The role of c-kit and imatinib mesylate in uveal melanoma

Abstract

Background: Uveal melanoma (UM) is the most common primary intraocular tumor in adults, leading to metastasis in 40% of the cases and ultimately to death in 10 years, despite local and/or systemic treatment. The c-kit protein (CD117) is a membrane-bound tyrosine kinase receptor and its overexpression has been observed in several neoplasms. Imatinib mesylate is a FDA approved compound that inhibits tyrosine quinase receptors, as well as c-kit. Imatinib mesylate controls tumor growth in up to 85% of advanced gastrointestinal stromal tumors, a neoplasia resistant to conventional therapy.

Methods: Fifty-five specimens of primary UM selected from the archives of the Ocular Pathology Laboratory, McGill University, Montreal, Canada, were immunostained for c-kit. All cells displaying distinct immunoreactivity were considered positive. Four human UM cell lines and 1 human uveal transformed melanocyte cell line were tested for in vitro proliferation Assays (TOX-6) and invasion assay with imatinib mesylate (concentration of 10 microM).

Results: The c-kit expression was positive in 78.2% of the UM. There was a statistical significant decrease in the proliferation and invasion rates of all 5 cell lines.

Conclusion: The majority of UM expressed c-kit, and imatinib mesylate does decrease the proliferation and invasion rates of human UM cell lines. These results justify the need for a clinical trial to investigate in vivo the response of UM to imatinib mesylate.

Figure 1

A. Choroidal UM displaying high expression of c-kit. The above retina is somewhat detached. Figure 1B. UM composed of epithelioid cells showing a cell membrane pattern of immunostain.

Figure 3

The graph shows the invasion assay results for each cell line with experimental conditions. The blue bar for each represents the control proliferation without Imatinib Mesylate, and the red bar with the compound. A statistical difference was seen for the five cell lines after 10 μM exposure.

Figure 4

The graph shows the proliferation assay results comparing a control and the Imatinib mesylate exposure cells. A statistical difference was seen for the five cell lines after 10 μM exposure.

Figure 2

A. Photomicrograph of UM cells without Imatinib mesylate (control) invading through Matrigel (200×). Figure 2B. Photomicrograph of UM cells treated with Imatinib mesylate invading through Matrigel (200×).