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(American Journal of Pathology. 2000;157:1523-1535.)
© 2000 American Society for Investigative Pathology

Regular Articles

Induction of Angiogenesis by Hyperplastic Colonic Mucosa Adjacent to Colon Cancer

Hiroki Kuniyasu^*, Wataru Yasui, Hisashi Shinohara^*, Seiji Yano^*, Lee M. Ellis^*, Michael R. Wilson^*, Corazon D. Bucana^*, Tadayoshi Rikita^§, Eiichi Tahara and Isaiah J. Fidler^*

From the Departments of Cancer Biology^*
and Surgical Oncology,
The University of Texas M. D. Anderson Cancer Center, Houston, Texas; the J. R. Hiroshima General Hospital of the West Japan Railway Company, ^§
Hiroshima, Japan; and the First Department of Pathology,
Hiroshima University School of Medicine, Hiroshima, Japan

We determined whether hyperplastic mucosa adjacent to colon cancer contributes to neoplastic angiogenesis. Surgical specimens of human colon cancer (40 Dukes’ stage B and 34 Dukes’ stage C) were analyzed by immunohistochemistry for expression of proliferative and angiogenic molecules. The mucosa adjacent to Dukes’ stage C tumors (but not Dukes’ stage B tumors) had a higher Ki-67 labeling index and a higher expression of epidermal growth factor receptor and transforming growth factor- than distant mucosa. The expression levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin-8, and the vascular density in the adjacent mucosa were similar to those in the tumor lesions and significantly higher than those in the distant mucosa. The expression of interferon-ß inversely correlated with the level of pro-angiogenic molecules and the vascular density. The injection of metastatic human colon cancer cells and murine colon cancer cells into the cecal wall of mice induced hyperplastic changes in the adjacent mucosa which expressed higher levels of epidermal growth factor receptor, basic fibroblast growth factor, and vascular endothelial growth factor, and lower levels of interferon-ß than did the control mucosa, which directly correlated with the degree of hyperplasia. These data suggest that metastatic human colon cancer cells can induce hyperplasia in the adjacent mucosa, which in turn produces angiogenic molecules that contribute to neoplastic angiogenesis.

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