Nitric Oxide in Mammary Tumor Progression
Annual rept. 1 Jul 1997-30 Jun 1998
UNIVERSITY OF WESTERN ONTARIO LONDON
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Nitric Oxide NO is a potent bioactive molecule produced in the presence of endothelial e, neuronal n or inducible i types of NO synthase NOS enzymes. We had earlier shown that treatment with NOS inhibitors reduced tumor growth and metastasis of C3HHeJ murine mammary carcinomas, mitigated IL-2 therapy-induced capillary leakage and improved antitumor effects of IL-2. These results suggested that NO promoted mammary tumor progression and mediated IL-2 therapy-induced capillary leakage. Present proposal was to identify the underlying mechanisms for the above. Results to date reveal that eNOS expression by tumor cells is positively associated with metastasis in spontaneous C3HHeJ mammary tumors and their clonal derivatives differing in their ability for spontaneous lung metastasis that endogenous and induced NO promoted invasiveness of the highly metastatic C3L5 mammary tumor line owing to an upregulation of matrix-degrading enzyme matrix metalloprotease MMP-2 and downregulation of MMP inhibitors TIMP-2 and TIMP-3 that endogenous NO promoted C3L5 mammary tumor angiogenesis in a tumor-angiogenesis model devised in this laboratory. Thus NOS inhibitors may have a valuable role in cancer therapy.
- Anatomy and Physiology
- Medicine and Medical Research