Molecular Mechanisms of Inflammation Affecting Human Melanoma

Many cancers contain the products of inflammation, believed to be a result of both intrinsic cancer cell processes, and those from the microenvironment. Data in human melanoma suggests that the unique cancer-related form of “para-inflammation” leads to the production of reactive oxidants, which support tumor cell survival, proliferation and other functions. Molecules from the microenvironment driving melanoma include responses to the IL-1s ^[1] and IFNg ^[2], leading to poor patient prognosis associated with expression of inducible nitric oxide synthase (iNOS or NOS2), macrophage migration inhibitory factor and additional downstream mediators to be presented. Inflammatory molecules associating with good survival of melanoma patients are rare, but a strong association of CD-74 (MHC Class II invariant chain) protein expression in both the melanoma cells and also tumor-infiltrating lymphocytes has been recently confirmed by us (Ekmekcioglu, submitted). At the biochemical level, nitric oxide leads to the oxidation of important molecules, and identification of these post-translationally oxidized proteins in cancer cells mediating various effects has been studied, with both nitro-tyrosine (NT) and cysteinyl-S-nitrosylation (S-NO) now identified as providing insight into a novel mechanism of potentially targetable pathways ^[3].

1. Qin, Y., et al., Constitutive aberrant endogenous interleukin-1 facilitates inflammation and growth in human melanoma. Mol Cancer Res, 2011. 9(11): p. 1537-50.
2. Tanese, K., E.A. Grimm, and S. Ekmekcioglu, The role of melanoma tumor-derived nitric oxide in the tumor inflammatory microenvironment: its impact on the chemokine expression profile, including suppression of CXCL10. Int J Cancer, 2012. 131(4): p. 891-901.
3. Grimm, E.A., A.G. Sikora, and S. Ekmekcioglu, Molecular pathways: inflammation-associated nitric-oxide production as a cancer-supporting redox mechanism and a potential therapeutic target. Clin Cancer Res, 2013. 19(20): p. 5557-63.