Inducible nitric oxide synthase and nitrotyrosine in human metastatic melanoma tumors correlate with poor survival

Despite recognition of the malignant potential of human melanomas, the mech anisms responsible for the pathobiological characteristics contributing to tumor growth, vascular invasiveness, and distant organ metastasis remain un defined, Recent studies have shown that various human tumors express an ind ucible form of nitric oxide synthase (iNOS) and nitrotyrosine (NT), which s uggests a mechanistic role of tumor-associated nitric oxide (NO) in tumorig enesis. We investigated iNOS and NT expression by immunohistochemistry in 2 0 human metastatic melanoma tissue specimens specifically with respect to i NOS-expressing cell types in the tumor area, pathological and clinical resp onse to systemic therapy, potential role as a prognostic indicator, and NT formation, Our results showed that melanoma cells from 12 of 20 tumors expr ess iNOS, yet the expression of this molecule in the tumor did not correlat e with pathological or clinical response to therapy. More importantly, iNOS and NT expression by the melanoma cells strongly correlated with poor surv ival in patients with stage 3 disease (P < 0.001 and P = 0.020, respectivel y), suggesting a pathway whereby iNOS might contribute to enhanced tumor pr ogression, In conclusion, our findings strongly suggest that iNOS expressio n has potential to be considered as a prognostic factor and NO as a critica l mediator of an aggressive tumor phenotype in human metastatic melanomas.