Transgenic mice with pigmented intraocular tumors: Tissue of origin and treatment

PURPOSE. To describe the cell of origin, tumor progression, light and elect ron microscopic appearance, immunohistochemical properties, and response to frequently used anticancer therapies in two transgenic models of intraocul ar melanoma. METHODS. Two lines of transgenic mice that develop pigmented intraocular tu mors were produced with the SV40 T and t antigens under the control of the mouse tyrosinase gene. Tumors were sequentially studied and characterized b y light microscopy, electron microscopy, and immunohistochemistry stains. T umor response to two cycles of dacarbazine was assessed on the basis of tum or size in one group of animals. Response to external beam irradiation was measured by survival time in other animals. RESULTS. Two lines of transgenic mice developed bilateral intraocular tumor s with complete penetrance and without primary cutaneous melanomas. Tumors developed first in the retinal pigment epithelial layer, with subsequent re tinal and choroidal invasion, extraocular extension, and metastasis. Tumors stained positive for S-100, HMB-45, and Fas-ligand. Electron microscopy re vealed polarization of tumor cells with basement membrane formation, microv illi, immature melanosomes, and abundant endoplasmic reticulum. Dacarbazine significantly reduced tumor size in these mice, and a trend toward dose-de pendent decrease in survival was found with external beam irradiation. CONCLUSIONS. Tumors developed from the retinal pigment epithelium. Their hi stology and growth, however, closely resembled that of human choroidal mela noma. This model map be a useful tool for future studies of endogenous prim ary pigmented tumors limited to the eye. Response to standard therapies sug gests it can serve as a model with which to evaluate therapeutic modalities .