Role of nitric oxide in tumour progression with special reference to a murine breast cancer model

• Published in: Canadian journal of physiology and pharmacology 2002-02, Vol.80 (2), p.125-135
• Main Authors: Jadeski, Lorraine C, Chakraborty, Chandan, Lala, Peeyush K
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Breast cancer; Cell Division; Cyclooxygenase 2; Disease Models, Animal; Disease Progression; Female; Guanylate Cyclase - metabolism; Gynecology. Andrology. Obstetrics; HSP70 Heat-Shock Proteins - metabolism; Humans; Isoenzymes - metabolism; Mammary gland diseases; Mammary Neoplasms, Experimental - blood supply; Mammary Neoplasms, Experimental - enzymology; Mammary Neoplasms, Experimental - pathology; Medical sciences; Membrane Proteins; Metalloendopeptidases - metabolism; Mice; Mitogen-Activated Protein Kinases - metabolism; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Nitric oxide; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - physiology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Prostaglandin-Endoperoxide Synthases - metabolism; Tumor Suppressor Protein p53 - physiology; Tumors
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/y02-007

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.Key words: nitric oxide, carcinogenesis, invasion, metastasis, angiogenesis.