Ovarian cancer (OvCa) patients are often diagnosed with advanced disease due to lack of early detection
methods. Once detected patients undertake surgery to remove tumor tissue and subsequently undergo
chemotherapy. However majority of patients come back with a recurrent disease resistant to available
treatment. Since 1999 when liposomal doxorubicin (Doxil®) was introduced, the survival of patients with
the disease has only improved minimally. In addition, emergence of chemoresistant tumors has severely
limited effective therapy, necessitating further research to identify and target new molecules.
OvCa arising from either the surface of the ovary or the distal end (fimbriae) of the fallopian tube has a unique mode of spread. Cancer cells are shed from the primary tumor and are freely spread by the peritoneal fluid homing primarily to the omentum (80%), a fat pad of about 20x15x2 cm in size covering the bowl. Metastatic ovarian cancer cells at the omentum are exposed to a lipid rich environment and the cells respond by enhancing uptake and intracellular accumulation of lipids. The omentum largely composed of adipocytes (fat cells) provides a unique environment for the metastatic progression of OvCa cells. Adipocytes and adipocyte-secreted factors have been implicated in the proliferation of several types of cancer, including breast, colon, and prostate. We previously reported how adipocytes promote OvCa metastasis, invasion, and proliferation.
Our preliminary data in this proposal suggests that certain factors secreted by adipocytes increase amount of a protein (Hif-1a) known to be present in cells under reduced oxygen concentration. It is possible that there exist a new pathway by which cancer cells can increase this protein to help them cope with unfavorable condition. Increased presence of hif-1a can facilitate cancer cells to change their nutrient source and opt for ones that are readily available and help cancer cells to multiply. Through this proposal we plan to identify the factor/s that increases this protein amount in cancer cells. Then we will try to understand how cancer cells benefit from this protein and ultimately we will use mouse experiments to understand how loss or increased amount of Hif-1a affects tumor formation. Hence this proposal has the potential to identify a target for therapy against OvCa.