c-Kit-dependent growth of uveal melanoma cells: a potential therapeutic target?
2004 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, Vol. 45, no 7, 2075-82 p.Article in journal (Refereed) Published
PURPOSE: This study was conducted to investigate the expression and functional impact of the proto-oncogene c-kit in uveal melanoma. METHODS: Based on immunohistochemical (IHC) study of paraffin-embedded specimens from 134 uveal melanomas and Western blot analysis on eight fresh-frozen samples the expression of c-kit in uveal melanoma was studied. Furthermore, the phosphorylation of c-kit and the impact of the tyrosine kinase inhibitor STI571 was examined in the three uveal melanoma cell lines OCM-1, OCM-3, and 92-1. RESULTS: Eighty-four of 134 paraffin-embedded samples and six of eight fresh-frozen samples expressed c-kit. c-Kit was strongly expressed and tyrosine phosphorylated in cultured uveal melanoma cells compared with cutaneous melanoma cells. Moreover, in contrast to cutaneous melanoma cell lines c-kit maintained a high phosphorylation level in serum-depleted uveal melanoma cells. No activation-related mutations in exon 11 of the KIT gene were found. On the contrary, expression of the stem cell growth factor (c-kit ligand) was detected in all three uveal melanoma cell lines, suggesting the presence of autocrine (paracrine) stimulation pathways. Treatment of uveal melanoma cell lines with STI571, which blocks c-kit autophosphorylation, resulted in cell death. The IC(50) of the inhibitory effects on c-kit phosphorylation and cell proliferation was of equal size and less than 2.5 microM. CONCLUSIONS: The results confirm that c-kit is vastly expressed in uveal melanoma, suggest that the c-kit molecular pathway may be important in uveal melanoma growth, and point to its use as a target for therapy with STI571.
Place, publisher, year, edition, pages
2004. Vol. 45, no 7, 2075-82 p.
Adult, Aged, Aged; 80 and over, Blotting; Western, Cell Division, Female, Humans, Immunoenzyme Techniques, Male, Melanoma/*metabolism/*pathology, Middle Aged, Paraffin Embedding, Phosphorylation/drug effects, Polymerase Chain Reaction, Proto-Oncogene Proteins c-kit/genetics/*metabolism, Pyrimidines/pharmacology, RNA; Messenger/metabolism, Skin Neoplasms/metabolism/pathology, Tumor Cells; Cultured, Tyrosine/metabolism, Uveal Neoplasms/*metabolism/*pathology
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-10325DOI: 10.1167/iovs.03-1196PubMedID: 15223779OAI: oai:DiVA.org:uu-10325DiVA: diva2:38093