Uveal melanoma is the most prevalent ocular tumor originating in the eye. The genetic alterations underlying the disease are unknown, and there are few prognostic indicators that can be observed clinically. In addition, events leading to systemic metastases may have occurred by the time the ocular symptoms are recognized, and death due to hepatic disease often ensues. Improved methods are needed for the early detection and treatment of the disease. We hypothesize that the malignant and metastatic properties of such tumors depend in part on the expression of Cyr61 and Tissue Factor (TF) and their modulation of the tumor microcirculation. The microcirculation is comprised of pre-existing blood vessels, new or angiogenic vessels, and channels or networks owing to de-differentiated tumor cells. The expression of Cyr61 and TF will be measured as a function of each of these sources of the tumor microcirculation using methods of laser capture microdissection and Real-Time PCR. In addition, regions of chromosome 1p, encompassing the genes for both Cyr61 and TF, may be amplified and act as a predisposing factor for tumor development. Cytogenetic approaches, including FISH, will be used to determine the frequency of 1p amplification associated with uveal melanoma, and whether such occurrences correlate with prognostic tumor parameters. Finally, a novel pathway involving the receptor tyrosine kinase Axl, regulating Cyr61 expression, will be further delineated using biochemical methods and compared at sites of primary tumor and metastatic growth. These regulatory pathways may be important for the survival of long-lived micrometastases.
Specific Aims i nclude: 1. Determine the Frequency of Cyr61 and TF Gene Amplification as a Predisposing Factor for Uveal Melanoma. 2. Test Correlations Between Prognostic Tumor Parameters and the Expression of Cyr61 and TF Using Specimens of Human Uveal Melanoma. 3. Correlate the Expression of Cyr61 and TF with Patient Outcome in Specimens of Human Uveal Melanoma. 4. Evaluate the Function of Cyr61 and TF in Animal Models of Uveal Melanoma. 5. Characterize Cyr61 Modulation by Axl in Primary Uveal Melanoma and Principal Sites of Metastasis.
