Integrin Linked Kinase and Ovarian Cancer Metastasis

描述（由申请人提供）：本申请的直接目标是为拉娜布鲁尼女士提供高水平的博士前研究培训，并增加科学劳动力的多样性。上皮性卵巢癌（EOC）是美国女性癌症死亡的第五大原因。2008年，15，520例死亡直接归因于EOC，另有21，650例被诊断。当EOC在转移性扩散之前被诊断时，总体5年生存率为93%;然而，超过75%的EOC女性被诊断为已经存在转移，生存率下降至低于20%。EOC转移的过程是独特的，因为上皮细胞从原发性肿瘤上脱落，并脱落到腹膜腔中，成为单细胞和多细胞聚集体（MCA），粘附在腹膜内。这些MCA局部浸润到间质富含胶原的间皮下基质中，在那里它们增殖成锚继发性病变。控制从脱离的细胞到腹膜锚定的转移性病变的转变的确切机制仍然未知。我们已经为阐明这一机制迈出了初步的步伐。21整合素活化是卵巢癌转移性扩散的关键事件，并调节参与转移的几种基因产物的表达，包括膜型1基质金属蛋白酶（MT 1- MMP）。我们对MT 1-MMP胞质尾磷酸化功能的研究揭示了MT 1-MMP在MCA形成和侵袭中的作用。整合素连接激酶（ILK）是一种21整合素胞质结构域相互作用因子，由整合素介导的细胞粘附激活。ILK激活已被证明调节抑制失巢凋亡和促进侵袭的几个生物学过程，这是卵巢癌转移中的两个关键事件。该建议的目的是解决整合素连接激酶（ILK）活性在卵巢癌腹膜内转移中起作用的中心假设。提出的目的将表征整合素连接激酶（ILK）在卵巢癌细胞和组织中的表达;检查ILK在MT 1-MMP的翻译后修饰中的潜在作用，并研究ILK活化对卵巢癌转移的体外和体内模型的贡献。总之，这些实验的结果将提供评价ILK作为临床管理EOC转移的潜在治疗靶点所需的关键临床前数据。

DESCRIPTION (provided by applicant): The immediate objectives of this application are to provide high level pre-doctoral research training to Ms. Lana Bruney and to increase the diversity of the scientific workforce. Epithelial ovarian cancer (EOC) is the fifth leading cause of overall cancer death among American women. In 2008, 15,520 deaths were directly attributed to EOC, and an additional 21,650 cases were diagnosed. When EOC is diagnosed prior to metastatic dissemination, the overall 5 year survival rate is 93%; however, over 75% of women with EOC are diagnosed with metastasis already present, dropping the survival rate to less than 20%. The process of EOC metastasis is unique in that epithelial cells detach from the primary tumor and are shed into the peritoneal cavity as single cells and multicellular aggregates (MCA), that adhere intraperitoneally. These MCAs undergo localized invasion into the interstitial collagen-rich submesothelial matrix, where they proliferate to anchor secondary lesions. The exact mechanism that controls the transition from detached cells to peritoneally anchored metastatic lesions is still unknown. We have made initial steps toward elucidating this mechanism. 21 integrin activation is a key event in ovarian carcinoma metastatic dissemination and regulates expression of several gene products involved in metastasis, including membrane type 1 matrix metalloproteinase (MT1- MMP). Our studies on the function of MT1-MMP cytoplasmic tail phosphorylation have uncovered a role for MT1-MMP in MCA formation and invasion. Integrin-linked kinase (ILK), a 21 integrin cytoplasmic domain interactor, is activated by integrin-mediated cell adhesion. ILK activation has been shown to regulate several biological processes that suppress anoikis and promote invasion, two key events in ovarian cancer metastasis. The goal of this proposal is to address the central hypothesis that integrin-linked kinase (ILK) activity plays a role in ovarian cancer intraperitoneal metastasis. Proposed aims will characterize the expression of integrin linked kinase (ILK) in ovarian cancer cells and tissues; examine the potential role of ILK in the post- translational modification of MT1-MMP and investigate the contribution of ILK activation to in vitro and in vivo models of ovarian cancer metastasis. Taken together, the results from these experiments will provide key preclinical data necessary to evaluate ILK as a potential therapeutic target for clinical management of EOC metastasis.