Cancer-associated fibroblasts in hepatocellular carcinoma

Abstract

The hepatic stellate cells in the liver are stimulated sustainably by chronic injury of the hepatocytes, activating myofibroblasts, which produce abundant collagen. Myofibroblasts are the major source of extracellular proteins during fibrogenesis, and may directly, or secreted products, contribute to carcinogenesis and tumor progression. Cancer-associated fibroblasts (CAFs) are one of the components of the tumor microenvironment that promote the proliferation and invasion of cancer cells by secreting various growth factors and cytokines. CAFs crosstalk with cancer cells stimulates tumor progression by creating a favorable microenvironment for progression, invasion, and metastasis through the epithelial-mesenchymal transition. Basic studies on CAFs have advanced, and the role of CAFs in tumors has been elucidated. In particular, for hepatocellular carcinoma, carcinogenesis from cirrhosis is a known fact, and participation of CAFs in carcinogenesis is supported. In this review, we discuss the current literature on the role of CAFs and CAF-related signaling in carcinogenesis, crosstalk with cancer cells, immunosuppressive effects, angiogenesis, therapeutic targets, and resistance to chemotherapy. The role of CAFs is important in cancer initiation and progression. CAFtargeted therapy may be effective for suppression not only of fibrosis but also cancer progression.

Keywords: Cancer associated fibroblast; Hepatic stellate cell; Hepatocellular carcinoma; Immunosuppression; Therapeutic target.

Figure 1

Microenvironment to be formed with cancer-associated fibroblasts and tumor-associated macrophages. Cancer-associated fibroblasts (CAFs) mainly located at the tumor marginal zone and secreted the various cytokines such as HGF and crosstalk with hepatocellular carcinoma cells and stimulate the tumor progression, invasion and metastasis through the epithelial mesenchymal transition. TIMP-1 suppressed the tumor cell apoptosis via SDF-1/PI3K/AKT signaling. Angiogenesis is occured by the angiogenic factors including VEGF, PDGF, ang-1 and ang-2 secreted by CAFs. TAMs and CAFs make the microenvironment to the immunosuppressive condition to create favorable microenvironment for tumor progression. TAM: Tumor associated macrophage.