Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis.
Cutaneous melanoma preferentially metastasizes via the lymphatic route. However, the mechanisms of lymphatic invasion and metastasis to regional lymph nodes are poorly understood. Nitric oxide is a free radical molecule synthesized from L-arginine by nitric oxide synthases that plays a critical role in various physiological and pathological processes, including tumor growth and angiogenesis. We have tested whether inducible nitric oxide synthase expression correlates with lymphatic vessel density identified with D2-40 antibody and/or blood microvessel density identified with CD105/endoglin in a series of melanocytic nevi (n=28) and cutaneous melanomas (n=38), representative of various pT. Inducible nitric oxide synthase expression was significantly lower in melanocytic nevi in comparison with primary and metastatic melanomas (P<0.001). Mean microvessel density was significantly higher in primary and metastatic melanomas in comparison with melanocytic nevi (P<0.001 for intratumoral and P=0.001 for peritumoral vessels). Vertical growth phase melanomas showed a higher intratumoral microvessel density in comparison with radial growth phase melanomas (P=0.02). The number of peritumoral lymphatics was significantly lower in nevi as compared with primary and metastatic melanomas (P=0.01). No correlation between microvessel or lymphatic vessel and clinical outcome was found in melanomas. A significant direct correlation was observed between inducible nitric oxide synthase immunostaining in melanocytic tumor cells and the density of lymphatic vessels (peritumoral: P=0.001; intratumoral: P=0.08), and the density of peritumoral blood microvessel (P=0.02). Our findings support the hypothesis that inducible nitric oxide synthase is implicated not only in blood, but also in lymphatic vascular neoformation in melanoma. Mechanistic studies are needed to address the possibility that inducible nitric oxide synthase controls lymphangiogenesis, dissemination and lymphatic borne metastases.
Massi
Daniela
D
Department of Human Pathology and Oncology, University of Florence, Florence, Italy. daniela.massi@unifi.it
De Nisi
Maria C
MC
Franchi
Alessandro
A
Mourmouras
Vasileios
V
Baroni
Gianna
G
Panelos
John
J
Santucci
Marco
M
Miracco
Clelia
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000378:metabolism; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000378:metabolism; D000071063:Endoglin; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D009508:Nevus, Pigmented / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D011956:Receptors, Cell Surface / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C500987:monoclonal antibody D2-40; D052247:Nitric Oxide Synthase Type II