Metabolic changes in ovarian cancer cells initiated by metastasis to adipose tissue The biology of ovarian cancer (OvCa) is clearly distinct from that of most epithelial tumors, in that hematogenous metastases are rare, and ovarian tumors remain confined to the peritoneal cavity. The omentum, a large pad of fat tissue (20x13x3cm) covering the bowel, is the most common site of OvCa metastasis. It consists primarily of adipocytes, which become the principal microenvironment for the OvCa cells. Our preliminary results suggest that primary human omental adipocytes promote the me- tastasis of OvCa cells to the omentum and their subsequent growth. Once metastasis to the omentum has occurred, OvCa cells induce lipolysis in the adipocytes, and the cancer cells use the energy de- rived from these lipids to proliferate. The underlying hypothesis for this application is that adipocyte- derived faty acids alter the global metabolism of OvCa cells. Adipocyte-derived lipids promote proliferation and metastasis by providing signaling metabolites, energy, and biosynthetic building blocks. Based on our findings that OvCa cells upregulate the CD36 FA transporter we plan, in Aim #1, to visualize and characterize the mechanism of FA uptake into the OvCa cells using a 3D organotypic model of the omentum. This will be followed by detailed studies of the functional (invasion/metastasis) and metabolic consequences of CD36 expression and deficiency in cancer cells. Because adipocytes induce both -oxidation and glycolysis in OvCa we propose, in Aim #2, to expand these studies with a detailed lip- idomic analysis of primary human OvCa cells and primary human adipocytes cultured alone and co- cultured in 3D culture. Based on our results, experiments will be performed to determine how specific adipocyte derived Fas including oxidized lipids, and glycerol regulate lipid and glucose metabolism in OvCa cells.
In Aim #3 we will build on our results, which show that OvCa metastasis is significantly impaired in FABP4-/- mice and that adipocytes induce FABP4 expression in OvCa cells. After determining the contribution of host and cancer cell FABP4 to OvCa invasion and metastasis we will follow with experiments to determine what factor(s) regulate FABP4 and the mechanism(s) by which FABP4 affects invasion and metastasis. FABP4 functions, in addition to FA transport (e.g. NF?B and PPAR-? activation, regulation of lipases), will be explored to determine if they contribute to metastasis. Complement- ing these studies, will be FABP4 inhibitor studies using orthotopic injection of human or mouse OvCa cells in vivo to assess the ability of the inhibitors to reduce OvCa metastasis. Taken together, the studies in this application will contribute to our understanding of how the interaction of cancer cells with adipocytes modulates tumor cell energy metabolism. We ultimately hope our experiments will lead us to an improved understanding of OvCa metabolism upon which to build rational therapies that can interfere with the metabolic pathways regulating metastasis.
Metabolic changes in ovarian cancer cells initiated by metastasis to adipose tissue. It is currently unknown why ovarian cancer preferentially seeds to the omentum and other fat containing tissue within the abdomen. The purpose of this application is to understand the interaction of fat cells (adipocytes) with ovarian cancer cells and, in particular, determine the mechanism through which cancer cells use the lipids provided by adipocytes for faster growth. With a better understanding of the interactions between cancer cells and adipocytes, we will be able to develop new metabolically-targeted therapies to reduce metastasis to fat-containing tissue, inhibit fat utilization by cancer cells, and ultimately slow te progression of a number of cancers.
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