Metabolic changes in ovarian cancer cells initiated by metastasis to adipose tiss

卵巢癌（OvCa）的生物学与大多数上皮性肿瘤明显不同，因为血液转移很少，卵巢肿瘤仍然局限于腹膜腔。网膜是覆盖在肠道上的一大块脂肪组织（20x13x3cm），是OvCa最常见的转移部位。它主要由脂肪细胞组成，脂肪细胞成为OvCa细胞的主要微环境。我们的初步结果表明，原代人网膜脂肪细胞促进OvCa细胞向网膜的转移及其随后的生长。一旦转移到大网膜，OvCa细胞诱导脂肪细胞的脂质分解，癌细胞利用这些脂质产生的能量增殖。这种应用的基本假设是脂肪细胞衍生的脂肪酸改变了OvCa细胞的整体代谢。脂肪细胞衍生的脂质通过提供信号代谢物、能量和生物合成构建块来促进增殖和转移。基于我们的发现，OvCa细胞上调CD36 FA转运蛋白，我们计划在Aim #1中使用网膜的3D器官型模型来可视化和表征FA摄取到OvCa细胞的机制。接下来将详细研究癌细胞中CD36表达和缺乏的功能（侵袭/转移）和代谢后果。因为脂肪细胞会诱导两者？在Aim #2中，我们建议通过对单独培养和在3D培养中共培养的原代人OvCa细胞和原代人脂肪细胞进行详细的唇特征分析来扩展这些研究。基于我们的结果，我们将进行实验来确定特定脂肪细胞衍生的Fas（包括氧化脂质和甘油）如何调节OvCa细胞的脂质和葡萄糖代谢。在Aim #3中，我们将以我们的结果为基础，该结果表明，FABP4-/-小鼠的OvCa转移明显受损，脂肪细胞诱导FABP4在OvCa细胞中的表达。在确定宿主和癌细胞FABP4对OvCa侵袭和转移的贡献后，我们将通过实验确定哪些因子调控FABP4以及FABP4影响侵袭和转移的机制。除了FA传输(如NF？B和PPAR-？激活，调节脂肪酶)，将探讨，以确定他们是否有助于转移。作为这些研究的补充，将进行FABP4抑制剂的研究，在体内原位注射人或小鼠OvCa细胞，以评估这些抑制剂减少OvCa转移的能力。综上所述，本研究将有助于我们理解癌细胞与脂肪细胞的相互作用如何调节肿瘤细胞的能量代谢。我们最终希望我们的实验将使我们更好地了解OvCa代谢，从而建立合理的治疗方法，干扰调节转移的代谢途径。

DESCRIPTION (provided by applicant): 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.