Expression of transforming growth factor β type II receptor reduces tumorigenicity in human gastric cancer cells

Abstract

Expression of transforming growth factor beta (TGF-beta) receptor type II (RII) is required for the growth-inhibitory effects of TGF-beta on proliferating epithelial cells, TGF-beta RII mutations have been identified in a broad spectrum of human epithelial malignancies, including colon and gastric cancers, and are highly correlated with development of TGF-beta resistance in cell lines derived from these tumors, In this study, the role of TGF-beta RII in regulating the tumorigenic potential of the SNU-638 human gastric cancer cell line was investigated by infecting these cells with retroviral construct (MFG) expressing TGF-beta RII, The SNU-638 cell line displays the DNA replication error phenotype and encodes a truncated, inactive TGF-beta RII protein, Infection of these cells with retroviral constructs expressing wild-type TGF-beta RII led to significant increases in TGF-beta RII mRNA and protein expression, These cells responded to exogenous TGF-beta with reduced proliferation compared to that of control cells infected with retroviral vector expressing chloramphenicol acetyltranferase. Addition of TGF-beta-neutralizing antibodies led to increased proliferation of wild-type TGF-beta RII-expressing SNU-638 cells but had no effect on control cells, The latter finding suggests that TGF-beta acts in an autocrine fashion to inhibit cell proliferation in SNU-638 cells, When transplanted into athymic nude mice, wild-type TGF-beta RII-expressing SNU-638 cells showed decreased and delayed tumorigenicity compared with control cells, This study suggests a strong association between the expression of wild-type TGF-beta RII and the degree of malignancy in human gastric cancer cells.