The Role of Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and the Value of Traditional Chinese Medicine Treatment

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Dec 6

PMID 34868982

Citations 18

Authors

Wentao Jia

Shufang Liang

Binbin Cheng

Changquan Ling

Affiliations

Soon will be listed here.

Abstract

Invasion and metastasis are the main reasons for the high mortality of liver cancer, which involve the interaction of tumor stromal cells and malignant cells. Cancer-associated fibroblasts (CAFs) are one of the major constituents of tumor stromal cells affecting tumor growth, invasion, and metastasis. The heterogeneous properties and sources of CAFs make both tumor-supporting and tumor-suppression effects possible. The mechanisms for CAFs in supporting hepatocellular carcinoma (HCC) progression can be categorized into upregulated aggressiveness and stemness, transformed metabolism toward glycolysis and glutamine reductive carboxylation, polarized tumor immunity toward immune escape of HCC cells, and increased angiogenesis. The tumor-suppressive effect of fibroblasts highlights the functional heterogenicity of CAF populations and provides new insights into tumor-stromal interplay mechanisms. In this review, we introduced several key inflammatory signaling pathways in the transformation of CAFs from normal stromal cells and the heterogeneous biofunctions of activated CAFs. In view of the pleiotropic regulation properties of traditional Chinese medicine (TCM) and heterogeneous effects of CAFs, we also introduced the application and values of TCM in the treatment of HCC through targeting CAFs.

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References

Bonner J . Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004; 15(4):255-73. DOI: 10.1016/j.cytogfr.2004.03.006. View

Zhao Z, Bai S, Wang R, Xiong S, Li Y, Wang X . Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy. Cancer Manag Res. 2019; 11:5737-5744. PMC: 6598753. DOI: 10.2147/CMAR.S197634. View

Wang Y, Wang R, Wang Y, Peng R, Wu Y, Yuan Y . Ginkgo biloba extract mitigates liver fibrosis and apoptosis by regulating p38 MAPK, NF-κB/IκBα, and Bcl-2/Bax signaling. Drug Des Devel Ther. 2015; 9:6303-17. PMC: 4671772. DOI: 10.2147/DDDT.S93732. View

Sferra R, Vetuschi A, Catitti V, Ammanniti S, Pompili S, Melideo D . Boswellia serrata and Salvia miltiorrhiza extracts reduce DMN-induced hepatic fibrosis in mice by TGF-beta1 downregulation. Eur Rev Med Pharmacol Sci. 2012; 16(11):1484-98. View

Nio K, Yamashita T, Kaneko S . The evolving concept of liver cancer stem cells. Mol Cancer. 2017; 16(1):4. PMC: 5282887. DOI: 10.1186/s12943-016-0572-9. View

Wilde L, Roche M, Domingo-Vidal M, Tanson K, Philp N, Curry J . Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. Semin Oncol. 2017; 44(3):198-203. PMC: 5737780. DOI: 10.1053/j.seminoncol.2017.10.004. View

Khomich O, Ivanov A, Bartosch B . Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells. 2019; 9(1). PMC: 7016711. DOI: 10.3390/cells9010024. View

Liu Z, Chen M, Zhao R, Huang Y, Liu F, Li B . CAF-induced placental growth factor facilitates neoangiogenesis in hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai). 2019; 52(1):18-25. DOI: 10.1093/abbs/gmz134. View

Liu C, Liu L, Chen X, Cheng J, Zhang H, Zhang C . LSD1 Stimulates Cancer-Associated Fibroblasts to Drive Notch3-Dependent Self-Renewal of Liver Cancer Stem-like Cells. Cancer Res. 2017; 78(4):938-949. DOI: 10.1158/0008-5472.CAN-17-1236. View

10.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

11.

Ozdemir B, Pentcheva-Hoang T, Carstens J, Zheng X, Wu C, Simpson T . Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25(6):719-34. PMC: 4180632. DOI: 10.1016/j.ccr.2014.04.005. View

12.

Wang J, Luo J, Yin X, Huang W, Cao H, Wang G . Jiedu Granule Combined with Transcatheter Arterial Chemoembolization and Gamma Knife Radiosurgery in Treating Hepatocellular Carcinoma with Portal Vein Tumor Thrombus. Biomed Res Int. 2019; 2019:4696843. PMC: 6614979. DOI: 10.1155/2019/4696843. View

13.

Lin Z, Hsu C, Jeng Y, Hu F, Pan H, Wu Y . Klotho-beta and fibroblast growth factor 19 expression correlates with early recurrence of resectable hepatocellular carcinoma. Liver Int. 2019; 39(9):1682-1691. DOI: 10.1111/liv.14055. View

14.

Schrader J, Gordon-Walker T, Aucott R, van Deemter M, Quaas A, Walsh S . Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology. 2011; 53(4):1192-205. PMC: 3076070. DOI: 10.1002/hep.24108. View

15.

Liu S, Yu J, He L, Yu H, Luo H . [Effects of nuclear factor kappaB and transforming growth factor beta1 in the anti-liver fibrosis process using Ginkgo biloba extract]. Zhonghua Gan Zang Bing Za Zhi. 2005; 13(12):903-7. View

16.

Zhang F, Zhang Z, Chen L, Kong D, Zhang X, Lu C . Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells. J Cell Mol Med. 2014; 18(7):1392-406. PMC: 4124023. DOI: 10.1111/jcmm.12286. View

17.

Song T, Dou C, Jia Y, Tu K, Zheng X . TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1/CXCR4 signaling in hepatocellular carcinoma. Oncotarget. 2015; 6(14):12061-79. PMC: 4494923. DOI: 10.18632/oncotarget.3616. View

18.

Li J, Wang Y, Ma M, Jiang S, Zhang X, Zhang Y . Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling. EBioMedicine. 2019; 40:43-55. PMC: 6412555. DOI: 10.1016/j.ebiom.2019.01.009. View

19.

Chen Q, Shu C, Laurence A, Chen Y, Peng B, Zhen Z . Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut. 2018; 67(11):2006-2016. DOI: 10.1136/gutjnl-2018-315983. View

20.

Zhou Y, Wu R, Cai F, Zhou W, Lu Y, Zhang H . Xiaoyaosan decoction alleviated rat liver fibrosis via the TGFβ/Smad and Akt/FoxO3 signaling pathways based on network pharmacology analysis. J Ethnopharmacol. 2020; 264:113021. DOI: 10.1016/j.jep.2020.113021. View