title: Fatty liver creates a pro-metastatic microenvironment for hepatocellular carcinoma through activation of hepatic stellate cells.
abstract: Fatty liver (FL) is associated with development of hepatocellular carcinoma (HCC). However, whether FL itself promotes the progression of HCC is unclear. We recently found that hepatic stellate cells (HSCs) were prominently activated in the steatotic liver. Here, we investigated whether steatotic livers promote HCC progression and whether HSCs of steatotic liver are associated with HCC progression. We implanted rat HCC cells into diet-induced steatotic livers in rats via portal vein injection. Thereafter, HSCs and HCC cells were co-implanted subcutaneously into nude rats. Migration and proliferation of HCC cells were measured, and activation of ERK and Akt in these cells was determined by western blotting. Chemokines secreted from HSCs and HCC cells were also evaluated by ELISA. Steatotic livers significantly promoted HCC metastasis compared with non-steatotic livers. Additionally, co-implantation of HCC cells with HSCs from steatotic livers produced significantly larger tumors in recipient rats as compared to those induced by HCC cells co-implanted with HSCs from normal livers (NLs). HSCs isolated from steatotic livers, compared with HSCs isolated from NLs, secreted greater amounts of interleukin-1α, vascular endothelial growth factor, and transforming growth factor-β. These cytokines may enhance the proliferation and migration of HCC cells by increasing the phosphorylation of ERK and Akt in HCC cells. Moreover, we noted that the Rho-kinase inhibitor deactivated activated HSCs and attenuated HCC progression. In conclusion, the rat steatotic liver microenvironment favors HCC metastasis, and this effect appears to be promoted by activated HSCs in the steatotic liver.
authors: Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Japan.
authors: Yoshihiro
authors: Y
authors: Mikuriya
authors: Hirotaka
authors: H
authors: Tashiro
authors: Shintaro
authors: S
authors: Kuroda
authors: Junko
authors: J
authors: Nambu
authors: Tsuyoshi
authors: T
authors: Kobayashi
authors: Hironobu
authors: H
authors: Amano
authors: Yuka
authors: Y
authors: Tanaka
authors: Hideki
authors: H
authors: Ohdan
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D055166:Hepatic Stellate Cells / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D009368:Neoplasm Transplantation; D011915:Rats, Inbred BUF; D011916:Rats, Inbred F344; D011923:Rats, Nude; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines
keywords: HCC; Rho-kinase; fatty liver; hepatic stellate cell