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 p roliferative ability of normal hepatocytes was correlated with a marke d elevation in hepatic concentration of the potent mito-inhibitory fac tor, transforming growth factor-beta 1 (TGF-beta 1). PB also increased the mannose 6-phosphate/insulin-like growth factor-II (M6P/IGF-II) re ceptor concentration in hepatocytes, with a concomitant up-regulation in gene expression. Since the M6P/IGF-II receptor facilitates the prot eolytic 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-bet a 1 in response to PB. These findings emphasize the potential importan ce 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 t he tumor cells with an important selective growth advantage.