Controlled release of TGF-beta1 impedes rat colon carcinogenesis in vivo.

ABSTRACT

Transforming growth factor beta1 (TGF-beta1) is a cytokine known to play a key role in the control of cell growth. TGF-beta1 potently inhibits the proliferation of human and rodent-derived epithelial cells. Colonic precancerous and moderately differentiated cancer cells are responsive to TGF-beta1, whereas malignant colon cancer cells are resistant to the inhibitory action of the cytokine. These observations have been derived exclusively from in vitro studies. Therefore, the main aim of our study was to determine whether TGF-beta1 exerts a growth-restraining action on colon carcinogenesis in vivo. TGF-beta1 was sequestered into ethylene acetate copolymer matrices and "loaded" preparations were implanted intraperitoneally (i.p.) in rats. One week later, the animals were treated with dimethylhydrazine (DMH), a colon procarcinogen. Empty matrices devoid of TGF-beta1 but containing bovine serum albumin (BSA) carrier served as the appropriate control preparations. The number of aberrant crypt foci (ACF), considered to be preneoplastic lesions of the colon, was scored. Tumor formation and size were assessed at the appropriate times. TGF-beta1 released in a sustained manner from copolymer matrices (i) markedly inhibited colonic ACF formation and the number of aberrant crypts and (ii) significantly reduced colonic tumor formation and size.