Nitric Oxide in Mammary Tumor Progression
Abstract
Nitric Oxide (NO) is a potent bioactive molecule produced in the presence of endothelial (e), neuronal (n) and inducible (i) types of NO synthase (NOS) enzymes. We discovered that IL-2 therapy-induced capillary leakage was due to iNOS induction followed by overproduction of NO and then peroxyhnitrite. 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 C 10 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 resulted from an upregulation of MMP-2 and a downregulation of MMP inhibitors TIMP-2 and TIMP-3. Migration stimulation by NO resulted from activation of MAP- kinase pathway Thus NOS inhibitors should have a valuable therapeutic role for blocking multiple steps in mammary tumor growth and metastasis such as tumor cell migration, invasion and angiogenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA384092
Entities
People
- Peeyush Lala
Organizations
- Western University