Regulation of mannose 6-phosphate/insulin-like growth factor-II receptors and transforming growth factor beta during liver tumor promotion with phenobarbital.

Chronic exposure of rats to the liver tumor promoter phenobarbital (PB) significantly reduces the ability of normal hepatocytes, but not of initiated hepatocytes, to respond to mitogenic stimuli. This reduced proliferative ability of normal hepatocytes was correlated with a marked elevation in hepatic concentration of the potent mito-inhibitory factor, transforming growth factor-beta 1 (TGF-beta 1). PB also increased the mannose 6-phosphate/insulin-like growth factor-II (M6P/IGF-II) receptor concentration in hepatocytes, with a concomitant up-regulation in gene expression. Since the M6P/IGF-II receptor facilitates the proteolytic activation of TGF-beta 1, this suggests that PB increases the capacity of normal hepatocytes to activate TGF-beta 1. In contrast, a subset of preneoplastic lesions induced with N-nitrosodiethylamine did not demonstrate elevated levels of the M6P/IGF-II receptor or TGF-beta 1 in response to PB. These findings emphasize the potential importance of TGF-beta 1 during liver tumor promotion with PB and suggest that reduction of M6P/IGF-II receptor levels in liver tumors may provide the tumor cells with an important selective growth advantage.