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

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Abstract
Nitric oxide (NO) is involved in many physiological processes. In cancer, low levels of NO are thought to enhance tumour progression and metastasis. NO is generated from arginine by NO synthase (NOS); the Ca2+-dependent neuronal isoform or nNOS (expressed by neurones and inhibited by the protein inhibitor of nNOS, PIN), is also expressed by cultured normal melanocytes and by all malignant melanoma (MM) cell lines. We studied the expression of nNOS and PIN in paraffin sections of 177 and 58 pigment cell lesions, respectively, using immunohistochemistry; the activity of the necessary cofactor NADPH was studied in 26 frozen cases. Normal melanocytes in situ lacked nNOS and PIN expression, but were NADPH +. Almost half of common acquired benign naevi expressed nNOS; however, halo naevi and congenital naevi expressed nNOS very frequently. Dysplastic naevi and MM showed variable nNOS immunoreactivity 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 radial growth phase expressed nNOS in the papillary dermis. In contrast, only 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 malignant cases, NADPH activity was not accompanied by nNOS expression. We conclude that nNOS expression is induced de novo in benign and malignant pigment cell lesions which have all the requirements (NADPH, PIN) necessary for the production and modulation of NO. We postulate that the frequent expression of nNOS in the junctional part of dysplastic naevi may be responsible for their particular histological features. NO generated by the neoplastic dermal cells in the invasive radial growth phase may contribute to the increased number of blood vessels in the papillary dermis.