Tumor-associated macrophages can potentially kill tumor cells via the high concentrations of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS); however , tumor-associated macrophages actually support tumor growth , as they are skewed toward M2 activation , which is characterized by low amounts of NO production and is proangiogenic. We show that the mouse renal cell carcinoma cell line, RENCA , which , on stimulation , expresses high levels of iNOS mRNA , loses its ability to express the iNOS protein. This effect is mediated by the microRNA miR146a , as inhibition of RENCA cells with anti-miR146a restores iNOS expression and NO production Tumor-associated macrophages (TAMs) typically infiltrate and accumulate in solid tumors, 1 and are equipped with efficient killing mechanisms, such as production of high cytotoxic amounts of nitric oxide (NO) by the enzyme inducible nitric oxide synthase (iNOS).2,3 High NO concentrations can either initiate tumor cell apoptosis (cytotoxic effects) or arrest cell cycle (cytostatic effects), as NO or its derivatives cause nitrosative stress that can release cytochrome c, increase nuclear accumulation of wild-type p53, and reduce Bcl-2.4 -6 However, the factors that determine whether the mechanism used would lead to cytotoxicity or cytostasis are still unknown.Expression of iNOS is up-regulated in many tumors, but immunohistochemistry reveals that it is mostly expressed in TAMs and only to a lesser degree in the tumor cells themselves. 7 However, TAMs are often ineffective in tumor killing and actually promote tumor growth. The paradox of strong iNOS expression that is correlated 8 with aggressiveness and high incidence of metastasis (eg, in breast, gastric, and colorectal carcinomas 7 ), is explained by the levels of NO that are, in fact, generated. While high levels of NO cause tumor-cell death, low amounts of NO actually promote tumor growth, angiogenesis, and metastasis by regulating blood flow, increasing vascular permeability, and up-regulating vascular endothelial growth factor and matrix metalloproteinases. -11Control over NO production is subject to the polarization of TAMs toward an alternative or M2 activation by anti-inflammatory mediators that are secreted by tumor cells; eg, interleukin-10, transforming growth factor , and prostaglandin E 2 . These mediators can induce arginase-1, which competes with iNOS for the common substrate L-arginine, causing reduced NO generation.9 Hypoxia, characterizing solid tumors, can also reduce NO production by disrupting protein-protein interactions that are required for iNOS activity.
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