Investigate the Role of Obesity in Ovarian Cancer Initiation and Progression
Abstract
Epithelial ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer death in women in the United States. To date, there are no efficient screening methods that would allow prevention and early detection, so at the time of diagnosis the majority of patients present with late-stage disease with extremely poor prognosis. Epidemiological studies suggest that obesity is associated with increased risk for the development and progression of ovarian cancer, among other types of cancer. Fat tissue of obese individuals is chronically inflamed and highly dysfunctional. Chronic inflammation is known to promote tumorigenesis for various types of cancer, such as colon and liver, but the role of dysfunctional and inflamed fat tissue of obese individuals in ovarian cancer initiation and progression has not been addressed. With this proposal we plan to investigate whether and how obesity affects ovarian cancer initiation and progression. Recent findings indicate that epithelial ovarian cancer originates from ovarian stem cells that carry tumorigenic mutations. We will test the effects of obesity on ovarian stem cell activity, tumor growth, and metastases. We will also identify genes and pathways in ovarian cells that are altered by obesity and promote ovarian cancer, as well as factors secreted by adipose tissue and influence ovarian cells in obesity. In addition, we will test the hypothesis that loss of adipose SIRT1 promotes ovarian cancer initiation and progression. SIRT1 is an enzyme expressed in various mammalian tissues and protects from a number of diseases, including cancer, diabetes, and neurodegenerative diseases. In fat tissue, SIRT1 protects from obesity and associated inflammation and metabolic dysfunction. Importantly, specific compounds can activate SIRT1, so if our results show that adipose SIRT1 counteracts ovarian cancer, SIRT1 activators might represent a novel strategy to protect against ovarian cancer. In addition, we will investigate which genes and pathways operating in ovarian stem cells are altered in obesity. These studies might set the basis for the identification of new targets and the development of novel therapeutic approaches against ovarian cancer. Our results will provide insights into the mechanisms by which obesity influences ovarian cancer initiation, progression, and recurrence. So individuals with family history of ovarian cancer or patients who are being or have been treated for ovarian cancer could directly benefit from our findings by making lifestyle changes. In addition, if our results lead to the identification of new target proteins, our research will set the basis for novel therapeutic strategies. The development of drugs that efficiently inhibit ovarian cancer progression will greatly benefit patients. Military Service women, as well as women family members of military service individuals diagnosed with ovarian cancer should also benefit from the results of our research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510095
Entities
People
- Leonard P. Guarente
Organizations
- Harvard University
- United States Army