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Lana Bruney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，有15,520例死亡直接归因于EOC，另有21,650例确诊病例。如果在转移性扩散之前诊断出EOC，总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，使生存率降至不到20%。EOC转移过程的独特之处在于上皮细胞从原发肿瘤中分离并以单细胞和多细胞聚集体（MCA）的形式脱落到腹腔内，并粘附在腹腔内。这些MCAs经过局部浸润进入富含胶原的间质间皮基质，在那里它们增殖以固定继发性病变。控制从分离细胞到腹膜锚定转移病变的确切机制尚不清楚。我们已经在阐明这一机制方面迈出了初步步骤。整合素激活是卵巢癌转移传播的关键事件，并调节包括膜1型基质金属蛋白酶（MT1- MMP）在内的几种参与转移的基因产物的表达。我们对MT1-MMP细胞质尾部磷酸化功能的研究揭示了MT1-MMP在MCA形成和侵袭中的作用。整合素连接激酶（integrin- linked kinase， ILK）是一种21整合素细胞质域相互作用因子，可被整合素介导的细胞粘附激活。ILK的激活已被证明可以调节一些生物过程，这些过程可以抑制细胞凋亡和促进细胞侵袭，这是卵巢癌转移的两个关键事件。本提案的目的是解决整合素连接激酶（ILK）活性在卵巢癌腹腔内转移中起作用的中心假设。拟议的目标将表征整合素连接激酶（ILK）在卵巢癌细胞和组织中的表达；研究ILK在MT1-MMP翻译后修饰中的潜在作用，并研究ILK激活对体外和体内卵巢癌转移模型的贡献。综上所述，这些实验的结果将为评估ILK作为EOC转移临床管理的潜在治疗靶点提供关键的临床前数据。

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.