and Singh S: A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma. Oncogenesis. 7:782018. View Article : Google Scholar : PubMed/NCBI

Öhlund D, Elyada E and Tuveson D: Fibroblast heterogeneity in the cancer wound. J Cell Biol. 211:1503–1523. 2014.

Brennen WN, Isaacs JT and Denmeade SR: Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther. 11:257–266. 2012. View Article : Google Scholar : PubMed/NCBI

Huber MA, Kraut N, Park JE, Schubert RD, Rettig WJ, Peter RU and Garin-Chesa P: Fibroblast activation protein: Differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors. J Investig Dermatol. 120:182–188. 2003. View Article : Google Scholar : PubMed/NCBI

Berdiel-Acer M, Sanz-Pamplona R, Calon A, Cuadras D, Berenguer A, Sanjuan X, Paules MJ, Salazar R, Moreno V, Batlle E, et al: Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information. Mol Oncol. 8:1290–1305. 2014. View Article : Google Scholar : PubMed/NCBI

Fearon DT: The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2:187–193. 2014. View Article : Google Scholar : PubMed/NCBI

Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al: Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 110:20212–20217. 2013. View Article : Google Scholar : PubMed/NCBI

Brennen WN, Rosen DM, Wang H, Isaacs JT and Denmeade SR: Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst. 104:1320–1334. 2012. View Article : Google Scholar : PubMed/NCBI

Yoshida GJ: Regulation of heterogeneous cancer-associated fibroblasts: The molecular pathology of activated signaling pathways. J Exp Clin Cancer Res. 39:1122020. View Article : Google Scholar : PubMed/NCBI

Raghavan S, Snyder CS, Wang A, McLean K, Zamarin D, Buckanovich RJ and Mehta G: Carcinoma-associated mesenchymal stem cells promote chemoresistance in ovarian cancer stem cells via PDGF signaling. Cancers (Basel). 12:20632020. View Article : Google Scholar

Rizvi S, Mertens JC, Bronk SF, Hirsova P, Dai H, Roberts LR, Kaufmann SH and Gores GJ: Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis. J Biol Chem. 289:22835–22849. 2014. View Article : Google Scholar : PubMed/NCBI

Raz Y, Cohen N, Shani O, Bell RE, Novitskiy SV, Abramovitz L, Levy C, Milyavsky M, Leider-Trejo L, Moses HL, et al: Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J Exp Med. 215:3075–3093. 2018. View Article : Google Scholar : PubMed/NCBI

Ishibashi M, Neri S, Hashimoto H, Miyashita T, Yoshida T, Nakamura Y, Udagawa H, Kirita K, Matsumoto S, Umemura S, et al: CD200-positive cancer associated fibroblasts augment the sensitivity of epidermal growth factor receptor mutation-positive lung adenocarcinomas to EGFR tyrosine kinase inhibitors. Sci Rep. 7:466622017. View Article : Google Scholar : PubMed/NCBI

Mizutani Y, Kobayashi H, Iida T, Asai N, Masamune A, Hara A, Esaki N, Ushida K, Mii S, Shiraki Y, et al: Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Res. 79:5367–5381. 2019. View Article : Google Scholar : PubMed/NCBI

Alcaraz J, Carrasco JL, Millares L, Luis IC, Fernández-Porras FJ, Martínez-Romero A, Diaz-Valdivia N, De Cos JS, Rami-Porta R, Seijo L, et al: Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer. Lung Cancer. 135:151–160. 2019. View Article : Google Scholar : PubMed/NCBI

Schulze AB, Schmidt LH, Heitkötter B, Huss S, Mohr M, Marra A, Hillejan L, Görlich D, Barth PJ, Rehkämper J and Evers G: Prognostic impact of CD34 and SMA in cancer-associated fibroblasts in stage I–III NSCLC. Thorac Cancer. 11:120–129. 2020. View Article : Google Scholar : PubMed/NCBI

Hao J, Zeltz C, Pintilie M, Li Q, Sakashita S, Wang T, Cabanero M, Martins-Filho SN, Wang DY, Pasko E, et al: Characterization of distinct populations of carcinoma-associated fibroblasts from non-small cell lung carcinoma reveals a role for ST8SIA2 in cancer cell invasion. Neoplasia. 21:482–493. 2019. View Article : Google Scholar : PubMed/NCBI

Kilvaer TK, Khanehkenari MR, Hellevik T, Al-Saad S, Paulsen EE, Bremnes RM, Busund LT, Donnem T and Martinez IZ: Cancer associated fibroblasts in stage I–IIIA NSCLC: Prognostic impact and their correlations with tumor molecular markers. PLoS One. 10:e01349652015. View Article : Google Scholar : PubMed/NCBI

Cohen SJ, Alpaugh RK, Palazzo I, Meropol NJ, Rogatko A, Xu Z, Hoffman JP, Weiner LM and Cheng JD: Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas. 37:154–158. 2008. View Article : Google Scholar : PubMed/NCBI

Yoshida T, Ishii G, Goto K, Neri S, Hashimoto H, Yoh K, Niho S, Umemura S, Matsumoto S, Ohmatsu H, et al: Podoplanin-positive cancer-associated fibroblasts in the tumor microenvironment induce primary resistance to EGFR-TKIs in lung adenocarcinoma with EGFR mutation. Clin Cancer Res. 21:642–651. 2015. View Article : Google Scholar : PubMed/NCBI

Neri S, Ishii G, Hashimoto H, Kuwata T, Nagai K, Date H and Ochiai A: Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma. Int J Cancer. 137:784–796. 2015. View Article : Google Scholar : PubMed/NCBI

Edlund K, Lindskog C, Saito A, Berglund A, Pontén F Göransson-Kultima H, Isaksson A, Jirström K, Planck M, Johansson L, et al: CD99 is a novel prognostic stromal marker in non-small cell lung cancer. Int J Cancer. 131:2264–2273. 2012. View Article : Google Scholar : PubMed/NCBI

Mitchell MI and Engelbrecht AM: Metabolic hijacking: A survival strategy cancer cells exploit? Crit Rev Oncol Hematol. 109:1–8. 2017. View Article : Google Scholar : PubMed/NCBI

Suzuki A, Puri S, Leland P, Puri A, Moudgil T, Fox BA, Puri RK and Joshi BH: Subcellular compartmentalization of PKM2 identifies anti-PKM2 therapy response in vitro and in vivo mouse model of human non-small-cell lung cancer. PLoS One. 14:e02171312019. View Article : Google Scholar : PubMed/NCBI

Wang D, Zhao C, Xu F, Zhang A, Jin M, Zhang K, Liu L, Hua Q, Zhao J, Liu J, et al: Cisplatin-resistant NSCLC cells induced by hypoxia transmit resistance to sensitive cells through exosomal PKM2. Theranostics. 11:2860–2875. 2021. View Article : Google Scholar : PubMed/NCBI

Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI

Thiery JP: Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 15:740–746. 2003. View Article : Google Scholar : PubMed/NCBI

Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ and Choi W: Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69:5820–5828. 2009. View Article : Google Scholar : PubMed/NCBI

McConkey DJ, Choi W, Marquis L, Martin F, Williams MB, Shah J, Svatek R, Das A, Adam L, Kamat A, et al: Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev. 28:335–344. 2009. View Article : Google Scholar : PubMed/NCBI

Mallini P, Lennard T, Kirby J and Meeson A: Epithelial-to-mesenchymal transition: What is the impact on breast cancer stem cells and drug resistance. Cancer Treat Rev. 40:341–348. 2014. View Article : Google Scholar : PubMed/NCBI

Ye Q, Su L, Chen D, Zheng W and Liu Y: Astragaloside IV Induced miR-134 expression reduces EMT and increases chemotherapeutic sensitivity by suppressing CREB1 signaling in colorectal cancer cell line SW-480. Cell Physiol Biochem. 43:1617–1626. 2017. View Article : Google Scholar : PubMed/NCBI

Ding X, Ji J, Jiang J, Cai Q, Wang C, Shi M, Yu Y, Zhu Z and Zhang J: HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis. Cell Death Dis. 9:8672018. View Article : Google Scholar : PubMed/NCBI

Shintani Y, Fujiwara A, Kimura T, Kawamura T, Funaki S, Minami M and Okumura M: IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial-mesenchymal transition signaling. J Thorac Oncol. 11:1482–1492. 2016. View Article : Google Scholar : PubMed/NCBI

Gherardi E, Birchmeier W, Birchmeier C and Vande Woude G: Targeting MET in cancer: Rationale and progress. Nat Rev Cancer. 12:89–103. 2012. View Article : Google Scholar : PubMed/NCBI

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA and Dick JE: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 367:645–648. 1994. View Article : Google Scholar : PubMed/NCBI

Leon G, MacDonagh L, Finn SP, Cuffe S and Barr MP: Cancer stem cells in drug resistant lung cancer: Targeting cell surface markers and signaling pathways. Pharmacol Ther. 158:71–90. 2016. View Article : Google Scholar : PubMed/NCBI

Shafee N, Smith CR, Wei S, Kim Y, Mills GB, Hortobagyi GN, Stanbridge EJ and Lee EY: Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Res. 68:3243–3250. 2008. View Article : Google Scholar : PubMed/NCBI

Schöning JP, Monteiro M and Gu W: Drug resistance and cancer stem cells: The shared but distinct roles of hypoxia-inducible factors HIF1α and HIF2α. Clin Exp Pharmacol Physiol. 44:153–161. 2017. View Article : Google Scholar : PubMed/NCBI

Chen Z, Shi T, Zhang L, Zhu P, Deng M, Huang C, Hu T, Jiang L and Li J: Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 370:153–164. 2016. View Article : Google Scholar : PubMed/NCBI

Kinugasa Y, Matsui T and Takakura N: CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment. Stem Cells. 32:145–156. 2014. View Article : Google Scholar : PubMed/NCBI

Najafi M, Farhood B and Mortezaee K: Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 120:2782–2790. 2019. View Article : Google Scholar : PubMed/NCBI

Keeratichamroen S, Lirdprapamongkol K and Svasti J: Mechanism of ECM-induced dormancy and chemoresistance in A549 human lung carcinoma cells. Oncol Rep. 39:1765–1774. 2018.PubMed/NCBI

De Rosa V, Iommelli F, Monti M, Fonti R, Votta G, Stoppelli MP and Del Vecchio S: Reversal of warburg effect and reactivation of oxidative phosphorylation by differential inhibition of EGFR signaling pathways in non-small cell lung cancer. Clin Cancer Res. 21:5110–5120. 2015. View Article : Google Scholar : PubMed/NCBI

Iderzorig T, Kellen J, Osude C, Singh S, Woodman JA, Garcia C and Puri N: Comparison of EMT mediated tyrosine kinase inhibitor resistance in NSCLC. Biochem Biophys Res Commun. 496:770–777. 2018. View Article : Google Scholar : PubMed/NCBI

Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, Kim CH and Lee JC: Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer. 63:219–226. 2009. View Article : Google Scholar : PubMed/NCBI

Yoshida T, Song L, Bai Y, Kinose F, Li J, Ohaegbulam KC, Muñoz-Antonia T, Qu X, Eschrich S, Uramoto H, et al: ZEB1 mediates acquired resistance to the epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer. PLoS One. 11:e01473442016. View Article : Google Scholar : PubMed/NCBI

You J, Li M, Cao LM, Gu QH, Deng PB, Tan Y and Hu CP: Snail1-dependent cancer-associated fibroblasts induce epithelial-mesenchymal transition in lung cancer cells via exosomes. QJM. 112:581–590. 2019. View Article : Google Scholar : PubMed/NCBI

Yi Y, Zeng S, Wang Z, Wu M, Ma Y, Ye X, Zhang B and Liu H: Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling. Biochim Biophys Acta Mol Basis Dis. 1864:793–803. 2018. View Article : Google Scholar : PubMed/NCBI

Zhou J, Wang J, Zeng Y, Zhang X, Hu Q, Zheng J, Chen B, Xie B and Zhang WM: Implication of epithelial-mesenchymal transition in IGF1R-induced resistance to EGFR-TKIs in advanced non-small cell lung cancer. Oncotarget. 6:44332–44345. 2015. View Article : Google Scholar : PubMed/NCBI

Choe C, Shin YS, Kim C, Choi SJ, Lee J, Kim SY, Cho YB and Kim J: Crosstalk with cancer-associated fibroblasts induces resistance of non-small cell lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibition. Oncol Targets Ther. 8:3665–3678. 2015. View Article : Google Scholar

Della Corte CM, Bellevicine C, Vicidomini G, Vitagliano D, Malapelle U, Accardo M, Fabozzi A, Fiorelli A, Fasano M, Papaccio F, et al: SMO gene amplification and activation of the hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer. Clin Cancer Res. 21:4686–4697. 2015. View Article : Google Scholar : PubMed/NCBI

Murakami A, Takahashi F, Nurwidya F, Kobayashi I, Minakata K, Hashimoto M, Nara T, Kato M, Tajima K, Shimada N, et al: Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor. PLoS One. 9:e864592014. View Article : Google Scholar : PubMed/NCBI

Petrova V, Annicchiarico-petruzzelli M, Melino G and Amelio I: The hypoxic tumour microenvironment. Oncogenesis. 7:102018. View Article : Google Scholar : PubMed/NCBI

Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A, et al: Inhibition of ABCB1 overcomes cancer stem cell-like properties and acquired resistance to MET inhibitors in non-small cell lung cancer. Mol Cancer Ther. 14:2433–2440. 2015. View Article : Google Scholar : PubMed/NCBI

Zhang Q, Yang J, Bai J and Ren J: Reverse of non-small cell lung cancer drug resistance induced by cancer-associated fibroblasts via a paracrine pathway. Cancer Sci. 109:944–955. 2018. View Article : Google Scholar : PubMed/NCBI

Li F, Mei H, Gao Y, Xie X, Nie H, Li T, Zhang H and Jia L: Co-delivery of oxygen and erlotinib by aptamer-modified liposomal complexes to reverse hypoxia-induced drug resistance in lung cancer. Biomaterials. 145:56–71. 2017. View Article : Google Scholar : PubMed/NCBI

Bridgford JL, Xie SC, Cobbold SA, Pasaje CFA, Herrmann S, Yang T, Gillett DL, Dick LR, Ralph SA, Dogovski C, et al: Artemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome. Nat Commun. 9:38012018. View Article : Google Scholar : PubMed/NCBI

Chou CW, Wang CC, Wu CP, Lin YJ, Lee YC, Cheng YW and Hsieh CH: Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1. Neuro Oncol. 14:1227–1238. 2012. View Article : Google Scholar : PubMed/NCBI

Raju S, Joseph R and Sehgal S: Review of checkpoint immunotherapy for the management of non-small cell lung cancer. Immunotargets Ther. 7:63–75. 2018. View Article : Google Scholar : PubMed/NCBI

Kloten V, Lampignano R, Krahn T and Schlange T: Circulating tumor Cell PD-L1 expression as biomarker for therapeutic efficacy of immune checkpoint inhibition in NSCLC. Cells. 8:8092019. View Article : Google Scholar

Pu X, Wu L, Su D, Mao W and Fang B: Immunotherapy for non-small cell lung cancers: Biomarkers for predicting responses and strategies to overcome resistance. BMC Cancer. 18:10822018. View Article : Google Scholar : PubMed/NCBI

Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A, Mami-Chouaib F and Donnadieu E: Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 122:899–910. 2012. View Article : Google Scholar : PubMed/NCBI

Nicolas-Boluda A, Vaquero J, Barrin S, Kantari-Mimoun C, Ponzo M, Renault G, Deptuła P, Pogoda K, Bucki R, Cascone I, et al: Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment. Cold Spring Harbor. 2020.

Zeltz C, Pasko E, Cox TR, Navab R and Tsao MS: LOXL1 is regulated by integrin α11 and promotes non-small cell lung cancer tumorigenicity. Cancers (Basel). 11:7052019. View Article : Google Scholar

Saunier EF and Akhurst RJ: TGF beta inhibition for cancer therapy. Curr Cancer Drug Targets. 6:565–578. 2006. View Article : Google Scholar : PubMed/NCBI

Ford K, Hanley CJ, Mellone M, Szyndralewiez C, Heitz F, Wiesel P, Wood O, Machado M, Lopez MA, Ganesan AP, et al: NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res. 80:1846–1860. 2020. View Article : Google Scholar : PubMed/NCBI

Lakins MA, Ghorani E, Munir H, Martins CP and Shields JD: Cancer-associated fibroblasts induce antigen-specific deletion of CD8 ⁺ T Cells to protect tumour cells. Nat Commun. 9:9482018. View Article : Google Scholar : PubMed/NCBI

Teramoto K, Igarashi T, Kataoka Y, Ishida M, Hanaoka J, Sumimoto H and Daigo Y: Clinical significance of PD-L1-positive cancer-associated fibroblasts in pN0M0 non-small cell lung cancer. Lung Cancer. 137:56–63. 2019. View Article : Google Scholar : PubMed/NCBI

Kilvaer TK, Rakaee M, Hellevik T, Østman A, Strell C, Bremnes RM, Busund LT, Dønnem T and Martinez-Zubiaurre I: Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer. PLoS One. 13:e01921572018. View Article : Google Scholar : PubMed/NCBI

Hanley CJ, Mellone M, Ford K, Thirdborough SM, Mellows T, Frampton SJ, Smith DM, Harden E, Szyndralewiez C, Bullock M, et al: Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. J Natl Cancer Inst. 110:109–120. 2018. View Article : Google Scholar

Fujiwara A, Funaki S, Fukui E, Kimura K, Kanou T, Ose N, Minami M and Shintani Y: Effects of pirfenidone targeting the tumor microenvironment and tumor-stroma interaction as a novel treatment for non-small cell lung cancer. Sci Rep. 10:109002020. View Article : Google Scholar : PubMed/NCBI

Kakarla S, Chow K, Mata M, Shaffer DR, Song XT, Wu MF, Liu H, Wang LL, Rowley DR, Pfizenmaier K and Gottschalk S: Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther. 21:1611–1620. 2013. View Article : Google Scholar : PubMed/NCBI

Masuda T, Nakashima T, Namba M, Yamaguchi K, Sakamoto S, Horimasu Y, Miyamoto S, Iwamoto H, Fujitaka K, Miyata Y, et al: Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts. J Cell Mol Med. 23:29842019. View Article : Google Scholar : PubMed/NCBI

Duan S, Tsai Y, Keng P and Chen Y, Lee SO and Chen Y: IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and DNA repair associated molecules. Oncotarget. 6:27651–27660. 2015. View Article : Google Scholar : PubMed/NCBI

Wang L, Li X, Ren Y, Geng H, Zhang Q, Cao L, Meng Z, Wu X, Xu M and Xu K: Cancer-associated fibroblasts contribute to cisplatin resistance by modulating ANXA3 in lung cancer cells. Cancer Sci. 110:1609–1620. 2019. View Article : Google Scholar : PubMed/NCBI

Wei JR, Dong J and Li L: Cancer-associated fibroblasts-derived gamma-glutamyltransferase 5 promotes tumor growth and drug resistance in lung adenocarcinoma. Aging (Albany NY). 12:13220–13233. 2020. View Article : Google Scholar : PubMed/NCBI

Tao L, Huang G, Wang R, Pan Y, He Z, Chu X, Song H and Chen L: Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Sci Rep. 6:384082016. View Article : Google Scholar : PubMed/NCBI

Shien K, Papadimitrakopoulou VA, Ruder D, Behrens C, Shen L, Kalhor N, Song J, Lee JJ, Wang J, Tang X, et al: JAK1/STAT3 activation through a proinflammatory cytokine pathway leads to resistance to molecularly targeted therapy in non-small cell lung cancer. Mol Cancer Ther. 16:2234–2245. 2017. View Article : Google Scholar : PubMed/NCBI

Foster JG, Wong SC and Sharp TV: The hypoxic tumor microenvironment: Driving the tumorigenesis of non-small-cell lung cancer. Future Oncol. 10:2659–2674. 2014. View Article : Google Scholar : PubMed/NCBI

Rebelo SP, Pinto C, Martins TR, Harrer N, Estrada MF, Loza-Alvarez P, Cabeçadas J, Alves PM, Gualda EJ, Sommergruber W and Brito C: 3D-3-culture: A tool to unveil macrophage plasticity in the tumour microenvironment. Biomaterials. 163:185–197. 2018. View Article : Google Scholar : PubMed/NCBI