Rat hepatic stellate cells alter the gene expression profile and promote the growth, migration and invasion of hepatocellular carcinoma cells

Abstract

The aim of the present study was to examine the effects of activated hepatic stellate cells (HSCs) and their paracrine secretions, on hepatocellular cancer cell growth and gene expression in vitro and in vivo. Differentially expressed genes in McA-RH7777 hepatocellular carcinoma (HCC) cells following non-contact co-culture with activated stellate cells, were identified by a cDNA microarray. The effect of the co-injection of HCC cells and activated HSCs on tumor size in rats was also investigated. Non-contact co-culture altered the expression of 573 HCC genes by >2-fold of the control levels. Among the six selected genes, ELISA revealed increased protein levels of hepatic growth factor, matrix metalloproteinase-2 (MMP-2) and −9 (MMP-9). Incubation of HCC cells with medium conditioned by activated HSCs significantly increased the proliferation rate (P<0.001), migration rate and the number of invasive HCC cells (P=0.001). Co-injection of HCC cells and activated HSCs into rats significantly increased the weight of the resulting HCC tumors (P<0.01). The paracrine activity of activated HSCs markedly altered the gene expression profile of HCC cells and affected their growth, migration and invasiveness. The results from the present study indicate that the interaction between the activated HSCs and HCC has an important role in the development of HCC.

The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

“…Multiple studies have shown poor survival as well as increased metastasis and recurrence following resection in HCC patients with positive HSC gene signatures or high expression of α-SMA (50, 53, 80, 81). Similar findings were made in animal models, where coinjection of activated HSC and HCC cells into mice enhanced subcutaneous or orthotopic tumor growth (53, 80–85). However, these studies lacked the proper hepatic environment in which HCCs develop and progress and may have led to unphysiological interactions between HSC and HCC cells that normally do not occur in hepatocarcinogenesis.…”

IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells

“…A bi-directional cross-talk between hepatocytes and HSCs has been previously described [1,2,16]. A bi-directional cross-talk between hepatocytes and HSCs has been previously described [1,2,16].…”

“…Both direct cell-cell interactions and soluble factors/cytokines from these interactions contribute to a proinflammatory and profibrotic microenvironment [1,2]. HSCs are in close contact and interact with hepatocytes.…”

Hepatic Stellate Cells and Liver Cancer

“…Increased proliferation, migration and invasion capacity of HCC cells when cultured in activated LX-2 conditioned medium [58] (Continued) Co-culture Hep3B Accelerated tumor cell/HSC spheroid formation in 3D culture system [35] McA-RH7777 Increased secretion of HGF, IL-6, MMP2, and MMP9 from HCC cells when co-cultured with rat HSCs [36] HepaRG, HuGB, Huh7, HepG2…”

“…McA-RH7777 Increased tumor weight and volume in HCC cells co-injected with culture-activated rat HSCs [36] MIMR Twofold increase in tumor formation resulting from co-transplantation with M1-4HSCs [38] Hepa1-6 Increased tumor proliferation and volume due to increased Treg accumulation [61] H22 Increased tumor volume resulting from decreased lymphocyte infiltration, increased apoptosis of mononuclear cells, and increased Treg infiltration in tumor [60] MHCC97H Accelerated tumor growth when co-injected with LX-2 cells [58] Orthotopic co-transplantation H22 Threefold increase in tumor burden resulting from increased angiogenesis, lymphangiogenesis, and increased infiltration of Tregs and myeloid-derived suppressor cells [52] MHCC97L Decreased metastatic ability of HCC cells when co-injected with epimorphin-null LX-2 cells [58] (Continued)…”