EFFECT OF TRANSFORMING GROWTH-FACTOR-BETA ON RAT HEPATOCYTE CELL-LINES DEPENDS UPON THE STATE OF TUMORIGENIC PROGRESSION

The effect of transforming growth factor beta (TGF-beta) on morphology , actin cytoskeleton organization, anchorage-dependent proliferation, anchorage-independent proliferation, and alpha-fetoprotein secretion i n a series of related hepatocyte-derived cell lines was measured, We r eported previously that TGF-beta 1 partially suppressed the transforme d phenotype of a ras-transformed SV40-immortalized hepatocyte cell lin e designated NR4, In the present study, the CWSV14 cell line, which wa s derived by transfecting rat hepatocytes with SV40 DNA, was analyzed at low (14LP), mid (14MP), and high (14HP) passage, CWSV14 cells are w eakly tumorigenic at low passage and spontaneously transform with in v itro passaging. Tumor cell lines (14T1 and 14T2) derived from hepatoce llular carcinomas produced by CWSV14 cells were also analyzed, TGF-bet a 1 partially suppressed the transformed phenotype of 14HP, 14T1, and 14T2 cells but had no effect on cell proliferation in these cells, In contrast, TGF-beta 1 induced apoptosis in 14LP and 14MP cells, Studies using both the NR4 and 14T1 cells showed that suppression of the tran sformed phenotype also could be induced by TGF-beta 2 or TGF-beta 3, W e conclude that TGF-beta-induced suppression of the transformed phenot ype can be observed in ras- and spontaneously transformed hepatocyte c ell lines, It is also apparent that the effect of TGF-beta 1 on hepato cyte cell lines differs depending upon the state of progression toward malignancy; that is, while TGF-beta 1 suppressed the transformed phen otype in highly transformed and tumor cell lines representing late sta ges in progression, it induced apoptosis in weakly or moderately trans formed cell lines representing early stages in progression.