Expression and prognostic significance of iNOS in uveal melanoma

Abstract

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Disease metastasis occurs in half of the patients and is uniformly fatal despite systemic therapy. Inducible nitric oxide synthase (iNOS) is associated with disease progression in various malignancies including cutaneous melanoma. In this retrospective cohort, we examined the prognostic value of iNOS in UM by performing immunohistochemistry on paraffin-embedded sections of primary tumors (90 patients) and matched primary and metastatic hepatic tumors (19 patients) with complete histopathological and clinical data. We show that iNOS is expressed in UM (57% of the patients) and high iNOS levels significantly (p 5 0.04; hazard ratio (HR) 5 2.3) predict disease-specific survival (DSS) as assessed by Kaplan-Meier analysis and univariate Cox's proportional hazards regression model. Furthermore, high iNOS expression in the UM primary tissue was significantly associated with metastatic disease and vice versa. Expression of iNOS in hepatic metastases significantly (p 5 0.02) predicted a shortened survival as assessed by Kaplan-Meier analysis. However, iNOS did not appear to be a significant (p 5 0.16; HR 5 1.9) factor in the multivariate Cox's regression analysis performed together with the clinical parameters tumor diameter, tumor cell type, and tumor location in which only tumor diameter predicted DSS. In conclusion, iNOS predicts DSS in UM and may play a role in disease progression but it is not an independent prognostic factor.Uveal melanoma (UM) is the most common primary intraocular tumor in adults with an annual incidence of approximately seven cases per million.1 Tumors arise from neural crest-derived melanocytes of the uveal tract including the iris, ciliary body, and choroid of the eye. Even with its low frequency, UM accounts for 13% of all deaths from melanoma. The most common age at diagnosis is 50-60 years. Notwithstanding improvements in the diagnosis and treatment of the primary tumor, the 5-year mortality rate of UM patients has not significantly changed since 1973, and metastasis occurs in 50% of UM patients. 2 The primary target organ for metastasis is the liver, which is involved in up to 87% of the patients with metastatic disease. [3][4][5] Metastases are uniformly fatal despite systemic therapy. 5-7Nitric oxide (NO) produced during the conversion of L-arginine to L-citrulline by NO synthase (NOS) is an important bioactive agent and signaling molecule. Nitric oxide is essential for many physiological functions including vasorelaxation, neurotransmission, and cytotoxicity. The production of NO from L-arginine was first identified in endothelial cells and macrophages. 8,9 It was subsequently demonstrated that inflammatory stimuli induced the expression of a specific isoform of NO synthase (iNOS) in myeloid cells and other cell types.10 There are multiple roles for iNOS in different disease processes.11 A majority of human and experimental tumors are stimulated by NO, which contributes to tumor growth and metastasis by promotin...

Nitric oxide synthase 2 is involved in the pro-tumorigenic potential of γδ17 T cells in melanoma

“…In particular, NOS2 favors IL-17 production by gd T cells that leads to the recruitment of PMN-MDSCs and subsequently to metastasis formation. As gd T cells from WT mice already display a higher capacity to produce IL-17 than their counterparts in NOS2KO mice at steady state, our data suggest that NOS2 predetermines gd T cell polarization toward a pro-tumor phenotype Global NOS2 expression has been associated with a poor prognosis in human cutaneous 21,22 as well as uveal 23 melanoma, but the mechanisms by which NOS2 is involved in tumor escape remains poorly explored. In Ret mice with a NOD genetic background, we have shown that the rapid tumor cell dissemination strongly correlates with a reduced dectin-1 expression on myeloid cells that is prevented by NOS2 inactivation.…”

Nitric oxide – the endothelium-derived relaxing factor and its role in endothelial functions

“…(Katušic and Vanhoutte 1986;Rubanyi and Vanhoutte 1986 a,b;Rubanyi 1988;Yanagishawa et al 1988;Lüscher et al 1992). It participates and plays a substantial role in the generation of various diseases like atherosclerosis (Ross 1993(Ross , 1999Heitzer et al 1996;Besler et al 2008;Heistad 2008), essential hypertension (Lüscher 1988;Vanhoutte 1992;Taddei et al 1995;Besler et al 2008), diabetes mellitus and diabetic vasculopathies (Makimattila et al 1996;Bakker et al 2009;Nathanson and Nyström 2009), chronic obstructive pulmonary disease -COPD (Peinado et al 2008), rheumatoid arthritis (Hansel et al 2003;Szekanecz and Koch 2008), psoriatic arthritis (Gonzalez-Juanatey et al 2007), osteoarthritis (Miller et al 2007), ankylosing spondylitis (Sari et al 2006), systemic lupus erythematosus (Piper et al 2007), cancer metastasis (Johansson et al 2010;Takala et al 2010), migraine and stroke (Besler et al 2008;Elliott 2008), anaphylactic and traumatic shock (Menardi et al 2006;Shi et al 2007;Nakashidze 2009), systemic inflammatory response syndrome (Neary and Redmond 1999;Hingorani et al 2000;Menardi et al 2006), NO-induced vasoplegia in sepsis (Stawicki et al 2008;Funk et al 2009) and cardiac surgery …”

Inducible nitric oxide synthase expression correlates with angiogenesis, lymphangiogenesis, and poor prognosis in gastric cancer patients

“…However, endothelial NO synthase and neuronal NO synthase are found in the order of nanomolar [11,12]. Moreover, iNOS expression has been found in most tumor tissues specimens and cultured tumor cells [13][14][15][16][17][18][19][20], suggesting a role for iNOS in cancer development and progression. However, there are few studies focusing on iNOS expression and its correlation with angiogenesis and lymphangiogenesis in GC.…”