The Role of Mesothelial Omentin in Ovarian Cancer Progression
Abstract
Approximately 22,000 new cases of epithelial ovarian cancer will be diagnosed in the United States in 2016. Over 14,000 deaths per year will occur, making this cancer the most lethal gynecologic malignancy. Advanced epithelial ovarian cancer, which accounts for the majority new diagnoses, occurs most frequently in postmenopausal women and metastasizes preferentially to the omentum. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Advanced ovarian cancer metastasizes through dissemination from the primary ovarian or the fallopian tubal sites preferentially to the omentum, which is a fold of peritoneal tissue with a lot of blood vessels passing through and is a major site of intra-abdominal fat accumulation. Omentum is covered by a layer of mesothelial cells. Disseminated ovarian cancer cells have to adhere to and invade through the mesothelial cell layer before they can colonize in the omentum. Omentin is a protein secreted from mesothelial cells, which is also known Intestinal Lactoferrin Receptor. We showed for the first time that circulating omentin levels is significantly lower in patients with high-grade serous ovarian cancer (HGSOC) compared with those in the body mass index (BMI) matched healthy individuals (p<0.0001, n=150 patients). Survival correlation studies demonstrated that high levels of preoperative serum omentin (>350 ng/ml) in patients with HGSOC were associated with longer survival times. All these data were collected at MD Anderson Cancer Center. Using a mouse animal model, and ovarian cancer cells and mesothelial cells in culture, we have evidence that the presence of ovarian cancer cells decreased the expression and secretion of omentin from mesothelial cells of the omentum and that exogenous recombinant omentin reduced the motility and invasion of ovarian cancer cells and impaired the attachment of ovarian cancer cells to mesothelial cells. All of these observations suggest that increase of omentin secretion from mesothelial cells can suppress the progression of ovarian cancer. The aims of this proposal are to delineate the mechanisms of how omentin suppresses the motility, invasion, and the growth of ovarian cancer cells using both cells in culture and animal models. We will also evaluate whether increasing the circulating levels of omentin can suppress ovarian cancer growth and increase survival using a newly developed genetic mouse model of HGSOC. The circulating level of omentin will be increased by injection of recombinant omentin or increasing omentin expression using adeno-associated virus (AAV). AAV has many advantages over other gene transfer technologies and is currently the most actively pursued approach for clinical gene therapies. AAV has no inherent pathological effects, very low immunogenicity, and a very long duration of gene expression. Ovarian cancer is the fifth leading cause of cancer deaths in women in the United States, which include military Service member and their families. Our proposed study will determine how omentin can prevent the transformation of omentum into a favorite spot for ovarian cancer to spread. Our findings will allow us to develop novel therapeutic strategies based on induction or supplementation of omentin in ovarian cancer patients, which will reduce ovarian cancer recurrent risk, suppress ovarian cancer progression, and thus improve survival. These research goals are in line with the mission of the Ovarian Cancer Research Program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710146
Entities
People
- Kay-Pong Yip
Organizations
- United States Army
- University of South Florida