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Abnormalities in the Expression of Cell Cycle-related Proteins in Tumors of the Small Bowel¹

Gastrointestinal Oncology Unit, Department of Gastroenterology, Tel Aviv Sourasky Medical Center [N. A., D. R.] and Department of Histology and Cell Biology, Tel-Aviv University [N. A., A. S., I. S., D. R., I. F.], Tel Aviv 64239, Israel; the Herbert Irving Comprehensive Cancer Center [H. H., A. I. N., Y. Y., I. B. W., P. R. H.], Departments of Pathology [H. H., B. W.] and Medicine [A. I. N., I. B. W., P. R. H.], and School of Public Health [A. I. N.], College of Physicians and Surgeons, Columbia University and Division of Gastroenterology, St. Luke’s-Roosevelt Hospital Center [P. R. H.], New York, New York 10032; Division of Biostatistics, San Jose University California [A. H.]; and First Department of Pathology, Hiroshima University School of Medicine, Hiroshima 565-0875, Japan [W. Y., H. Y., E. T.]

Tumors of the small bowel are quite rare for unknown reasons, although they resemble colorectal tumors in many respects. The purpose of this study was to determine whether abnormalities in the expression of several cell cycle control genes are of importance in small bowel tumorigenesis by comparing a series of samples of normal mucosa, adenomatous polyps, and adenocarcinomas. The levels of cyclin D1, cyclin E, p16, p21, p27, and p53 proteins were determined by immunohistochemistry in samples of normal small bowel (n = 16), small bowel adenomas (n = 20), and small bowel adenocarcinomas (n = 24). Normal small bowel mucosa expressed p27 protein, but not the other cell cycle-related proteins. About 20% of the tumors displayed a decrease in the expression of this protein. The most frequent alteration in the tumors was an increase in the p16 protein. Increased expression of p53 was associated with tumor progression because it was overexpressed in 45% of the adenomas and 65% of the adenocarcinomas (P < 0.05). Advanced age and increased detection of cyclin D1 and p53 were associated with a decreased 3-year survival (P < 0.05). Cell cycle abnormalities are early and important events in the multistep process of small bowel tumorigenesis, thus resembling colorectal carcinogenesis. As in colon cancer, deregulated expression of G₁ proteins may perturb cell cycle control in benign adenomas of the small bowel and thereby enhance tumor progression. Increased expression of cell cycle inhibitors in tumors may serve as a defense mechanism for tumor progression.

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