Nitric Oxide in Mammary Tumor Progession
Abstract
Nitric Oxide (NO) is a potent bioactive molecule produced in the presence of endothelial (e), neuronal (n) and inducible (i) types of NO synthases (NOS) enzymes. We have shown that NO was responsible for IL-2 therapy-induced capillary leakage because of iNOS induction in various tissues by IL-2 therapy. We also found that tumor-derived NO promoted mammary tumor progression in C3H/HeJ mice. eNOS expression by tumor cells was positively correlated with metastasis in spontaneous C3H/HeJ mammary tumors and transplants of two clonal derivatives of a spontaneous tumor differing in metastatic phenotype: highly metastatic C3L5 and weakly metastatic Cl0 cell lines. These cell lines also exhibited a parallel difference in invasiveness in vitro and growth rates as well as angiogenic abilities in vivo. A causal relationship between NO production by the tumor cells and invasive, migratory and angiogenic abilities was demonstrated. Invasion stimulation by NO was mediated by an upregulation of matrix degrading enzyme matrix metalloprotease (MMP)2 and a downregulation of MMP inhibitors TIMP-2 and TIMP-3. Thus tumor-derived NO promoted mammary tumor progression by stimulating tumor cell migration, invasiveness and angiogenesis, indicating a valuable therapeutic role of NOS inhibitors for blocking multiple steps in tumor growth and metastasis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1999
- Accession Number
- ADB252024
Entities
People
- Peeyush K. Lala
Organizations
- Western University