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

描述(申请人提供)：卵巢癌细胞因转移到脂肪组织而引起的代谢变化卵巢癌(OvCa)的生物学与大多数上皮性肿瘤明显不同，因为血液转移很少见，卵巢肿瘤仍然局限在腹膜腔内。大网膜是覆盖在肠道上的一大片脂肪组织(20x13x3厘米)，是OvCa转移的最常见部位。它主要由脂肪细胞组成，成为OvCa细胞的主要微环境。我们的初步结果表明，原代人大网膜脂肪细胞促进了OvCa细胞向大网膜的迁移和随后的生长。一旦发生大网膜转移，OvCa细胞就会诱导脂肪细胞的脂解，癌细胞就会利用这些脂类产生的能量进行增殖。这一应用的基本假设是脂肪细胞衍生的脂肪酸改变了卵巢细胞的整体新陈代谢。脂肪细胞衍生的脂类通过提供信号代谢物、能量和生物合成构件来促进增殖和转移。基于我们的发现，OvCa细胞上调CD36 FA转运蛋白，我们计划在目标1中，使用大网膜的3D器官模型来可视化和表征OvCa细胞摄取FA的机制。接下来将详细研究CD36在癌细胞中的表达和缺失对功能(侵袭/转移)和代谢的影响。由于脂肪细胞在OvCa中诱导β-氧化和糖酵解，我们建议在目标2中，通过对原代人类OvCa细胞和在3D培养中单独培养和共同培养的原代人类脂肪细胞进行详细的脂肪组学分析来扩大这些研究。基于我们的结果，我们将进行实验，以确定特定的脂肪细胞如何获得包括氧化脂质在内的Fas，以及甘油如何调节OvCa细胞的脂和糖代谢。在目标#3中，我们将以我们的结果为基础，这些结果表明FABP4-/-小鼠的OvCa转移显著减弱，脂肪细胞诱导OvCa细胞中FABP4的表达。在确定宿主和癌细胞FABP4在卵巢癌细胞侵袭转移中的作用后，我们将继续进行实验，以确定什么因素(S)调控FABP4，以及FABP4影响侵袭转移的机制(S)。除了FA转运外，FABP4还具有其他功能(例如，NF？B和PPAR-？脂肪酶的激活、调节)，以确定它们是否有助于转移。作为对这些研究的补充，FABP4抑制剂研究将利用人或小鼠OvCa细胞在体内的原位注射来评估这些抑制剂减少OvCa转移的能力。综上所述，这一应用中的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对OvCa代谢有更好的理解，并在此基础上建立合理的治疗方法，以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.