Elsevier

The Lancet Oncology

Volume 2, Issue 3, March 2001, Pages 149-156
The Lancet Oncology

Review
Role of nitric oxide in carcinogenesis and tumour progression

https://doi.org/10.1016/S1470-2045(00)00256-4Get rights and content

Summary

Nitric oxide(NO) is a short-lived molecule required for many physiological functions, produced from Larginine by NO synthases (NOS). It is a free radical, producing many reactive intermediates that account for its bioactivity. Sustained induction of the inducible form of NOS (iNOS) in chronic inflammation may be mutagenic, through NO-mediated DNA damage or hindrance to DNA repair, and thus potentially carcinogenic. Expression of iNOS is positively associated with P53 mutation in tumours of the colon, lung, and oropharynx. Progression of a large majority of human and experimental tumours seems to be stimulated by NO resulting from activation of iNOS or constitutive NOS, whereas inhibition is documented in others. This discrepancy is largely explained by differential sensitivity of tumour cells to NO-mediated cytostasis or apoptosis and clonal evolution of NO resistant and NO-dependent cells. P53 mutation or loss is one of many events linked with NO resistance and dependence. NO can stimulate tumour growth and metastasis by promoting migratory, invasive, and angiogenic abilities of tumour cells, which may also be triggered by activation of cyclo-oxygenase (COX)-2. Thus, selective inhibitors of NOS, COX, or both may have a therapeutic role in certain cancers.

Section snippets

Role of NO in carcinogenesis

Transition of a normal somatic cell to a cancer cell is generally the result of many genetic changes, involving activation of oncogenes or inactivation of tumoursuppressor genes. These changes allow the cell to escape normal control mechanisms in cell proliferation, differentiation, migration, and death, which collectively maintain the normal cellular architecture and functions in an organised tissue. The frequency of somatic mutations leading to carcinogenesis in human beings is dictated

Role of NO in tumour progression

Progression of a newly developed tumour involves sequential changes in both cellular phenotype and genotype (Figure 1). These changes have been best correlated during the progression of colonic tumours. Phenotypically, these tumours appear as non-invasive benign adenomatous polyps, some of which progress into invasive carcinomas, and metastatic spread of carcinoma cells to distant organs follows. Some of the genetic changes associated with these phenotypically defined stages have been

Positive association of NO with tumour progression

This type of association has been overwhelming for many human and experimental tumours. The amount of immunoreactive NOS protein, its activity, or both, in the tumour has been positively related to the degree of malignancy for tumours of the human reproductive tract,21 breast22, 23 and central nervous system.24 In breast cancer, iNOS expression by macrophages, stromal cells, and tumour cells22, 23, 25 accounted for most of the NOS activity. In a sample of 111 tumours (43 in situ and 68 invasive

Inverse association between NO and tumour progression

The amount of NOS protein and NOS enzyme activity were reported to decline during the transition of human colonic mucosa to polyps and then to carcinomas.36 However, as discussed earlier, similar findings by Ambs and colleagues37 and their correlation with P53 mutation17 were interpreted as high NOS activity in colonic adenomas contributing to P53 mutation as well as angiogenic responses promoting transition to carcinomas. In various murine melanoma cell lines, NOS activity was inversely

Possible reasons for the conflicting roles of NO in tumour progression

Of the many variables that may explain the discrepancies in the results described above, the most important seems to be the genetic constitution of cells that may determine NO sensitivity or resistance. We have proposed that the genetic make-up of tumour cells and the concentrations of NO in the tumour-cell microenvironment are the main determinants of the role of NO.3 During clonal evolution of tumours in the presence of high NO concentrations, NO-sensitive cells may be deleted and

NO and tumour-cell proliferation/survival

There is no compelling evidence that NO can directly stimulate tumour-cell proliferation. By contrast, cytostatic and cytotoxic roles have been demonstrated. NO stimulates the accumulation of P53 protein in many cells, at least partly by inhibition of proteosomal degradation of the protein.41 Because P53 causes transcriptional activation of many genes that lead to cell-cycle arrest (eg P21, cyclin G) and apoptosis (eg BAX and FAS), NO at high concentrations can cause P53-dependent cell-cycle

NO and tumour-cell apoptosis

The apoptotic process generally starts with the release of cytochrome C from mitochondria into the cytosol, where it binds to an adaptor molecule, apoptotic-protease-activating factor 1. The resultant complex activates the initiation caspases8, 9, 10 which in turn, activate execution caspases,3, 6, 7 and these catalyse the final events, DNA fragmentation and formation of apoptotic bodies.

The role of NO in tumour-cell apoptosis and survival depends on the cell type, the concentration of NO in

Role of other events in NO resistance or sensitivity to apoptosis

COX-2 is involved in conferring NO resistance.51, 52 When NO-sensitive cells (RAW264.7 macrophage line) were transfected with a COX-2 expression vector51 or pretreated with small amounts of NO to induce the enzyme through the activation of nuclear factor-κB and activator protein-1,52 the cells became resistant to high doses of NO.

The amount and activity of Cu, Zn-superoxide dismutase dictated the outcome of NO challenge to a human neuroblastoma cell line SH-SY5Y, transfected with a functional

NO and angiogenesis

Angiogenesis is defined as the process of development of new blood vessels from pre-existing vessels, as opposed to vasculogenesis, which is the process of de novo formation of blood vessels from vasculogenic precursor cells in the embryo. Angiogenesis occurs normally in the ovary and the uterus during the reproductive cycle, in the pregnant uterus, and as part of wound healing. It also occurs under various pathological conditions, including the growth of solid tumours, which require

Role of NO in host antitumour immunity

Cells of the host immune system able to mount antitumour defence are activated natural killer cells, T cells, and activated macrophages. Of the effector molecules released by these cells that can inflict damage on tumour target cells, NO is important primarily for cytotoxic macrophages3 and, to a lesser extent, for natural killer cells.71 However, at the same time, there is strong evidence to suggest that macrophage-derived NO inhibits antitumour responses of cytotoxic T lymphocytes in vivo,

Role of COX-2 in NO-mediated stimulation of tumour progression

NO can also promote tumour progression by stimulating COX-2, the rate-limiting enzyme for high-output production of prostanoids. Concentrations of both NO and prostaglandins have been positively associated with inflammation and with tumour progression. Several studies in inflammation models have shown reciprocal interactions between NOS and cyclo-oxygenase pathways, most of which show stimulation of COX-2 by NO, although inhibition has also been documented in some cases. Conversely, NOS enzymes

Conclusion

The role of NO in tumour biology is complex, because it has both facilitatory and inhibitory roles in cellular processes depending on the conditions, such as the genetic make-up of the cells, the local concentration of NO, and the presence of other regulators such as NO scavengers. Nevertheless, we now have a better knowledge of how these variables regulate NO action on cellular processes responsible for carcinogenesis and tumour progression. Some of the molecular pathways have been identified.

Search strategy and selection criteria

Referred papers were identified by MEDLINE search through the PubMed database (1986 – 2000) by combining the key word 'nitric oxide' with the keywords: carcinogenesis, mutagenesis, apoptosis and tumour, endothelial cell and tumour, angiogenesis. Further search was made by combining the words 'nitric oxide and tumour' for the following journals: Cancer Research, Journal of the National Cancer Institute, British Journal of Cancer, Journal of Biological Chemistry, Journal of Clinical

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