A majority of women diagnosed with ovarian cancer (OvCa) have recurrence within two years and face a 75% mortality rate, highlighting a desperate need for new treatments. Clinical observations indicate the most common site of OvCa metastasis is the omentum, which is primarily composed of adipocytes. Metastasis is highly dependent on the surrounding microenvironment, but little is known regarding the preferential spread of OvCa cells to the omentum. Fatty acid binding protein 4 (FABP4), which is primarily expressed by adipocytes, functions in the transport, uptake, and metabolism of fatty acids. The preliminary experiments completed for this application reveal overexpression of FABP4 in omental metastases from OvCa patients as compared to the primary tumor, reduced tumor burden in a FABP4-deficient animal model of OvCa, and dysregulated lipid metabolism in interacting OvCa cells and adipocytes. However, a relationship between FABP4 and OvCa metastasis has yet to be elucidated. The purpose of the proposed project is to understand the role of FABP4 in OvCa metastasis. Thus, the hypothesis for the proposed investigation is FABP4 promotes OvCa metastasis. The following aims have been designed to test this hypothesis: (1) Determine the contribution of FABP4 to OvCa metastasis;(2) Understand the mechanism underlying FABP4 regulation of ovarian tumorigenesis;(3) Investigate a FABP4 inhibitor in the treatment of OvCa using a preclinical model. Using a 3D organotypic culture constructed with human cells isolated from the omentum;adhesion, invasion and proliferation will be evaluated following treatment with a FABP4 inhibitor. In addition, alterations in lipid metabolism will be assessed in OvCa cells cocultured with human omental adipocytes, following FABP4 inhibition, using radioisotopic assays. To determine if FABP4 expression in OvCa cells is relevant to tumorigenesis, we will establish OvCa cells that lack FABP4 using shRNAi and inject them into wild-type and FABP4-deficient mice. Novel mechanisms of FABP4 regulation will be investigated using the established FABP4-deficient OvCa cells and adipogenic cell lines isolated from wild-type and FABP4 knockout mice. Finally, a selective, orally- administered FABP4 inhibitor will be tested in the treatment of OvCa using an in vivo preclinical model. This research plan has the potential to unravel a novel mechanism for FABP4 in metastasis. Understanding the interaction between OvCa cells and adipocytes has vast potential for the development of new treatment methods. Moreover, these findings will likely be relevant to other cancers, such as breast, where adipocytes are a major component of the surrounding tissue.
This research plan has the potential to unravel a novel mechanism for fatty acid binding protein 4 (FABP4) in tumorigenesis. Moreover, FABP4 could be a critical link between cancer and energy metabolism. Understanding the metabolic changes that occur in ovarian cancer cells allowing metastasis has huge potential for the development of new treatment methods, not only for ovarian cancer but in other cancers (e.g. breast) where adipocytes are a major component of the surrounding environment.
|Nieman, Kristin M; Romero, Iris L; Van Houten, Bennett et al. (2013) Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta 1831:1533-41|