BIOLOGY OF OVARIAN CANCER

一个互动的、跨学科的小组将专注于卵巢癌在遗传、分子、细胞和整个生物体水平上的病理生物学。1)第一个项目将使用通过阵列CGH和表达阵列分析的基因组拷贝数和表达谱来检测和定位重复的基因组拷贝数或基因表达变化及其与组织学、进展和临床结果的关系；将使用组织微阵列来验证相关性；以及2)使用高分辨率阵列CGH来检测复发基因组变化的区域，比较基因组测序以确定与狭义区域相关的基因，以及分析存在于基因组拷贝数改变和在人类肿瘤中差异表达的基因的功能。在第二个项目中，基于这样的假设，即了解LPA产生和作用的潜在机制将提高对肿瘤发生、进展和结果的了解，并将导致新的诊断和治疗方法，将表征LPA及其受体在癌症发生中的作用，确定LPA在卵巢癌细胞中诱导的基因，并评估LPA水平在检测和管理中的可能用途。第三个项目是在发现一种新的肿瘤抑制基因ARHI的基础上，研究ARHI在恶性卵巢上皮细胞中表达缺失的临床意义和机制，包括：1)ARHI表达对卵巢癌细胞增殖、侵袭、转移和生存的影响；2)ARHI干扰信号转导的机制；以及3)利用ARHI进行卵巢癌移植瘤的基因治疗。在第四个项目中，由于80%的卵巢癌中PI3-K的拷贝数增加，PI3K通路的异常在发病机制中的作用，PI3-K通路的异常对生长因子的反应性的影响，以及通过PI3-K级联反应调节卵巢癌细胞信号的机制将被确定。这些项目将得到三个核心的支持：行政、生物测量和组织/病理学。

An interactive, interdisciplinary group will focus on the pathobiology of ovarian cancer at the genetic, molecular, cellular, and whole organism levels. 1) The first project will employ genome copy number and expression profiling by array CGH and expression array analysis to detect and localize recurrent genome copy number or gene expression changes and their association with histology, progression and clinical outcome; associations will be validated with tissue microarrays and 2) gene discovery using high-resolution array CGH to detect regions of recurrent genomic changes, comparative genomic sequencing to identify genes associated with narrowly defined regions, and analyzing functions of genes present at altered genome copy number and differentially expressed in human tumors. In the second project, based on the hypothesis that understanding mechanisms underlying production and action of LPA will improve understanding of tumorigenesis progression, and outcome and will lead to new diagnostic and therapeutic approaches, the role of LPA and its receptors in carcinogenesis will be characterized, the genes induced by LPA in ovarian cancer cells identified, and the possible use of LPA levels in detection and management assessed. The third project, based on the discovery of a putative novel tumor suppressor gene, ARHI, the clinical significance and mechanism of loss of ARHI expression in malignant ovarian epithelial cells, will be studied by determining: 1) effects of ARHI expression of proliferation, invasion, metastasis and survival of ovarian cancer cells, 2) mechanisms by which ARHI interferes with signal transduction; and 3) use of ARHI for gene therapy of ovarian cancer xenografts with our without cytotoxic drugs. In the fourth project, because of an increased copy number in PI3-K in 80% of ovarian cancers, the role of abnormalities in the PI3K pathway in pathogenesis, the effect of abnormalities in the PI3-K pathway on responsiveness to growth factors and, the mechanisms regulating signaling through the PI3-K cascade in ovarian cancer cells will be determined. The projects will be subserved by three cores: Administration, Biometry and Tissue/Pathology.