Expression of the inducible isoform of nitric oxide synthase in pigment cell lesions of the skin

Nitric oxide (NO) is a small molecule produced during the conversion of L-a rginine to L-citrulline by NO synthase (NOS). Several isoforms of NOS exist , of which the Ca2+-independent, inducible NOS (iNOS or NOS2) is most promi nently expressed by macrophages. iNOS activity and increased levels of iNOS have been found in various tumours and tumour cell lines but not in normal tissues; however, the precise role of NO in tumour progression has yet to be elucidated. We studied the expression of iNOS in paraffin sections of 41 benign naevi and 52 primary malignant melanomas (MM) of the skin, as well as in 13 metastatic MM, In addition, nitrotyrosine, indicative of NO produc tion and formation of peroxynitrite, was studied in frozen sections of 13 n aevi and 30 MM. Virtually all naevi expressed iNOS, but very few expressed nitrotyrosine, indicating either that NOS in naevi is functionally inactive , or that naevus cells lack reactive oxygen radicals and thus do not form p eroxynitrite. Normal melanocytes in adjacent uninvolved skin were unreactiv e for both markers. In MM, iNOS was most frequently expressed in the 'pure' and 'invasive' radial growth phase (RGP), whereas expression in the vertic al growth phase (VGP) and metastatic phase occurred only in 76% of cases; m oreover, in these latest phases of tumour progression, iNOS staining was we al; and focal, We conclude that iNOS is expressed de novo in most benign pi gment cell lesions. In MM (iNOS-generated) NO appears to play an important part in the early steps of invasion (i.e. the 'invasive' RGP), where it may stimulate neo-angiogenesis and may be a prerequisite for further tumour pr ogression; this view is also supported by the finding of iNOS in the associ ated blood vessels in the papillary dermis. Finally our data suggest that ( iNOS-generated) NO plays a less significant part in the VGP and in metastat ic melanoma.