title: Role of nitric oxide in tumour progression with special reference to a murine breast cancer model.
abstract: Nitric oxide (NO) is a potent bioactive molecule produced in the presence of NO synthase (NOS) enzymes, which mediates numerous physiological functions under constitutive conditions. Sustained overproduction of NO (and NO-reaction products), typically under inductive conditions, can lead to cell cycle arrest and cellular apoptosis. Furthermore, carcinogenesis may result from mutational events following NO-mediated DNA damage and hindrance to DNA repair (e.g., mutation of tumour-suppressor gene p53). In a majority of human and experimental tumours, tumour-derived NO appears to stimulate tumour progression; however, for a minority of tumours, the opposite has been reported. This apparent discrepancy may be explained by differential susceptibility of tumour cells to NO-mediated cytostasis or apoptosis, and the emergence of NO-resistant and NO-dependent clones. NO-resistance may be mediated by p53 inactivation, and upregulation of cyclo-oxygenase-2 and heat shock protein 70 (HSP70). In a murine mammary tumour model, tumour-derived NO promoted tumour growth and metastasis by enhancing invasive, angiogenic, and migratory capacities of tumour cells. Invasion stimulation followed the altered balance of matrix metalloproteases and their inhibitors; migration stimulation followed activation of guanylate cyclase and MAP kinase pathways. Selective NOS inhibitors may have a therapeutic role in certain cancers.
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Canada.
authors.forename: Lorraine C
authors.initials: LC
authors.lastname: Jadeski
authors.forename: Chandan
authors.initials: C
authors.lastname: Chakraborty
authors.forename: Peeyush K
authors.initials: PK
authors.lastname: Lala
mesh_terms: D000818:Animals; D002455:Cell Division; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D018840:HSP70 Heat-Shock Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases; D006162:Guanylate Cyclase