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Expression of Transforming Growth Factor ß Type II Receptor Reduces Tumorigenicity in Human Gastric Cancer Cells¹

Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892 [J. C., D. K., S-J. K.]; Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea [K. P., W. S. K.]; and Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea [Y-J. B.]

Expression of transforming growth factor ß (TGF-ß) receptor type II (RII) is required for the growth-inhibitory effects of TGF-ß on proliferating epithelial cells. TGF-ß 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-ß resistance in cell lines derived from these tumors. In this study, the role of TGF-ß 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-ß RII. The SNU-638 cell line displays the DNA replication error phenotype and encodes a truncated, inactive TGF-ß RII protein. Infection of these cells with retroviral constructs expressing wild-type TGF-ß RII led to significant increases in TGF-ß RII mRNA and protein expression. These cells responded to exogenous TGF-ß with reduced proliferation compared to that of control cells infected with retroviral vector expressing chloramphenicol acetyltransferase. Addition of TGF-ß-neutralizing antibodies led to increased proliferation of wild-type TGF-ß RII-expressing SNU-638 cells but had no effect on control cells. The latter finding suggests that TGF-ß acts in an autocrine fashion to inhibit cell proliferation in SNU-638 cells. When transplanted into athymic nude mice, wild-type TGF-ß 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-ß RII and the degree of malignancy in human gastric cancer cells.

¹ Supported in part by HAN Project of Korean Ministry of Science and Technology (MOST 8-1-10). J. C. and K. P. contributed equally to this work.

² Present address: Department of Orthopedic Surgery, Massachusetts General Hospital, Boston, MA 02115.

³ To whom requests for reprints should be addressed, at Laboratory of Chemoprevention, National Cancer Institute, Building 41, Room B1106, Bethesda, MD 20892-5055.

Received 4/ 3/97. Accepted 5/29/97.

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