Abstract
Lung cancer (LC) is a leading cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) is a well-known phenomenon that promotes the invasive and metastatic capabilities of LC. Especially, EMT is assumed to be a pivotal mechanism for tumor cell invasion and metastasis, thereby limiting the efficacy of surgery and medical treatments, resulting in poor patient prognoses. Thus, the elucidation and reversal of EMT could provide changes in therapeutic strategies for LC. To overcome the limitations of currents treatment regimens for LC, it is important for surgeons to be familiar with this complex tumor characteristic. In this review, the activating signaling pathways underlying EMT and the associated tumor phenotypes are briefly described.
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Shimizu H, Okada M, Tangoku A, Doki Y, Endo S, Fukuda H, et al. Thoracic and cardiovascular surgeries in Japan during 2017: Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg. 2020;68:414–49.
Hay E. An overview of transformation. Acta Anat (Basel). 1995;154:8–20.
Their JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer. 2002;2:442–54.
Kalluri R, Weinberg RA. Review series The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.
Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952–61.
Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AM, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA. 2006;103:13180–5.
Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5:816–26.
Sulzer MA, Leers MPG, Van Noord JA, Bollen ECM, Theunissen PHMH. Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med. 1998;157:1319–23.
Soltermann A, Tischler V, Arbogast S, Braun J, Probst-Hensch N, Weder W, et al. Prognostic significance of epithelial-mesenchymal and mesenchymal- epithelial transition protein expression in non-small cell lung cancer. Clin Cancer Res. 2008;14:7430–7.
Menju T, Sowa T, Sonobe M, Miyata R, Takahashi K, Nishikawa S, et al. Clinicopathologic significance of epithelio-mesenchymal transition in human lung adenocarcinomas: An integrative analysis, inclusive of genetic alterations, on 256 surgically resected cases. Cancer Treat Res Commun. 2017;12:62–8.
Ceteci F, Ceteci S, Karreman C, Kramer BW, Asan E, Götz R, et al. Disruption of tumor cell adhesion promotes angiogenic switch and progression to micrometastasis in RAF-driven murine lung cancer. Cancer Cell. 2007;12:145–59.
Richardson AM, Havel LS, Koyen AE, Konen JM, Shupe J, Wiles WG, et al. Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell–Cancer-associated fibroblast interactions during collective invasion. Clin Cancer Res. 2018;24:420–32.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.
Tirino V, Camerlingo R, Bifulco K, Irollo E, Montella R, Paino F, et al. TGF-β1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line, leading to an increase of migration ability in the CD133+ A549 cell fraction. Cell Death Dis. 2013;4:1–11.
Sowa T, Menju T, Sonobe M, Sozu T, Date H. Association between epithelial-mesenchymal transition and cancer stemness and their effect on the prognosis of lung adenocarcinoma. Cancer Med. 2015;4:1853–62.
Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760–74.
Stewart EL, Tan SZ, Liu G, Tsao M. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations: a review. Transl Lung Cancer Res. 2015;4:67–81.
Erin N, Grahovac J, Brozovic A, Efferth T. Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance. Drug Resist Updat. 2020;53:100715.
Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharm Sin B. 2015;5:390–401.
Yochum ZA, Cades J, Wang H, Chatterjee S, Simons BW, O’Brien JP, et al. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene. 2019;38:656–70.
Song KA, Niederst MJ, Lochmann TL, Hata AN, Kitai H, Ham J, et al. Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM. Clin Cancer Res. 2018;24:197–208.
Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn Y-H, Byers LA, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun. 2014;5:5241.
Lou Y, Diao L, Cuentas ERP, Denning WL, Chen L, Fan YH, et al. Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin Cancer Res. 2016;22:3630–42.
Raimondi C, Carpino G, Nicolazzo C, Gradilone A, Gianni W, Gelibter A, et al. PD-L1 and epithelial-mesenchymal transition in circulating tumor cells from non-small cell lung cancer patients: A molecular shield to evade immune system? Oncoimmunology. 2017;6:e1315488.
Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-β1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res. 2005;6:1–15.
Weidner KM, Sachs M, Birchmeier W. The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 1993;121:145–54.
Hecht SS. Tobacco Smoke Carcinogens and Lung Cancer. J Natl cancer Inst. 1999;91.
Zhao Y, Xu Y, Li Y, Xu W, Luo F, Wang B, et al. NF-κB-Mediated Inflammation Leading to EMT via miR-200c Is Involved in Cell Transformation Induced By Cigarette Smoke Extract. Toxicol Sci. 2013;135:265–76.
Shen HJ, Sun YH, Zhang SJ, Jiang JX, Dong XW, Jia YL, et al. Cigarette smoke-induced alveolar epithelial-mesenchymal transition is mediated by Rac1 activation. Biochim Biophys Acta. 2014;1840:1838–49.
Pillai S, Trevino J, Rawal B, Singh S, Kovacs M, Li X, et al. beta-arrestin-1 mediates nicotine-induced metastasis through E2F1 target genes that modulate epithelial-mesenchymal transition. Cancer Res. 2015;75:1009–20.
Derynck R, Muthusamy BP, Saeteurn KY. Signaling pathway cooperation in TGF-β-induced epithelial-mesenchymal transition. Curr Opin Cell Biol. 2014;31:56–66.
Moustakas A, Heldin CH. The regulation of TGFβ signal transduction. Development. 2009;136:3699–714.
Mu Y, Gudey SK, Landström M. Non-Smad signaling pathways. Cell Tissue Res. 2012;347:11–20.
Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 2007;67:9066–76.
Suh YJ, Lee HJ, Kim YJ, Kim KG, Kim H, Jeon YK, et al. Computed tomography characteristics of lung adenocarcinomas with epidermal growth factor receptor mutation: A propensity score matching study. Lung Cancer. 2018;123:52–9.
Tsuta K, Kawago M, Inoue E, Yoshida A, Takahashi F, Sakurai H, et al. The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations. Lung Cancer. 2013;81:371–6.
Pallier K, Cessot A, Côté JF, Just PA, Cazes A, Fabre E, et al. TWIST1 a new determinant of epithelial to mesenchymal transition in EGFR mutated lung adenocarcinoma. PLoS One. 2012;7.
Liu L, Chen X, Wang Y, Qu Z, Lu Q, Zhao J, et al. Notch3 is important for TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1. Cancer Gene Ther. 2014;21:364–72.
Xie M, He CS, Wei SH, Zhang L. Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo. Eur J Cancer. 2013;49:3559–72.
Zhang X, Zhao X, Shao S, Zuo X, Ning Q, Luo M, et al. Notch1 induces epithelial-mesenchymal transition and the cancer stem cell phenotype in breast cancer cells and STAT3 plays a key role. Int J Oncol. 2015;46:1141–8.
Li LC, Peng Y, Liu YM, Wang LL, Wu XL. Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. Oncol Lett. 2014;7:2160–4.
Ishida T, Hijioka H, Kume K, Miyawaki A, Nakamura N. Notch signaling induces EMT in OSCC cell lines in a hypoxic environment. Oncol Lett. 2013;6:1201–6.
Jin J, Zhan P, Qian H, Wang X, Katoh M, Phan K, et al. Prognostic value of wingless-type proteins in non-small cell lung cancer patients: A meta-analysis. Transl Lung Cancer Res. 2016;5:436–42.
Su J, Wu S, Wu H, Li L, Guo T. CD44 is functionally crucial for driving lung cancer stem cells metastasis through Wnt/β-catenin-FoxM1-Twist signaling. Mol Carcinog. 2016;55:1962–73.
Gnemmi V, Bouillez A, Gaudelot K, Hémon B, Ringot B, Pottier N, et al. MUC1 drives epithelial-mesenchymal transition in renal carcinoma through Wnt/β-catenin pathway and interaction with SNAIL promoter. Cancer Lett. 2014;346:225–36.
Hu T, Li C. Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol Cancer. 2010;9:1–7.
Polizio AH, Chinchilla P, Chen X, Manning DR, Riobo N a. Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gli-independent manner through coupling of smoothened to Gi proteins. Sci Signal. 2011;4:pt7.
Yue D, Li H, Che J, Zhang Y, Tseng HHK, Jin JQ, et al. Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. J Exp Clin Cancer Res. 2014;33:1–7.
Moroishi T, Hansen CG, Guan K-L. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15:73–9.
Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, et al. The hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72.
Xu W, Wei Y, Wu S, Wang Y, Wang Z, Sun Y, et al. Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790M mutation resistant to gefitinib. Cell Biosci. 2015/05/15. 2015;5:7.
Hu P, Shen M, Zhang P, Zheng C, Pang Z, Zhu L, et al. Intratumoral neutrophil granulocytes contribute to epithelial-mesenchymal transition in lung adenocarcinoma cells. Tumor Biol. 2015;36:7789–96.
Gu K, Li M, Shen J, Liu F, Cao J, Jin S, et al. Interleukin-17-induced EMT promotes lung cancer cell migration and invasion via NF-κB / ZEB1 signal pathway. Am J Cancer Res. 2015;5:1169–79.
Dohadwala M, Wang G, Heinrich E, Luo J, Lau O, Shih H, et al. The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC. Otolaryngol Head Neck Surg. 2010;142:753–9.
Chen J, Wang S. Interleukin-32 α inactivates JAK2/STAT3 signaling and reverses interleukin-6-induced epithelial–mesenchymal transition , invasion , and metastasis in pancreatic cancer cells. Onco Targets Ther. 2016;4225–37.
Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, Del Barrio MG, et al. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.
Olivos DJ, Mayo LD. Emerging non-canonical functions and regulation by p53: p53 and stemness. Int J Mol Sci. 2016;17:1–30.
Díaz-López A, Moreno-Bueno G, Cano A. Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manag Res. 2014;6:205–16.
Dong P, Karaayvaz M, Jia N, Kaneuchi M, Hamada J, Watari H, et al. Mutant p53 gain-of-function induces epithelial-mesenchymal transition through modulation of the miR-130b-ZEB1 axis. Oncogene. 2013;32:3286–95.
Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol. 2009;11:694–704.
Kogan-Sakin I, Tabach Y, Buganim Y, Molchadsky A, Solomon H, Madar S, et al. Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. Cell Death Differ. 2010/08/07. 2011;18:271–81.
Timpson P, McGhee EJ, Morton JP, Von Kriegsheim A, Schwarz JP, Karim SA, et al. Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53. Cancer Res. 2011;71:747–57.
Muller PAJ, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S, et al. Mutant p53 drives invasion by promoting integrin recycling. Cell. 2009;139:1327–41.
Dubois F, Keller M, Calvayrac O, Soncin F, Hoa L, Hergovich A, et al. RASSF1A suppresses the invasion and metastatic potential of human non-small cell lung cancer cells by inhibiting YAP activation through the GEF-H1/RhoB pathway. Cancer Res. 2016;76:1627–40.
Zhao R, Gong L, Li L, Guo L, Zhu D, Wu Z, et al. nm23-H1 is a negative regulator of TGF-β1-dependent induction of epithelial-mesenchymal transition. Exp Cell Res. 2013;319:740–9.
Kong F-FF, Zhu Y-LL, Yuan H-HH, Wang J-YY, Zhao M, Gong X-DD, et al. FOXM1 regulated by ERK pathway mediates TGF-β1-induced EMT in NSCLC. Oncol Res. 2015/02/24. 2014;22:29–37.
Tange S, Oktyabri D, Terashima M, Ishimura A, Suzuki T. JARID2 is involved in transforming growth factor-beta-induced epithelial-mesenchymal transition of lung and colon cancer cell lines. PLoS ONE. 2014;9:e115684.
Risolino M, Mandia N, Iavarone F, Dardaei L, Longobardi E, Fernandez S, et al. Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma. Proc Natl Acad Sci USA. 2014;111:E3775–84.
Liu Z, Chen X, Song H, Wang H, Zhang G, Wang H, et al. Snail regulated by PKC/GSK-3β pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells. Cell Tissue Res. 2014;358:491–502.
Capaccione KM, Hong X, Morgan KM, Liu W, Bishop JM, Liu L, et al. Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma. Oncotarget. 2014;5:3636–50.
Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HEM, Behrens J, et al. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol. 2002;4:222–31.
Jia D, Yan M, Wang X, Hao X, Liang L, Liu L, et al. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion. BMC Cancer. 2010;10:364.
Shintani Y, Maeda M, Chaika N, Johnson KR, Wheelock MJ. Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-β signaling. Am J Respir Cell Mol Biol. 2008;38:95–104.
Li L, Qi L, Liang Z, Song W, Liu Y, Wang Y, et al. Transforming growth factor-β1 induces EMT by the transactivation of epidermal growth factor signaling through HA/CD44 in lung and breast cancer cells. Int J Mol Med. 2015;36:113–22.
Kechagia JZ, Ivaska J, Roca-Cusachs P. Integrins as biomechanical sensors of the microenvironment. Nat Rev Mol Cell Biol. 2019;20:457–73.
Williams KC, Coppolino MG. SNARE-dependent interaction of Src, EGFR and β1 integrin regulates invadopodia formation and tumor cell invasion. J Cell Sci. 2014;127:1712–25.
Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong STC, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527:472–6.
Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–30.
Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22:725–36.
Ocaña OH, Córcoles R, Fabra Á, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012;22:709–24.
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This study was supported by a grant from the Japanese Society for the Promotion of Science (grant no. 20H03770).
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Menju, T., Date, H. Lung cancer and epithelial-mesenchymal transition. Gen Thorac Cardiovasc Surg 69, 781–789 (2021). https://doi.org/10.1007/s11748-021-01595-4
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DOI: https://doi.org/10.1007/s11748-021-01595-4