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

基本信息

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
项目类别：
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

项目摘要

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）：由转移至脂肪组织引发的卵巢癌细胞的代谢变化卵巢癌（OvCa）的生物学特性与大多数上皮性肿瘤明显不同，因为血行转移很少见，并且卵巢肿瘤仍然局限于腹膜腔。大网膜是覆盖肠道的一大片脂肪组织 (20x13x3cm)，是 OvCa 转移最常见的部位。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。一旦发生大网膜转移，OvCa 细胞会诱导脂肪细胞中的脂肪分解，癌细胞利用这些脂质产生的能量进行增殖。该应用的基本假设是脂肪细胞衍生的脂肪酸改变 OvCa 细胞的整体代谢。脂肪细胞来源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。基于我们的发现，即 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 3D 器官模型来可视化和表征 OvCa 细胞摄取 FA 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。由于脂肪细胞在 OvCa 中诱导 β-氧化和糖酵解，因此我们建议在目标 #2 中通过对原代人 OvCa 细胞和单独培养和在 3D 培养中共培养的原代人脂肪细胞进行详细的脂质组学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脂肪细胞衍生的 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，我们将基于我们的结果，该结果表明 FABP4-/- 小鼠中的 OvCa 转移显着受损，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 侵袭和转移的贡献后，我们将通过实验来确定哪些因素调节 FABP4 以及 FABP4 影响侵袭和转移的机制。除了 FA 转运（例如 NFκB 和 PPAR-γ 激活、脂肪酶调节）之外，还将探索 FABP4 功能，以确定它们是否有助于转移。作为这些研究的补充，FABP4 抑制剂研究将使用人或小鼠 OvCa 细胞体内原位注射来评估抑制剂减少 OvCa 转移的能力。总而言之，本申请中的研究将有助于我们了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够使我们更好地了解 OvCa 代谢，并在此基础上建立可以干扰调节转移的代谢途径的合理疗法。