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Decreased Transforming Growth Factor ß Type II Receptor Expression in Intestinal Adenomas From Min/+ Mice Is Associated with Increased Cyclin D1 and Cyclin-dependent Kinase 4 Expression¹

Departments of Surgery [T. Z., L. B. N., M. O. P., R. D. B.], Medicine [R. N. D.], Cell Biology [L. B. N., C. S. W., K. J. H., R. N. D., R. D. B.], and Pathology [L. L.], the Vanderbilt Cancer Center [R. N. D., R. D. B.], Vanderbilt University School of Medicine, and the Veterans Affairs Medical Center [L. B. N., R. N. D.], Nashville, Tennessee 37232

Tumor cells often become resistant to the growth-inhibitory effects of transforming growth factor ß (TGF-ß). Recent studies have identified TGF-ß type II receptor (RII) mutations in a subset of cancers, including colon cancer. To evaluate the expression of TGF-ß RII in premalignant intestinal adenomas and the relationship with cell cycle regulation, we investigated the expression of TGF-ß RII, cyclin D1, and cyclin-dependent kinase 4 (Cdk4) in Min/+ mouse intestinal adenomas. Immunohistochemistry indicated that TGF-ß RII cytoplasmic immunoreactivity was undetectable in the proliferative crypt zones of the normal small intestinal and normal colonic epithelium but was abundant toward the villus tips of the normal small intestine and the lumenal third of the colonic glands. As was observed in the proliferating crypt zones, TGF-ß RII immunoreactivity was dramatically decreased or undetectable in all adenomas examined in comparison to the abundant levels in adjacent normal differentiated intestinal epithelium. TGF-ß RII mRNA was also reduced in the adenomas in comparison to normal mucosa as determined by reverse transcription-PCR. In an inverse distribution to TGF-ß 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 in intestinal adenomas but not in normal intestinal epithelium as determined by immunohistochemistry, in situ hybridization, and reverse transcription-PCR. In summary, the lack of TGF-ß RII expression was associated with increased cyclin D1 and Cdk4 expression in Min/+ mouse intestinal adenomas. We hypothesize that the former may enable tumor cells to escape from the normal growth-constraining influence of TGF-ß, whereas the latter promotes inappropriate cell proliferation and adenoma progression.

¹ Supported by United States Public Health Service Grants CA69457 (to R. D. B.), DK47297 and ES00267 (to R. N. D.), and AR41943 and GM40439 (to L. B. N.) and by funds from the Department of Veterans' Affairs (to L. B. N., R. N. D.).

² To whom requests for reprints should be addressed, at the Department of Surgery, CC-2306 MCN, Vanderbilt University Medical Center, Nashville, TN 37232-2730. Phone: (615) 343-8401; Fax: (615) 343-1355; E-mail: daniel.beauchamp@mcmail.vanderbilt.edu.

Received 1/10/97. Accepted 3/20/97.

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