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.
Epithelial ovarian cancer (EOC) will affect 1 out of every 69 women born in the US today. Currently 80% of women newly diagnosed with EOC already have metastatic disease. The immediate objective of these studies is to provide high quality PhD research training to Ms. Lana Bruney and to promote diversity in the scientific workforce. The long-term goal of these studies is to gain a molecular level understanding of EOC metastasis to design strategies to more effectively target metastatic disease.
|Bruney, Lana; Conley, Kaitlynn C; Moss, Natalie M et al. (2014) Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/ CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium. Biol Chem 395:1221-31|