DECREASED TRANSFORMING-GROWTH-FACTOR-BETA-TYPE-II RECEPTOR EXPRESSIONIN INTESTINAL ADENOMAS FROM MIN + MICE IS ASSOCIATED WITH INCREASED CYCLIN D1 AND CYCLIN-DEPENDENT KINASE 4 EXPRESSION/

Tumor cells often become resistant to the growth-inhibitory effects of transforming growth factor beta (TGF-beta). Recent studies have ident ified TGF-beta type II receptor (RII) mutations in a subset of cancers , including colon cancer. To evaluate the expression of TGF-beta RII i n premalignant intestinal adenomas and the relationship with cell cycl e regulation, we investigated the expression of TGF-beta RII, cyclin D 1, and cyclin-dependent kinase 4 (Cdk4) in Min/+ mouse intestinal aden omas. Immunohistochemistry indicated that TGF-beta RII cytoplasmic imm unoreactivity was undetectable in the proliferative crypt zones of the normal small intestinal and normal colonic epithelium but was abundan t toward the villus tips of the normal small intestine and the lumenal third of the colonic glands. As was observed in the proliferating cry pt zones, TGF-beta RII immunoreactivity was dramatically decreased or undetectable in all adenomas examined in comparison to the abundant le vels in adjacent normal differentiated intestinal epithelium. TGF-beta RII mRNA was also reduced in the adenomas in comparison to normal muc osa as determined by reverse transcription-PCR. In an inverse distribu tion to TGF-beta RII, Cdk4 nuclear immunoreactivity was restricted to the crypt regions of the small and large intestine, whereas cyclin D1 immunoreactivity was uniformly absent in normal intestinal epithelium. For both cyclin D1 and Cdk4, protein and mRNA levels were increased i n intestinal adenomas but not in normal intestinal epithelium as deter mined by immunohistochemistry, in situ hybridization, and reverse tran scription-PCR. In summary, the lack of TGF-beta RII expression was ass ociated with increased cyclin D1 and Cdk4 expression in Min/+ mouse in testinal adenomas. We hypothesize that the former may enable tumor cel ls to escape from the normal growth-constraining influence of TGF-beta , whereas the latter promotes inappropriate cell proliferation and ade noma progression.