Transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta 1 receptors in normal, cirrhotic, and neoplastic human livers

Abstract

Transforming growth factor-Beta 1 (TGF-beta 1) is an important mediator of control of liver cell proliferation and replication. The aim of the current study was to compare TGF-beta 1 gene expression, protein synthesis, and cell membrane receptors in normal liver, cirrhotic nodules, and neoplastic human livers. Five surgical resections for metastasis in an otherwise normal liver and 25 resections for hepatocellular carcinoma with cirrhosis were included in this study. Messenger RNA (mRNA) and TGF-beta 1 protein were detected on serial tissue sections of normal, cirrhotic, and tumoral livers using in situ hybridization and immunohistochemistry. TGF-beta 1 type II receptors were detected on tissue sections using immunohistochemistry. In normal livers, TGF-beta 1 mRNA and protein were not significantly expressed. In cirrhotic nodules, a few sinusoidal cells and mesenchymal cells of fibrous septa displayed TGF-beta 1 mRNA. By immunohistochemistry, protein was detected in the extracellular matrix along the fibrous septa. Hepatocytes from normal and cirrhotic livers did not express TGF-beta 1. In contrast, the cytoplasm of hepatocytes in neoplastic nodules showed intense staining for TGF-beta 1 mRNA and protein. Although TGF-beta 1 receptor II was expressed on the plasma membrane of normal liver cells, tumoral hepatocytes no longer displayed membrane labeling but rather diffuse intracytoplasmic staining with perinuclear accumulation. This study suggests that the escape of tumoral hepatocytes from control of cell proliferation by TGF-beta 1, despite its overexpression by these cells, might be related to a defect in TGF-beta 1 receptor II processing on the liver cell membrane.