Ovarian cancer is the fifth leading cause of cancer deaths among women because this deadly insidious disease is typically asymptomatic until the malignancy has reached beyond the ovaries. Although the precise etiology remains unknown, the increasing evidence indicates ovarian cancer is one of inflammation-associated cancers derived from inflammatory diseases. Compared with normal ovarian epithelial cells, ovarian cancer cells expressed highly tumor necrosis factor-? (TNF) as a main proinflammatory cytokine that controls directly or indirectly chemokine networks. Growth-regulated oncogene (CXCL1) was significantly increased in ovarian cancer cells, and in the plasma and ascites of patients with ovarian cancer. Our recent studies have resulted that CXCL1, 2 and 8 are main inflammation-driven chemokines produced primarily and abundantly from ovarian cancer cells in response to inflammation. In other system, CXCL1 binds its specific receptor (CXCR2) and exert several functional roles such as cell proliferation, invasion, tumor formation and angiogenesis, which may be critical in the pathogenesis of ovarian cancer. These facts support that inflammation-driven chemokines promote ovarian cancer through inflammatory tumor microenvironments, which lead to massive ascites and widespread peritoneal dissemination as described in advanced ovarian cancer followed by the high mortality rate. In particular, genetic modifications such as p53 inactivity and EGFR/Akt overexpression are frequent in high- grade malignant ovarian cancer. The genetic modifications potentiate inflammation- driven chemokines, probably exacerbating the pathogenesis of ovarian cancer. However, the mechanisms inflammation-driven chemokines contribute to the pathogenesis of ovarian cancer are still poorly understood. The long-range goal of this research is to determine the specific contribution of chemokine networks to ovarian carcinogenesis. Targeting inflammation-driven chemokines will lead to a better understanding of the pathogenesis of ovarian cancer and provide important future applications for the potential use of chemokines as a biomarker and for use of specific chemokine receptor inhibitors and anti-inflammatory agents in the prevention and treatment of ovarian cancer. Preventing peritoneal dissemination and ameliorating ascites through blockage of inflammation-driven chemokines improve patient care and overall survival of women with ovarian cancer and other tumors related to inflammation.

Public Health Relevance

Ovarian cancer is often diagnosed at an advanced stage after the cancer has spread beyond the ovary and results to the highest mortality of all cancers of the female reproductive system. Although the precise etiology remains unknown, the increasing evidence has emerged to indicate an impact of inflammation in the development, growth and progression of ovarian cancer. This project to define roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer will provide a firm foundation for future long-term survival reducing ovarian cancer risks and help to envisage much- needed novel therapies for ovarian cancer and other tumors related to inflammation

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Enhancement Award (SC1)
Project #
5SC1AI089073-04
Application #
8310032
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (GC))
Program Officer
Davidson, Wendy F
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$358,962
Indirect Cost
$113,937
Name
Meharry Medical College
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
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