Expression of the neuronal isoform of nitric oxide synthase (nNOS) and itsinhibitor, protein inhibitor of nNOS, in pigment cell lesions of the skin

Nitric oxide (NO) is involved in many physiological processes. In cancer, l ow levels of NO are thought to enhance tumour progression and. metastasis. NO is generated from arginine by NO synthase (NOS); the Ca2+-dependent neur onal isoform or nNOS (expressed by neurones and inhibited by the protein in hibitor of nNOS, PIN), is also expressed by cultured normal melanocytes and by all malignant melanoma (MM) cell lines. We studied the expression of nN OS and PIN in paraffin sections of 177 and 58 pigment cell lesions, respect ively, using immunohistochemistry; the activity of the necessary cofactor N ADPH was studied in 26 frozen cases. Normal melanocytes in situ lacked nNOS and PIN expression, but were NADPH +. Almost half of common acquired benig n naevi expressed nNOS; however, halo naevi and congenital naevi expressed nNOS very frequently. Dysplastic naevi and MM showed variable nNOS immunore activity in 72% and 83% of cases, respectively. Early (Clark I and Clark II ) MM displayed nNOS staining most frequently, and all MM with an invasive r adial growth phase expressed nNOS in the papillary dermis. Tn contrast, onl y 67% of metastatic MM were nNOS +. PIN was coexpressed with nNOS in 40 of 58 lesions. NADPH activity was present in all nNOS + naevi, but in two mali gnant cases,. NADPH activity was not accompanied by nNOS expression. We con clude that nNOS expression is induced de novo in benign and malignant pigme nt cell lesions which have all the requirements (NADPH, PIN) necessary for the production and modulation of NO. We postulate that the frequent express ion of nNOS in the junctional part of dyspIastic naevi may be responsible f or their particular histological features. NO generated by the neoplastic d ermal cells in the invasive radial growth phase may contribute to the incre ased number of blood vessels in the papillary dermis.