Control of cancer and metastasis by endothelial-derived epoxyeicosatrienoic acids

内皮源性环氧二十碳三烯酸控制癌症和转移

• 批准号: 8472455
• 负责人: Dipak Panigrahy
• 金额: $ 26.34万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472455
• 关键词: Acids; Agonist; Anabolism; Animal Model; Arachidonic Acids; Attention; Autacoids; Axillary lymph node group; CYP2J2 gene; California; Cells; Chronic; Clinical; Collaborations; Cytochrome P450; Data; Disease; Distant Metastasis; Down-Regulation; Endothelial Cells; Endothelium; Enzymes; Epoxide hydrolase; Exhibits; Fibrates; Genetic; Goals; Growth; Homing; Human; Hypertension; Implant; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Intervention; Knock-out; Knockout Mice; Ligands; Lipids; Lung; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical center; Metastatic Neoplasm to the Liver; Modeling; Molecular; Mus; National Institute of Environmental Health Sciences; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Nuclear; Organ; Parabiosis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Pilot Projects; Play; Primary Neoplasm; Process; Role; Signaling Molecule; Site; Surgical Models; System; Systemic Therapy; Tail; Testing; Texas; Time; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Cell Invasion; Tumor Expansion; Tumor-Derived; United States National Institutes of Health; Universities; Vascular blood supply; Veins; Xenograft procedure; angiogenesis; antiangiogenesis therapy; autocrine; cancer risk; cancer therapy; clinically relevant; combat; cytokine; inhibitor/antagonist; lipid metabolism; macrophage; melanoma; migration; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; paracrine; preclinical study; promoter; public health relevance; receptor; small molecule; subcutaneous; tool; transcription factor; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): The tumor stroma is increasingly implicated in tumorigenesis, primarily through angiogenesis and inflammation. Most efforts to elucidate the mediators have focused on cytokines, giving little to no attention to non-proteinaceous autacoids in the tumor stroma. We recently discovered that the epoxyeicosatrienoic acids (EETs), which are cytochrome P450 (CYP) metabolites of arachidonic acid (AA), have potent tumor promoting activities. Overexpression of the CYP enzymes, or genetic abrogation of the enzyme soluble epoxide hydrolase (sEH) (which metabolizes EETs), resulted in increased EET levels in the endothelium of transgenic mice. In both cases, increased endothelial-derived EETs dramatically stimulated angiogenesis, primary tumor growth, and metastasis. Consistently, reducing endogenous EETs using specific EET-antagonists, or through endothelial-specific overexpression of sEH, inhibited tumor growth. Thus, we hypothesize that EETs in the endothelium are potent regulators of tumor growth and metastasis. Endothelial-derived EETs may be a key paracrine mediator of the tumor promoting role of the stroma. This is a novel concept for it attributes to endothelium a trophic and inflammation modulatory function in promoting tumors, in addition to its established role of providing blood supply. The overall goal of this project is to elucidate the mechanisms by which EETs stimulate tumor growth. Aim 1 will determine whether endogenous tumor-promoting EETs are derived from the endothelium, tumor cells or macrophages in the stroma (which all express the EET producing CYPs and EET metabolizing sEH). This will be dissected primarily by differential overexpression of CYPs or sEH in the tumor vs transgenic host compartments, employing xenograft tumor models. The drastic increase of number, size and spread of distant metastases, triggered by high EET levels, that we observed is unprecedented. Therefore, Aim 2 will determine whether endothelial-derived EETs facilitate dissemination at the site of the primary tumor (invasion, migration), or at the metastatic site (homing, colonization, dormancy escape). This will be achieved using a parabiosis model (the surgical joining of two mice) in which the donor mouse carrying the primary tumor has high EETs in its endothelium, and the recipient mouse has normal EET levels. Comparing the rate of metastasis into organs of the tumor-carrying donor with that of the recipient (across the parabiosis junction) will reveal the site of action of EETs. Finally, Aim 3 will test if EETs can serve as a pharmacological target for cancer therapy by determining if small molecule antagonists of EETs inhibit tumor growth, and will begin to explore their mechanism of action. Understanding the role of EETs in tumorigenesis is of direct clinical relevance for two reasons. (1) Drugs which increase EETs are cardioprotective and in phase II clinical trials for hypertension; in view of our preliminary results, the potential of cancer risk must be carefully evaluated. (2) The pharmacologically accessible autacoid system, including EETs, may offer an entirely new target for anti-stromal and anti-angiogenesis strategies in cancer therapy. PUBLIC HEALTH RELEVANCE: Understanding the precise role in cancer of epoxyeicosatrienoic acids (EETs), which have become known as mediators of inflammation, is of immediate clinical importance because drugs which increase EETs are in phase II clinical trial for hypertension; but, our pilot studies show that elevated EETs promote growth of cancer and metastasis. Conversely, blocking the EET pathway may offer a new strategy to block tumor blood vessels and, hence, help combat cancer. Thus, novel drugs which block EETs will be tested in preclinical trials to confirm their activity.

描述（由申请人提供）：肿瘤基质越来越多地参与肿瘤发生，主要通过血管生成和炎症。大多数阐明介质的努力都集中在细胞因子上，很少甚至没有关注肿瘤基质中的非蛋白质自体物质。我们最近发现环氧二十碳三烯酸 (EET) 是花生四烯酸 (AA) 的细胞色素 P450 (CYP) 代谢物，具有有效的肿瘤促进活性。 CYP 酶的过度表达，或可溶性环氧化物水解酶 (sEH)（代谢 EET）的基因消除，导致转基因小鼠内皮细胞中 EET 水平增加。在这两种情况下，内皮源性 EET 的增加都显着刺激了血管生成、原发性肿瘤生长和转移。一致地，使用特定的 EET 拮抗剂或通过内皮特异性 sEH 过度表达来减少内源性 EET，可抑制肿瘤生长。因此，我们假设内皮细胞中的 EET 是肿瘤生长和转移的有效调节因子。内皮源性 EET 可能是基质肿瘤促进作用的关键旁分泌介质。这是一个新颖的概念，因为它除了提供血液供应的既定作用外，还赋予内皮细胞促进肿瘤生长的营养和炎症调节功能。该项目的总体目标是阐明 EET 刺激肿瘤生长的机制。目标 1 将确定内源性肿瘤促进 EET 是否源自内皮、肿瘤细胞或基质中的巨噬细胞（它们均表达产生 CYP 的 EET 和代谢 sEH 的 EET）。这将主要通过使用异种移植肿瘤模型，通过肿瘤与转基因宿主区室中 CYP 或 sEH 的差异过度表达来进行剖析。我们观察到，由高 EET 水平引发的远处转移的数量、大小和扩散急剧增加是前所未有的。因此，目标 2 将确定内皮源性 EET 是否促进原发肿瘤部位（侵袭、迁移）或转移部位（归巢、定植、休眠逃逸）的传播。这将通过联体共生模型（两只小鼠的手术连接）来实现，其中携带原发性肿瘤的供体小鼠的内皮细胞具有高 EET，而受体小鼠具有正常的 EET 水平。比较携带肿瘤的供体器官和受体（穿过联体共生连接处）的器官转移率将揭示 EET 的作用位点。最后，目标3将通过确定EET的小分子拮抗剂是否抑制肿瘤生长来测试EET是否可以作为癌症治疗的药理学靶点，并将开始探索其作用机制。了解 EET 在肿瘤发生中的作用具有直接的临床意义，原因有两个。 (1) 增加EET的药物具有心脏保护作用，且处于治疗高血压的II期临床试验中；鉴于我们的初步结果，必须仔细评估潜在的癌症风险。 (2) 药理学上可利用的自体系统，包括 EET，可能为癌症治疗中的抗基质和抗血管生成策略提供全新的靶点。 公共健康相关性：了解环氧二十碳三烯酸 (EET) 在癌症中的确切作用（EET 已被称为炎症介质）具有直接的临床重要性，因为增加 EET 的药物正处于治疗高血压的 II 期临床试验中；但是，我们的初步研究表明 EET 升高会促进癌症的生长和转移。相反，阻断 EET 通路可能提供一种阻断肿瘤血管的新策略，从而有助于对抗癌症。因此，阻断 EET 的新药将在临床前试验中进行测试，以确认其活性。