A Role for Fatty Acid Binding Protein 4 in Ovarian Cancer Metastasis

脂肪酸结合蛋白 4 在卵巢癌转移中的作用

基本信息

批准号：
8316751
负责人：
Kristin Nieman
金额：
$ 4.08万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2012-11-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316751
关键词：
Abdomen Abdominal Cavity Address Adhesions Adipocytes Animal Model Binding Proteins Biological Assay Biology Breast Cancer Patient Cell Line Cells Clinical Coculture Techniques Development Diagnosis Energy Metabolism Environment Event Face Family Goals Hematogenous Human Injection of therapeutic agent Intestines Investigation Knockout Mice Knowledge Lead Link Lipid Binding Lipids Lipolysis Malignant Neoplasms Malignant neoplasm of ovary Metabolic Methods Molecular Chaperones Mus Neoplasm Metastasis Omentum Operative Surgical Procedures Oral Organ Ovarian Ovary Pancreas Peritoneal Fluid Pre-Clinical Model Primary Neoplasm Process Recurrence Regulation Research Role Site Stomach Testing Tissues Tumor Burden Visceral Woman cancer cell chemotherapy design fatty acid metabolism fatty acid oxidation human FABP4 protein in vivo inhibitor/antagonist lipid metabolism member mortality mouse model novel ovarian neoplasm overexpression research study treatment strategy tumorigenesis uptake

项目摘要

DESCRIPTION (provided by applicant): A majority of women diagnosed with ovarian cancer (OvCa) have recurrence within two years and face a 75% mortality rate, highlighting a desperate need for new treatments. Clinical observations indicate the most common site of OvCa metastasis is the omentum, which is primarily composed of adipocytes. Metastasis is highly dependent on the surrounding microenvironment, but little is known regarding the preferential spread of OvCa cells to the omentum. Fatty acid binding protein 4 (FABP4), which is primarily expressed by adipocytes, functions in the transport, uptake, and metabolism of fatty acids. The preliminary experiments completed for this application reveal overexpression of FABP4 in omental metastases from OvCa patients as compared to the primary tumor, reduced tumor burden in a FABP4-deficient animal model of OvCa, and dysregulated lipid metabolism in interacting OvCa cells and adipocytes. However, a relationship between FABP4 and OvCa metastasis has yet to be elucidated. The purpose of the proposed project is to understand the role of FABP4 in OvCa metastasis. Thus, the hypothesis for the proposed investigation is FABP4 promotes OvCa metastasis. The following aims have been designed to test this hypothesis: (1) Determine the contribution of FABP4 to OvCa metastasis; (2) Understand the mechanism underlying FABP4 regulation of ovarian tumorigenesis; (3) Investigate a FABP4 inhibitor in the treatment of OvCa using a preclinical model. Using a 3D organotypic culture constructed with human cells isolated from the omentum; adhesion, invasion and proliferation will be evaluated following treatment with a FABP4 inhibitor. In addition, alterations in lipid metabolism will be assessed in OvCa cells cocultured with human omental adipocytes, following FABP4 inhibition, using radioisotopic assays. To determine if FABP4 expression in OvCa cells is relevant to tumorigenesis, we will establish OvCa cells that lack FABP4 using shRNAi and inject them into wild-type and FABP4-deficient mice. Novel mechanisms of FABP4 regulation will be investigated using the established FABP4-deficient OvCa cells and adipogenic cell lines isolated from wild-type and FABP4 knockout mice. Finally, a selective, orally- administered FABP4 inhibitor will be tested in the treatment of OvCa using an in vivo preclinical model. This research plan has the potential to unravel a novel mechanism for FABP4 in metastasis. Understanding the interaction between OvCa cells and adipocytes has vast potential for the development of new treatment methods. Moreover, these findings will likely be relevant to other cancers, such as breast, where adipocytes are a major component of the surrounding tissue.

描述（由申请人提供）：大多数被诊断患有卵巢癌 (OvCa) 的女性会在两年内复发，死亡率高达 75%，这凸显了对新疗法的迫切需求。临床观察表明，OvCa 转移最常见的部位是大网膜，其主要由脂肪细胞组成。转移高度依赖于周围的微环境，但关于 OvCa 细胞优先扩散到大网膜的情况知之甚少。脂肪酸结合蛋白 4 (FABP4) 主要由脂肪细胞表达，在脂肪酸的运输、摄取和代谢中发挥作用。本申请完成的初步实验揭示了与原发肿瘤相比，OvCa 患者的网膜转移瘤中 FABP4 过度表达，FABP4 缺陷的 OvCa 动物模型中的肿瘤负荷减少，以及相互作用的 OvCa 细胞和脂肪细胞中的脂质代谢失调。然而，FABP4 和 OvCa 转移之间的关系尚未阐明。拟议项目的目的是了解 FABP4 在 OvCa 转移中的作用。因此，本研究的假设是 FABP4 促进 OvCa 转移。为了检验这一假设，我们设计了以下目标：（1）确定FABP4对OvCa转移的贡献； (2)了解FABP4调控卵巢肿瘤发生的机制； (3) 使用临床前模型研究 FABP4 抑制剂治疗 OvCa 的效果。使用从大网膜分离的人类细胞构建的 3D 器官型培养物；用 FABP4 抑制剂治疗后将评估粘附、侵袭和增殖。此外，在 FABP4 抑制后，将使用放射性同位素测定评估与人网膜脂肪细胞共培养的 OvCa 细胞中脂质代谢的变化。为了确定 OvCa 细胞中 FABP4 的表达是否与肿瘤发生相关，我们将使用 shRNAi 建立缺乏 FABP4 的 OvCa 细胞，并将其注射到野生型和 FABP4 缺陷小鼠体内。将使用从野生型和 FABP4 敲除小鼠中分离出的已建立的 FABP4 缺陷 OvCa 细胞和脂肪形成细胞系来研究 FABP4 调节的新机制。最后，将使用体内临床前模型测试选择性口服 FABP4 抑制剂治疗 OvCa 的效果。该研究计划有可能揭示 FABP4 在转移中的新机制。了解 OvCa 细胞和脂肪细胞之间的相互作用对于开发新的治疗方法具有巨大的潜力。此外，这些发现可能与其他癌症有关，例如乳腺癌，其中脂肪细胞是周围组织的主要组成部分。