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

卵巢癌细胞向脂肪组织转移引发的代谢变化

• 批准号: 8506841
• 负责人: Ernst Lengyel
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506841
• 关键词: Abdomen; Acids; Adipocytes; Adipose tissue; Affect; Biochemical; Biology; CD36 Antigens; CD36 gene; Cell Line; Coculture Techniques; Complement; Energy Metabolism; Epithelial; Event; FABP4 gene; Family; Fatty Acids; Fatty acid glycerol esters; Glycerol; Glycolysis; Goals; Greater sac of peritoneum; Growth; Hematogenous; Human; Injection of therapeutic agent; Intestines; Invaded; Knockout Mice; Knowledge; Lead; Light; Lip structure; Lipase; Lipids; Lipolysis; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular Chaperones; Mus; Neoplasm Metastasis; Nonesterified Fatty Acids; Omentum; Oxis; Peroxisome Proliferator-Activated Receptors; Pre-Clinical Model; Proliferating; Regulation; Role; Seeds; Signal Transduction; Site; Testing; Tissues; Triglycerides; Up-Regulation; Xenograft Model; base; cancer cell; defined contribution; fatty acid oxidation; fatty acid transport; fatty acid-binding proteins; glucose metabolism; improved; in vivo; inhibitor/antagonist; lipid metabolism; metabolic abnormality assessment; metabolomics; neoplastic cell; novel; ovarian neoplasm; oxidation; oxidized lipid; public health relevance; receptor; research study; trafficking; tumor; tumor growth; tumor metabolism; uptake

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.

描述（申请人提供）：转移到脂肪组织引起的卵巢癌细胞的代谢变化卵巢癌（OvCa）的生物学明显不同于大多数上皮性肿瘤，因为血行转移是罕见的，卵巢肿瘤仍然局限于腹膜腔。网膜是覆盖肠的大脂肪组织垫（20x13x3cm），是OvCa转移的最常见部位。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。一旦发生转移到网膜，OvCa细胞诱导脂肪细胞中的脂解，并且癌细胞使用从这些脂质获得的能量来增殖。该应用的基本假设是脂肪细胞来源的脂肪酸改变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、能量和生物合成构件来促进增殖和转移。基于OvCa细胞上调CD36 FA转运蛋白的发现，我们计划在目标#1中使用网膜的3D器官型模型来可视化和表征OvCa细胞中FA摄取的机制。随后将详细研究癌细胞中CD36表达和缺陷的功能（侵袭/转移）和代谢后果。因为脂肪细胞会同时诱导这两种反应？-在目标#2中，我们提出用单独培养和在3D培养物中共培养的原代人OvCa细胞和原代人脂肪细胞的详细脂质组学分析来扩展这些研究。基于我们的结果，将进行实验以确定特定脂肪细胞来源的Fas（包括氧化脂质和甘油）如何调节OvCa细胞中的脂质和葡萄糖代谢。在目标#3中，我们将建立在我们的结果的基础上，该结果显示OvCa转移在FABP4-/-小鼠中显著受损，并且脂肪细胞诱导OvCa细胞中的FABP4表达。在确定宿主和癌细胞FABP4对OvCa侵袭和转移的贡献之后，我们将进行实验以确定哪些因子调节FABP4以及FABP4影响侵袭和转移的机制。FABP4功能，除了FA运输（如NF？B和PPAR-？激活、调节脂肪酶），以确定它们是否有助于转移。作为这些研究的补充，将进行FABP4抑制剂研究，其使用人或小鼠OvCa细胞的体内原位注射来评估抑制剂减少OvCa转移的能力。总之，本申请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更好地了解OvCa代谢，在此基础上建立合理的治疗方法，可以干扰调节转移的代谢途径。