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Review
. 2008 Sep;19(2):95-102.
doi: 10.1016/j.niox.2008.04.021. Epub 2008 Apr 29.

Nitric oxide, apoptosis and macrophage polarization during tumor progression

Andreas Weigert  1 , Bernhard Brüne
Affiliations
Review

Nitric oxide, apoptosis and macrophage polarization during tumor progression

Andreas Weigert et al. Nitric Oxide. 2008 Sep.

Abstract

Decreased oxygen availability evokes adaptive responses, which are primarily under the gene regulatory control of hypoxia inducible factor-1 (HIF-1). Hypoxic cores of a growing tumor cell mass use this signaling circuit to gain access to further blood and nutrient supply that guarantees their continuing growth. Interestingly, NO shares with hypoxia the ability to block prolyl-hydroxylase (PHD) activity, and thus the ability to stabilize hypoxia inducible factor 1 alpha (HIF-1 alpha). Under these conditions NO mimics hypoxia, which might contribute to tumor development. Stimulating/triggering innate immune responses associated with macrophage activation often correlated with iNOS induction and massive NO release, which is known to kill NO-sensitive tumors. However, this safeguard mechanism will only be effective if all tumor cells are eliminated because apoptotic death of tumor cells implies mechanisms to stop macrophages from attacking the survivors. Apoptotic cells release factors, among others sphingosine-1-phosphate (S1P), which reprogram macrophages. Macrophage reprogramming shifts responses from a M1 and thus pro-inflammatory and killing phenotype, to a M2 phenotype, which is anti-inflammatory and pro-angiogenic. These polarized tumor associated macrophages (TAM) are actively contributing to tumor development. Apparently NO uses distinct signaling pathways that could serve as an explanation to understand how NO affects tumor development. Some of these pathways, especially the ability of NO to mimic hypoxia at the level of HIF-1 alpha, as well as the role of macrophage polarization by apoptotic cells with accompanying changes in the iNOS versus arginase ratio and activities, will be discussed to better understand how NO affects tumor growth.

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