Angiogenic Factors Associated with Uveal Melanoma

描述(申请人提供)：葡萄膜黑色素瘤是最常见的眼部肿瘤，起源于眼部。这种疾病背后的基因改变尚不清楚，临床上几乎没有可以观察到的预后指标。此外，当眼部症状被发现时，导致全身转移的事件可能已经发生，肝脏疾病导致的死亡通常随之而来。需要改进方法，以便及早发现和治疗该病。 我们推测，这种肿瘤的恶性和转移特性部分取决于Cyr61和组织因子(Tf)的表达及其对肿瘤微循环的调节。微循环由预先存在的血管、新的或血管生成的血管以及由于去分化的肿瘤细胞而形成的通道或网络组成。Cyr61和Tf的表达将作为这些肿瘤微循环来源中的每一个的函数，使用激光捕获显微切割和实时聚合酶链式反应方法来测量。此外，染色体1p的区域，包括Cyr61和Tf基因，可能会被扩增，并作为肿瘤发展的易感因素。细胞遗传学方法，包括FISH，将被用来确定与葡萄膜黑色素瘤相关的1p扩增的频率，以及这种发生是否与预后肿瘤相关。 参数。最后，涉及受体酪氨酸激酶Axl的调节Cyr61表达的新途径将进一步用生化方法描绘，并在原发肿瘤和转移生长部位进行比较。这些调控通路可能对长期存活的微转移瘤的生存很重要。 具体目标包括： 1.确定Cyr61和TF基因扩增频率与葡萄膜黑色素瘤的易感因素。 2.用葡萄膜黑色素瘤标本检验肿瘤预后参数与Cyr61和Tf表达的相关性。 3.葡萄膜黑色素瘤组织中Cyr61和Tf的表达与患者预后的关系 4.评价Cyr61和Tf在葡萄膜黑色素瘤动物模型中的作用。 5.研究原发葡萄膜黑色素瘤中Axl对Cyr61的调控作用及其主要转移部位。

DESCRIPTION (provided by applicant): 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 include: 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.