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Nitric Oxide, Prostanoids, Cyclooxygenase, and Angiogenesis in Colon and Breast Cancer¹

Huntington Medical Research Institutes, Department of Experimental Cardiology, Pasadena, California 91101 [R. J. B., M. M., K. A. R., N. H.]; Huntington Memorial Hospital, Department of Pathology, Pasadena, California 91109 [X. W., H. D. S.]; and University of Southern California, Department of Pathology, Los Angeles, California 90033 [S-R. S.]

Purpose: Several studies have shown an overexpression of cyclooxygenase-2 (COX-2) and elevated levels of prostacyclin (PGI₂) and thromboxane (TXA₂) in colon cancer. In this report, we determined the distribution of inducible form of nitric oxide synthase (iNOS), PGI₂, and TXA₂ in cancerous and adjoining areas of specimens from human colon and breast cancer obtained during surgery. Additionally, we investigated differences in expression and histological localization of COX-2 in colon and breast cancer.

Experimental Design: Specimens were obtained during surgery, one centrally located, the second from an adjacent, cancer-free area. Activity of iNOS was determined, using the conversion of L-[¹⁴C]arginine to L-[¹⁴C]citrulline. PGI₂ and TXA₂ were measured as their stable metabolites, using enzyme immunoassay. A standard immunoperoxidase method was used for immunohistochemical expression of COX-2.

Results: Significant differences in iNOS, PGI₂, and TXA₂ expressions between colon and breast cancer were noted, with an enhanced expression of COX-2 in colon cancer, including the cancerous, adjoining, and stromatous fields.

Conclusions: Increased expression of iNOS and production of prostanoids in colon cancer parallels the increase in COX-2, confirming the importance of this enzyme in colon cancer. The overexpression of COX-2, prostanoids, and nitric oxide in areas adjoining the tumor indicates increased metastatic potential for neoplastic cells in this area. Inflammatory changes in the tissue adjoining the cancer may play a role. COX-2 may result in the formation of new blood vessels and the spread of cancer.

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