Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-␤1 (TGF-␤1)and thus a potential target for antifibrotic treatment strategies. CTGF is up-regulated in disorders such as atherosclerosis, scleroderma, and fibrosis of kidneys and lungs. We investigated the temporospatial expression patterns of CTGF and TGF-␤1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl 4 ) and with advanced fibrosis (6 weeks after complete bile duct occlusion). Multiprobe ribonuclease protection assay revealed increasing TGF-␤1 and CTGF mRNA levels 6 hours after injection of CCl 4 , with peak levels after 72 hours. In biliary fibrosis TGF-␤1 and CTGF mRNA levels increased fourfold and sevenfold, respectively (P < 0.001). In situ hybridization combined with cell-specific markers revealed CTGF transcripts in desmin-positive cells after a single dose of carbon tetrachloride, whereas no transcripts were found in normal livers. In biliary fibrosis, however, proliferating bile duct epithelial cells were the predominant source of CTGF mRNA. We conclude that in rat liver fibrogenesis CTGF is up-regulated in close association with TGF-␤1 and that, contrary to a previous report, not solely hepatic stellate cells but ac- Connective tissue growth factor (CTGF) is a cysteine-rich polypeptide identified originally in human umbilical vein endothelial cells by its chemotactic and mitogenic effects on fibroblasts.

Insulin-like growth factor (IGF)-2 is overexpressed in hepatocellular carcinoma and accompanying dysplastic lesions. IGF-2 signalling is mediated through IGF-1 receptor (IGF-1R), while mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF-2R) controls pericellular levels of free IGF-2. We studied, by in situ hybridisation and immunohistology, 18 liver specimens with cirrhosis of different aetiology without neoplastic or dysplastic lesions. Immunohistology was also performed for insulin receptor IGF-1R and IGF-binding proteins 3 and 4. High focal levels of IGF-2 RNA were found in some hepatocytes of all livers with HBV-or HCV-induced cirrhosis (n ¼ 10), but in only one of the cirrhoses with nonviral aetiology (n ¼ 8). IGF-2 was overexpressed in biliary duct epithelial cells in one case. Compared with noncirrhotic liver, all cirrhotic specimens showed reduced hepatocellular expression of M6P/IGF-2R protein, which contrasted with enhanced expression in perisinusoidal cells. Immunostaining for the other antigens did not reveal significant differences. Upregulation of IGF-2 in some hepatocytes may lead to high focal IGF-2 levels sufficient to saturate local IGF-2 binding capacities, and may result in an increased susceptibility to cellular dedifferentiation and, ultimately, liver cancer. Downregulation of hepatocellular M6P/IGF-2R and upregulation of IGF-2 seem to be early events in hepatocarcinogenesis prior to the appearance of morphologically distinct dysplastic lesions. Elevated focal IGF-2 transcript levels may therefore indicate an increased risk for hepatocellular and cholangiocellular carcinomas.

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