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Current Protein & Peptide Science

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ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

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General Research Article

Intercellular Interactions Mediated by HGF And TGF-Β Promote the 3D Spherical and Xenograft Growth of Liver Cancer Cells

Author(s): Zheng Peng, Xiaolan Lv, Pengfei Zhang, Qiao Chen, Hongyu Zhang, Jianlin Chen, Xingxuan Ma, Bohui Ouyang, Meng Hao, Haibo Tong, Dongwei Guo, Yi Luo* and Shigao Huang*

Volume 25, Issue 1, 2024

Published on: 27 September, 2023

Page: [71 - 82] Pages: 12

DOI: 10.2174/1389203724666230825100318

Price: $65

Abstract

Background: Recently, the importance of the interactions between liver cancer cells and fibroblasts has been increasingly recognized; however, many details remain to be explored.

Methods: In this work, we first studied their intercellular interactions using conditioned medium from mouse embryonic fibroblasts (MEFs), then through a previously established coculture model.

Results: Culturing in a conditioned medium from MEFs could significantly increase the growth, migration, and invasion of liver cancer cells. The coculture model further demonstrated that a positive feedback loop was formed between transforming growth factor-β (TGF-β) from HepG2 cells and mHGF (mouse hepatocyte growth factor) from MEFs during coculture. In this feedback loop, c-Met expression in HepG2 cells was significantly increased, and its downstream signaling pathways, such as Src/FAK, PI3K/AKT, and RAF/MEK/ERK, were activated. Moreover, the proportion of activated MEFs was also increased. More importantly, the growth-promoting effects caused by the interaction of these two cell types were validated in vitro by a 3D spheroid growth assay and in vivo by a xenograft mouse model.

Conclusion: Collectively, these findings provide valuable insights into the interactions between fibroblasts and liver cancer cells, which may have therapeutic implications for the treatment of liver cancer.

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[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Xie, D.Y.; Ren, Z.G.; Zhou, J.; Fan, J.; Gao, Q. 2019 Chinese clinical guidelines for the management of hepatocellular carcinoma: Updates and insights. Hepatobiliary Surg. Nutr., 2020, 9(4), 452-463.
[http://dx.doi.org/10.21037/hbsn-20-480] [PMID: 32832496]
[3]
Zhou, J.; Sun, H.; Wang, Z.; Cong, W.; Wang, J.; Zeng, M.; Zhou, W.; Bie, P.; Liu, L.; Wen, T.; Han, G.; Wang, M.; Liu, R.; Lu, L.; Ren, Z.; Chen, M.; Zeng, Z.; Liang, P.; Liang, C.; Chen, M.; Yan, F.; Wang, W.; Ji, Y.; Yun, J.; Cai, D.; Chen, Y.; Cheng, W.; Cheng, S.; Dai, C.; Guo, W.; Hua, B.; Huang, X.; Jia, W.; Li, Y.; Li, Y.; Liang, J.; Liu, T.; Lv, G.; Mao, Y.; Peng, T.; Ren, W.; Shi, H.; Shi, G.; Tao, K.; Wang, W.; Wang, X.; Wang, Z.; Xiang, B.; Xing, B.; Xu, J.; Yang, J.; Yang, J.; Yang, Y.; Yang, Y.; Ye, S.; Yin, Z.; Zhang, B.; Zhang, B.; Zhang, L.; Zhang, S.; Zhang, T.; Zhao, Y.; Zheng, H.; Zhu, J.; Zhu, K.; Liu, R.; Shi, Y.; Xiao, Y.; Dai, Z.; Teng, G.; Cai, J.; Wang, W.; Cai, X.; Li, Q.; Shen, F.; Qin, S.; Dong, J.; Fan, J. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 Edition). Liver Cancer, 2020, 9(6), 682-720.
[http://dx.doi.org/10.1159/000509424] [PMID: 33442540]
[4]
Calderaro, J.; Ziol, M.; Paradis, V.; Zucman-Rossi, J. Molecular and histological correlations in liver cancer. J. Hepatol., 2019, 71(3), 616-630.
[http://dx.doi.org/10.1016/j.jhep.2019.06.001] [PMID: 31195064]
[5]
Affo, S.; Yu, L.X.; Schwabe, R.F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol., 2017, 12(1), 153-186.
[http://dx.doi.org/10.1146/annurev-pathol-052016-100322] [PMID: 27959632]
[6]
Nault, J.C.; Cheng, A.L.; Sangro, B.; Llovet, J.M. Milestones in the pathogenesis and management of primary liver cancer. J. Hepatol., 2020, 72(2), 209-214.
[http://dx.doi.org/10.1016/j.jhep.2019.11.006] [PMID: 31954486]
[7]
Liu, J.; Li, P.; Wang, L.; Li, M.; Ge, Z.; Noordam, L.; Lieshout, R.; Verstegen, M.M.A.; Ma, B.; Su, J.; Yang, Q.; Zhang, R.; Zhou, G.; Carrascosa, L.C.; Sprengers, D.; IJzermans, J.N.M.; Smits, R.; Kwekkeboom, J.; van der Laan, L.J.W.; Peppelenbosch, M.P.; Pan, Q.; Cao, W. Cancer-Associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance. Cell. Mol. Gastroenterol. Hepatol., 2021, 11(2), 407-431.
[http://dx.doi.org/10.1016/j.jcmgh.2020.09.003] [PMID: 32932015]
[8]
Huang, S.; Peng, Z.; Lv, X. Recent progress on the role of fibronectin in tumor stromal immunity and immunotherapy. Curr. Top. Med. Chem., 2022, 22(30), 2494-2505.
[http://dx.doi.org/10.2174/1568026622666220615152647] [PMID: 35708087]
[9]
Novikova, M.V.; Khromova, N.V.; Kopnin, P.B. Components of the hepatocellular carcinoma microenvironment and their role in tumor progression. Biochemistry., 2017, 82(8), 861-873.
[http://dx.doi.org/10.1134/S0006297917080016] [PMID: 28941454]
[10]
Baglieri, J.; Brenner, D.; Kisseleva, T. The role of fibrosis and liver-associated fibroblasts in the pathogenesis of hepatocellular carcinoma. Int. J. Mol. Sci., 2019, 20(7), 1723.
[http://dx.doi.org/10.3390/ijms20071723] [PMID: 30959975]
[11]
Peng, Z.; Hao, M.; Tong, H.; Yang, H.; Huang, B.; Zhang, Z.; Luo, K.Q. The interactions between integrin α 5 β 1 of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis. Int. J. Biol. Sci., 2022, 18(13), 5019-5037.
[http://dx.doi.org/10.7150/ijbs.72367] [PMID: 35982891]
[12]
Matsumoto, K.; Umitsu, M.; De Silva, D.M.; Roy, A.; Bottaro, D.P. Hepatocyte growth factor/MET in cancer progression and biomarker discovery. Cancer Sci., 2017, 108(3), 296-307.
[http://dx.doi.org/10.1111/cas.13156] [PMID: 28064454]
[13]
Fu, J.; Su, X.; Li, Z.; Deng, L.; Liu, X.; Feng, X.; Peng, J. HGF/c-MET pathway in cancer: From molecular characterization to clinical evidence. Oncogene., 2021, 40(28), 4625-4651.
[http://dx.doi.org/10.1038/s41388-021-01863-w] [PMID: 34145400]
[14]
Moosavi, F.; Giovannetti, E.; Saso, L.; Firuzi, O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit. Rev. Clin. Lab. Sci., 2019, 56(8), 533-566.
[http://dx.doi.org/10.1080/10408363.2019.1653821] [PMID: 31512514]
[15]
Imamura, R.; Matsumoto, K. Hepatocyte growth factor in physiology and infectious diseases. Cytokine, 2017, 98, 97-106.
[http://dx.doi.org/10.1016/j.cyto.2016.12.025] [PMID: 28094206]
[16]
Huang, X.; Li, E.; Shen, H.; Wang, X.; Tang, T.; Zhang, X.; Xu, J.; Tang, Z.; Guo, C.; Bai, X.; Liang, T. Targeting the HGF/MET Axis in cancer therapy: Challenges in resistance and opportunities for improvement. Front. Cell Dev. Biol., 2020, 8, 152.
[http://dx.doi.org/10.3389/fcell.2020.00152] [PMID: 32435640]
[17]
Uchikawa, E.; Chen, Z.; Xiao, G.Y.; Zhang, X.; Bai, X. Structural basis of the activation of c-MET receptor. Nat. Commun., 2021, 12(1), 4074.
[http://dx.doi.org/10.1038/s41467-021-24367-3] [PMID: 34210960]
[18]
Zambelli, A.; Biamonti, G.; Amato, A. HGF/c-Met signalling in the tumor microenvironment. Adv. Exp. Med. Biol., 2021, 1270, 31-44.
[http://dx.doi.org/10.1007/978-3-030-47189-7_2] [PMID: 33123991]
[19]
Lee, H.K.; Lim, H.M.; Park, S.H.; Nam, M.J. Knockout of hepatocyte growth factor by CRISPR/Cas9 system induces apoptosis in hepatocellular carcinoma cells. J. Pers. Med., 2021, 11(10), 983.
[http://dx.doi.org/10.3390/jpm11100983] [PMID: 34683124]
[20]
Nakamura, T.; Mizuno, S. The discovery of Hepatocyte Growth Factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci., 2010, 86(6), 588-610.
[http://dx.doi.org/10.2183/pjab.86.588] [PMID: 20551596]
[21]
Owusu, B.; Galemmo, R.; Janetka, J.; Klampfer, L. Hepatocyte growth factor, a key tumor-promoting factor in the tumor microenvironment. Cancers., 2017, 9(12), 35.
[http://dx.doi.org/10.3390/cancers9040035] [PMID: 28420162]
[22]
Jung, Y.Y.; Um, J.Y.; Sethi, G.; Ahn, K.S. Fangchinoline abrogates growth and survival of hepatocellular carcinoma by negative regulation of c‐met/HGF and its associated downstream signaling pathways. Phytother. Res., 2022, 36(12), 4542-4557.
[http://dx.doi.org/10.1002/ptr.7573] [PMID: 35867025]
[23]
Organ, S.L.; Tsao, M.S. An overview of the c-MET signaling pathway. Ther. Adv. Med. Oncol., 2011, 3(1_suppl)(Suppl.), S7-S19.
[http://dx.doi.org/10.1177/1758834011422556] [PMID: 22128289]
[24]
Wang, H.; Rao, B.; Lou, J.; Li, J.; Liu, Z.; Li, A.; Cui, G.; Ren, Z.; Yu, Z. The function of the HGF/c-Met Axis in hepatocellular carcinoma. Front. Cell Dev. Biol., 2020, 8, 55.
[http://dx.doi.org/10.3389/fcell.2020.00055] [PMID: 32117981]
[25]
Bouattour, M.; Raymond, E.; Qin, S.; Cheng, A.L.; Stammberger, U.; Locatelli, G.; Faivre, S. Recent developments of c‐Met as a therapeutic target in hepatocellular carcinoma. Hepatology., 2018, 67(3), 1132-1149.
[http://dx.doi.org/10.1002/hep.29496] [PMID: 28862760]
[26]
Asaoka, Y.; Tateishi, R.; Hayashi, A.; Ushiku, T.; Shibahara, J.; Kinoshita, J.; Ouchi, Y.; Koike, M.; Fukayama, M.; Shiina, S.; Koike, K. Expression of c-Met in primary and recurrent hepatocellular carcinoma. Oncology, 2020, 98(3), 186-194.
[http://dx.doi.org/10.1159/000504806] [PMID: 31846974]
[27]
Karin, D.; Koyama, Y.; Brenner, D.; Kisseleva, T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation., 2016, 92(3), 84-92.
[http://dx.doi.org/10.1016/j.diff.2016.07.001] [PMID: 27591095]
[28]
Kisseleva, T.; Brenner, D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol., 2021, 18(3), 151-166.
[http://dx.doi.org/10.1038/s41575-020-00372-7] [PMID: 33128017]
[29]
O’Leary, E.M.; Tian, Y.; Nigdelioglu, R.; Witt, L.J.; Cetin-Atalay, R.; Meliton, A.Y.; Woods, P.S.; Kimmig, L.M.; Sun, K.A.; Gökalp, G.A.; Mutlu, G.M.; Hamanaka, R.B. TGF-β promotes metabolic reprogramming in lung fibroblasts via mTORC1-dependent ATF4 activation. Am. J. Respir. Cell Mol. Biol., 2020, 63(5), 601-612.
[http://dx.doi.org/10.1165/rcmb.2020-0143OC] [PMID: 32668192]
[30]
Akhmetshina, A.; Palumbo, K.; Dees, C.; Bergmann, C.; Venalis, P.; Zerr, P.; Horn, A.; Kireva, T.; Beyer, C.; Zwerina, J.; Schneider, H.; Sadowski, A.; Riener, M.O.; MacDougald, O.A.; Distler, O.; Schett, G.; Distler, J.H.W. Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis. Nat. Commun., 2012, 3(1), 735.
[http://dx.doi.org/10.1038/ncomms1734] [PMID: 22415826]
[31]
Meng, X.; Nikolic-Paterson, D.J.; Lan, H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol., 2016, 12(6), 325-338.
[http://dx.doi.org/10.1038/nrneph.2016.48] [PMID: 27108839]
[32]
Tzavlaki, K.; Moustakas, A. TGF-β signaling. Biomolecules., 2020, 10(3), 487.
[http://dx.doi.org/10.3390/biom10030487] [PMID: 32210029]
[33]
Hao, Y.; Baker, D.; ten Dijke, P. TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis. Int. J. Mol. Sci., 2019, 20(11), 2767.
[http://dx.doi.org/10.3390/ijms20112767] [PMID: 31195692]
[34]
Chen, J.; Gingold, J.A.; Su, X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol. Med., 2019, 25(11), 1010-1023.
[http://dx.doi.org/10.1016/j.molmed.2019.06.007] [PMID: 31353124]
[35]
Biernacka, A.; Dobaczewski, M.; Frangogiannis, N.G. TGF-β signaling in fibrosis. Growth Factors, 2011, 29(5), 196-202.
[http://dx.doi.org/10.3109/08977194.2011.595714] [PMID: 21740331]
[36]
Chen, Y.; McAndrews, K.M.; Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol., 2021, 18(12), 792-804.
[http://dx.doi.org/10.1038/s41571-021-00546-5] [PMID: 34489603]
[37]
Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; Hynes, R.O.; Jain, R.K.; Janowitz, T.; Jorgensen, C.; Kimmelman, A.C.; Kolonin, M.G.; Maki, R.G.; Powers, R.S.; Puré, E.; Ramirez, D.C.; Scherz-Shouval, R.; Sherman, M.H.; Stewart, S.; Tlsty, T.D.; Tuveson, D.A.; Watt, F.M.; Weaver, V.; Weeraratna, A.T.; Werb, Z. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer, 2020, 20(3), 174-186.
[http://dx.doi.org/10.1038/s41568-019-0238-1] [PMID: 31980749]
[38]
Pelaz, S.G.; Tabernero, A. Src: Coordinating metabolism in cancer. Oncogene, 2022, 41(45), 4917-4928.
[http://dx.doi.org/10.1038/s41388-022-02487-4] [PMID: 36217026]
[39]
Huang, X.; Gan, G.; Wang, X.; Xu, T.; Xie, W. The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy, 2019, 15(7), 1258-1279.
[http://dx.doi.org/10.1080/15548627.2019.1580105] [PMID: 30786811]
[40]
Biffi, G.; Tuveson, D.A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev., 2021, 101(1), 147-176.
[http://dx.doi.org/10.1152/physrev.00048.2019] [PMID: 32466724]
[41]
Menyhárt, O.; Nagy, Á.; Győrffy, B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. R. Soc. Open Sci., 2018, 5(12), 181006.
[http://dx.doi.org/10.1098/rsos.181006] [PMID: 30662724]
[42]
Tang, Z.; Li, C.; Kang, B.; Gao, G.; Li, C.; Zhang, Z. GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res., 2017, 45(W1), W98-W102.
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[43]
Dhar, D.; Baglieri, J.; Kisseleva, T.; Brenner, D.A. Mechanisms of liver fibrosis and its role in liver cancer. Exp. Biol. Med., 2020, 245(2), 96-108.
[http://dx.doi.org/10.1177/1535370219898141] [PMID: 31924111]
[44]
Pulz, L.H.; Cordeiro, Y.G.; Huete, G.C.; Cadrobbi, K.G.; Rochetti, A.L.; Xavier, P.L.P.; Nishiya, A.T.; de Freitas, S.H.; Fukumasu, H.; Strefezzi, R.F. Intercellular interactions between mast cells and stromal fibroblasts obtained from canine cutaneous mast cell tumours. Sci. Rep., 2021, 11(1), 23881.
[http://dx.doi.org/10.1038/s41598-021-03390-w] [PMID: 34903806]
[45]
Granito, A.; Guidetti, E.; Gramantieri, L. c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma. J. Hepatocell Carcinoma., 2015, 2, 29-38.
[PMID: 27508192]

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