Biology of transforming growth factor beta in hepatocarcinogenesis

TGF-beta is an important factor in the regulation of liver growth. It is an inhibitor of hepatocyte DNA synthesis and may induce active cell death, e.g., to remove excessive tissue mass. Studies using transgenic mice suggest that expression in the resting liver has to be well balanced; either under- or overexpression appear to cause an increased turnover of hepatocytes and to predispose to hepatocarcinogenesis. TGF-beta overexpression is frequently observed in human hepatocellular carcinomas, probably as a late event in tumor development. In men and mice, TGF-beta overexpression appears to be associated with loss of TGF-beta responsiveness often by disruption of TGF-beta signaling. However, mechanisms as mutations in TGF-beta receptor II or Smad2 and 4 genes, frequently observed in other human cancers, have only rarely been observed in hepatocellular carcinomas. Further studies may clarify the mechanisms by which hepatocellular tumors escape TGF-beta growth control, as well as analyze possible roles of TGF-beta overexpression in immunosuppression and angiogenesis.