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(Investigative Ophthalmology and Visual Science. 2004;45:2075-2082.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-1196
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c-Kit–Dependent Growth of Uveal Melanoma Cells: A Potential Therapeutic Target?

Charlotta All-Ericsson,1,2 Leonard Girnita,2,3 Anja Müller-Brunotte,1 Bertha Brodin,3 Stefan Seregard,1 Arne Östman,4 and Olle Larsson3

1From St. Erik’s Eye Hospital, Stockholm, Sweden; 3Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Karolinska Hospital, Stockholm, Sweden; and the 4Ludwig Institute for Cancer Research, Uppsala, Sweden.

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 IC50 of the inhibitory effects on c-kit phosphorylation and cell proliferation was of equal size and less than 2.5 µM.

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.




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