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Contextual Effects of Transforming Growth Factor ß on the Tumorigenicity of Human Colon Carcinoma Cells¹

Department of Biochemistry and Molecular Biology, Medical College of Ohio at Toledo, Toledo, Ohio 43614-2595 [S-C. Y., W. L., J. L., S. V., J. G., M. G. B.], and Ireland Cancer Center and Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106 [J. M. F., E. Z., J. K. V. W.]

Transforming growth factor ßs (TGF-ßs) are a growth factor family with negative autocrine growth functions for most epithelial cells including colon carcinoma cell lines. Both type I (RI) and type II (RII) transmembrane TGF-ß receptors have been shown to be indispensable for TGF-ß-mediated cell growth regulation. Previous studies using different model systems have shown that both overexpression of TGF-ß1 and transfection of antisense TGF-ß1 to reduce TGF-ß1 expression could lead to increased tumorigenicity. These results are seemingly contradictory and suggest that effects of TGF-ß modulation on malignant properties of cancer cells may be contextual. This study addresses this issue using human colon carcinoma cells (CBS and FET) to determine the effects of modulation of the various components of the TGF-ß system on in vitro and in vivo growth properties in two independent isogenic models of colon carcinoma. Cells were stably transfected with a tetracycline-repressible RII expression vector (CBS4-RII), a tetracycline-repressible expression vector containing a truncated RII cDNA lacking the serine/threonine kinase domain (CBS4-RII and FET6-RII), or with a vector containing the TGF-ß1 cDNA (CBS4-ß1S and FET-ß1S). Expression of the truncated RII reduced TGF-ß sensitivity, whereas overexpression of RII increased TGF-ß sensitivity. TGF-ß overexpression did not affect TGF-ß response. In vivo tumorigenicity assays revealed that CBS4-RII cells had lower tumorigenicity than control cells, whereas CBS4-RII and CBS4-ß1S had higher tumorigenicity than controls. The CBS4 cells are poorly tumorigenic in athymic mice, and the wild-type FET6 cells are nontumorigenic. FET6-RII cells formed rapidly growing tumors, and FET-ß1S cells also formed tumors. These data illustrate the paradoxical tumor-promoting and -suppressing effects of TGF-ß signaling activity in two isogenic model systems from human colon carcinomas, thus demonstrating that the effects of modulation of TGF-ß expression or TGF-ß signaling capability affects malignancy in a contextual manner.

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