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: 8620622
• 负责人: Ernst Lengyel
• 金额: $ 31.8万
• 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/8620622
• 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（由申请人提供）：转移对脂肪组织发起的卵巢癌细胞的代谢变化显然与大多数上皮肿瘤的生物学明显不同，因为造血转移酶很少见，卵巢肿瘤仍然局限于腹膜腔。 Omentum是覆盖肠道的大脂肪组织（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，原发性人性脂肪细胞将OVCA细胞的味道促进了omentum及其随后的生长。一旦发生转移，OVCA细胞就会诱导脂肪细胞中的脂解，并且癌细胞利用从这些脂质中传递的能量来增殖。该应用的基本假设是脂肪细胞衍生的胖子改变了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产物，能量和生物合成构件来促进增殖和转移。根据我们的发现，OVCA细胞上调CD36 FA转运蛋白，我们计划使用Omentum的3D器官模型可视化和表征FA摄取到OVCA细胞的机理。随后将进行详细研究CD36表达和癌细胞缺乏的功能（侵袭/转移）和代谢后果。由于脂肪细胞在OVCA中诱导？ - 在AIM＃2中提出氧化和糖酵解，以通过对原代人OVCA细胞和单独培养并在3D培养中共同培养的原代人OVCA细胞和原代人脂肪细胞进行详细的唇样分析来扩展这些研究。根据我们的结果，将进行实验，以确定特定的脂肪细胞如何衍生的Fas（包括氧化脂质）以及甘油调节OVCA细胞中的脂质和葡萄糖代谢。在AIM＃3中，我们将基于我们的结果，这表明OVCA转移在Fabp4 - / - 小鼠中受到了显着损害，并且脂肪细胞在OVCA细胞中诱导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，以确定哪种因素调节FABP4以及FABP4影响侵袭和转移的机制。 FABP4功能除FA转运（例如NF？B和PPAR-激活，调节脂肪酶）外，还将探索以确定它们是否有助于转移。这些研究的补充将是FABP4抑制剂研究，使用人体或小鼠OVCA细胞在体内评估抑制剂减少OVCA转移的能力。综上所述，本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能量代谢。我们最终希望我们的实验能使我们对OVCA代谢有了深入的了解，以建立可以干扰调节转移的代谢途径的理性疗法。