Intercellular Interactions Mediated by HGF And TGF-Β Promote the 3D Spherical and Xenograft Growth of Liver Cancer Cells
- 作者: Tong H.1, Guo D.2, Luo Y.3, Huang S.4, Peng Z.5, Lv X.6, Zhang P.2, Chen Q.7, Zhang H.5, Chen J.8, Ma X.5, Ouyang B.5, Hao M.1
-
隶属关系:
- Faculty of Health Sciences, University of Macau
- Department of Pulmonary and Critical Care Medicine, Liuzhou Traditional Chinese Medical Hospital
- Department of Neurosurgery, Liuzhou Traditional Chinese Medical Hospital
- Department of Radiation Oncology, The First Affiliated Hospital, Air Force Medical University
- Department of Clinical Laboratory, Liuzhou Traditional Chinese Medical Hospital
- Department of Clinical Laboratory, Liuzhou Maternity and Child Healthcare Hospital
- Department of gastroenterology, Liuzhou Traditional Chinese Medical Hospital
- Shengli Clinical Medical College, Fujian Medical University
- 期: 卷 25, 编号 1 (2024)
- 页面: 71-82
- 栏目: Life Sciences
- URL: https://rjsvd.com/1389-2037/article/view/645496
- DOI: https://doi.org/10.2174/1389203724666230825100318
- ID: 645496
如何引用文章
全文:
详细
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
作者简介
Haibo Tong
Faculty of Health Sciences, University of Macau
Email: info@benthamscience.net
Dongwei Guo
Department of Pulmonary and Critical Care Medicine, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Yi Luo
Department of Neurosurgery, Liuzhou Traditional Chinese Medical Hospital
编辑信件的主要联系方式.
Email: info@benthamscience.net
Shigao Huang
Department of Radiation Oncology, The First Affiliated Hospital, Air Force Medical University
编辑信件的主要联系方式.
Email: info@benthamscience.net
Zheng Peng
Department of Clinical Laboratory, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Xiaolan Lv
Department of Clinical Laboratory, Liuzhou Maternity and Child Healthcare Hospital
Email: info@benthamscience.net
Pengfei Zhang
Department of Pulmonary and Critical Care Medicine, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Qiao Chen
Department of gastroenterology, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Hongyu Zhang
Department of Clinical Laboratory, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Jianlin Chen
Shengli Clinical Medical College, Fujian Medical University
Email: info@benthamscience.net
Xingxuan Ma
Department of Clinical Laboratory, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Bohui Ouyang
Department of Clinical Laboratory, Liuzhou Traditional Chinese Medical Hospital
Email: info@benthamscience.net
Meng Hao
Faculty of Health Sciences, University of Macau
Email: info@benthamscience.net
参考
- 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. doi: 10.3322/caac.21660 PMID: 33538338
- 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. doi: 10.21037/hbsn-20-480 PMID: 32832496
- 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. doi: 10.1159/000509424 PMID: 33442540
- Calderaro, J.; Ziol, M.; Paradis, V.; Zucman-Rossi, J. Molecular and histological correlations in liver cancer. J. Hepatol., 2019, 71(3), 616-630. doi: 10.1016/j.jhep.2019.06.001 PMID: 31195064
- 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. doi: 10.1146/annurev-pathol-052016-100322 PMID: 27959632
- 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. doi: 10.1016/j.jhep.2019.11.006 PMID: 31954486
- 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. doi: 10.1016/j.jcmgh.2020.09.003 PMID: 32932015
- 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. doi: 10.2174/1568026622666220615152647 PMID: 35708087
- 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. doi: 10.1134/S0006297917080016 PMID: 28941454
- 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. doi: 10.3390/ijms20071723 PMID: 30959975
- 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. doi: 10.7150/ijbs.72367 PMID: 35982891
- 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. doi: 10.1111/cas.13156 PMID: 28064454
- 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. doi: 10.1038/s41388-021-01863-w PMID: 34145400
- 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. doi: 10.1080/10408363.2019.1653821 PMID: 31512514
- Imamura, R.; Matsumoto, K. Hepatocyte growth factor in physiology and infectious diseases. Cytokine, 2017, 98, 97-106. doi: 10.1016/j.cyto.2016.12.025 PMID: 28094206
- 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. doi: 10.3389/fcell.2020.00152 PMID: 32435640
- 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. doi: 10.1038/s41467-021-24367-3 PMID: 34210960
- Zambelli, A.; Biamonti, G.; Amato, A. HGF/c-Met signalling in the tumor microenvironment. Adv. Exp. Med. Biol., 2021, 1270, 31-44. doi: 10.1007/978-3-030-47189-7_2 PMID: 33123991
- 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. doi: 10.3390/jpm11100983 PMID: 34683124
- 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. doi: 10.2183/pjab.86.588 PMID: 20551596
- 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. doi: 10.3390/cancers9040035 PMID: 28420162
- 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. doi: 10.1002/ptr.7573 PMID: 35867025
- 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. doi: 10.1177/1758834011422556 PMID: 22128289
- 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. doi: 10.3389/fcell.2020.00055 PMID: 32117981
- 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. doi: 10.1002/hep.29496 PMID: 28862760
- 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. doi: 10.1159/000504806 PMID: 31846974
- Karin, D.; Koyama, Y.; Brenner, D.; Kisseleva, T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation., 2016, 92(3), 84-92. doi: 10.1016/j.diff.2016.07.001 PMID: 27591095
- Kisseleva, T.; Brenner, D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol., 2021, 18(3), 151-166. doi: 10.1038/s41575-020-00372-7 PMID: 33128017
- OLeary, 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. doi: 10.1165/rcmb.2020-0143OC PMID: 32668192
- 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. doi: 10.1038/ncomms1734 PMID: 22415826
- Meng, X.; Nikolic-Paterson, D.J.; Lan, H.Y. TGF-β: The master regulator of fibrosis. Nat. Rev. Nephrol., 2016, 12(6), 325-338. doi: 10.1038/nrneph.2016.48 PMID: 27108839
- Tzavlaki, K.; Moustakas, A. TGF-β signaling. Biomolecules., 2020, 10(3), 487. doi: 10.3390/biom10030487 PMID: 32210029
- Hao, Y.; Baker, D.; ten Dijke, P. TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis. Int. J. Mol. Sci., 2019, 20(11), 2767. doi: 10.3390/ijms20112767 PMID: 31195692
- Chen, J.; Gingold, J.A.; Su, X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol. Med., 2019, 25(11), 1010-1023. doi: 10.1016/j.molmed.2019.06.007 PMID: 31353124
- Biernacka, A.; Dobaczewski, M.; Frangogiannis, N.G. TGF-β signaling in fibrosis. Growth Factors, 2011, 29(5), 196-202. doi: 10.3109/08977194.2011.595714 PMID: 21740331
- Chen, Y.; McAndrews, K.M.; Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol., 2021, 18(12), 792-804. doi: 10.1038/s41571-021-00546-5 PMID: 34489603
- 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. doi: 10.1038/s41568-019-0238-1 PMID: 31980749
- Pelaz, S.G.; Tabernero, A. Src: Coordinating metabolism in cancer. Oncogene, 2022, 41(45), 4917-4928. doi: 10.1038/s41388-022-02487-4 PMID: 36217026
- 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. doi: 10.1080/15548627.2019.1580105 PMID: 30786811
- Biffi, G.; Tuveson, D.A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev., 2021, 101(1), 147-176. doi: 10.1152/physrev.00048.2019 PMID: 32466724
- 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. doi: 10.1098/rsos.181006 PMID: 30662724
- 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. doi: 10.1093/nar/gkx247 PMID: 28407145
- 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. doi: 10.1177/1535370219898141 PMID: 31924111
- 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. doi: 10.1038/s41598-021-03390-w PMID: 34903806
- 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
补充文件
