Detection of the c‐met proto‐oncogene product in normal skin and tumours of melanocytic origin

Abstract

The proto-oncogene c-met product (c-MET) is a receptor tyrosine kinase and functions as a receptor for hepatocyte growth factor (HGF). Although the function of c-MET has yet to be fully clarified, HGF stimulates the phosphorylation of tyrosyl residues on c-MET and triggers the signal transduction pathways, resulting in a contribution to the malignant progression of melanonocytes with synergic factors such as basic fibroblast growth factor and mast cell growth factor. Using immunohistochemical methods, we have studied the localization of c-MET in normal skin and various melanocytic tumours. c-MET was detected in keratinocytes, melanocytes, sebaceous cells, and other cells of the skin. In particular, basal melanocytes almost always showed nuclear labelling. Melanocytic naevi generally revealed predominantly nuclear staining of cells in the epidermis, whereas only a few cases showed a distinct cytoplasmic localization of c-MET in dermal naevus cells. The distribution pattern of c-MET in melanoma cells was basically similar to that of benign lesions, although the numbers tested were small. Cultured human melanoma cells also showed predominantly nuclear labelling, but were unresponsive to exogenous c-MET ligand HGF. Treatment with the glucosidase inhibitor castanospermine caused accumulation of protein at 220 kD, without diminishing the amount of normally-processed 190-kD c-MET. Although there was no significant difference in c-MET distribution between benign and malignant melanocytic lesions, it is suggested that malignant transformation of melanocytes may be associated with loss of response to HGF or other growth-regulating factors.

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

“…Surprisingly, we observed that Met was also localized in the nucleus of several tumors. While this phenomenon has been observed in melanocytic and lung tumors, 54,55 to our knowledge, this is the first report of a nuclear localization of Met in ovarian cells. Unexpected nuclear localization in cancer tissues has also been reported for other growth factor receptors, such as those of the ErbB family, and was associated with the proliferative status of the cells.…”

Malignant melanoma: modern black plague and genetic black box

“…Other RTKs showing strong expression include Erb-B2, IGF1R, and Met. Robust c-met, but not HGF/SF, expression has been observed in melanoma tissue and cells, and in some cases has been associated with progression to the metastatic state (Natali et al 1993;Saitoh et al 1994;Rusciano et al 1995;Hendrix et al 1998). In human interconverted uveal melanoma cells, which are highly aggressive and preferentially disseminate to the liver, c-met expression has been correlated to high motogenic response and invasiveness (Hendrix et al 1998).…”

Immunohistochemical localisation of stem cell factor (SCF) with comparison of its receptor c-Kit proto-oncogene product (c-KIT) in melanocytic tumours

“…Interaction with receptors for these ligands, the proto-oncogenes c-Met and c-Kit, respectively, results in regulation of melanocyte proliferation and/or differentiation, mediated through signal transduction and protein phosphorylation [4]. Previous reports [7,16] showed that the effects of HGF and SCF occasionally differ between benign and malignant melanocytes. For example, Halaban et al [7] have shown that HGF could act as a potent mitogen for melanocytes, whereas cell proliferation is independent of the presence of exogenously supplied HGF when melanocytes become malignant.…”