Angiogenic Factors Associated with Uveal Melanoma

与葡萄膜黑色素瘤相关的血管生成因素

• 批准号: 6774429
• 负责人: ARTHUR S POLANS
• 金额: $ 40.48万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774429
• 关键词: RNase protection assay; angiogenesis; angiogenesis factor; angiostatins; cytogenetics; electron microscopy; eye neoplasms; gene expression; human tissue; immunocytochemistry; laboratory mouse; laboratory rabbit; laser capture microdissection; melanoma; metastasis; neoplasm /cancer blood supply; neoplasm /cancer genetics; nucleic acid sequence; prognosis; thromboplastin; tissue /cell culture; uvea; vascular endothelial growth factors

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.

描述（由申请人提供）：葡萄膜黑色素瘤是起源于眼睛的最常见的眼部肿瘤。该疾病背后的基因改变尚不清楚，临床上可以观察到的预后指标也很少。此外，在识别出眼部症状时，可能已经发生导致全身转移的事件，并且经常会因肝病而死亡。需要改进方法来早期发现和治疗该疾病。 我们假设此类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。使用激光捕获显微切割和实时 PCR 方法，将 Cyr61 和 TF 的表达作为肿瘤微循环来源的函数进行测量。此外，包含 Cyr61 和 TF 基因的 1p 染色体区域可能会被扩增，并成为肿瘤发生的诱发因素。包括 FISH 在内的细胞遗传学方法将用于确定与葡萄膜黑色素瘤相关的 1p 扩增频率，以及此类发生是否与肿瘤预后相关 参数。最后，将使用生化方法进一步描述涉及受体酪氨酸激酶 Axl 调节 Cyr61 表达的新途径，并在原发性肿瘤和转移性生长部位进行比较。这些调控途径可能对于长寿命微转移的存活很重要。 具体目标包括： 1. 确定 Cyr61 和 TF 基因扩增的频率作为葡萄膜黑色素瘤的诱发因素。 2. 使用人葡萄膜黑色素瘤标本测试预后肿瘤参数与 Cyr61 和 TF 表达之间的相关性。 3. 将人类葡萄膜黑色素瘤标本中 Cyr61 和 TF 的表达与患者结果相关联。 4.评估Cyr61和TF在葡萄膜黑色素瘤动物模型中的功能。 5. 表征原发性葡萄膜黑色素瘤和主要转移部位中 Axl 对 Cyr61 的调节。