Control of cancer and metastasis by endothelial-derived epoxyeicosatrienoic acids

内皮衍生的环氧二十碳三烯酸控制癌症和转移

• 批准号: 8281369
• 负责人: Dipak Panigrahy
• 金额: $ 28.02万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281369
• 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与肿瘤发生有关，主要是通过血管生成和炎症。阐明介质的大多数努力都集中在细胞因子上，几乎没有关注肿瘤基质中的非蛋白质肌动物。我们最近发现，环氧酸性酸（EET）是蛛网膜酸（AA）的细胞色素P450（CYP）代谢产物，具有有效的肿瘤促进活性。 CYP酶的过表达，或酶可溶性环氧化物水解酶（SEH）（代谢EET）的遗传废除，导致转基因小鼠内皮的EET水平升高。在这两种情况下，内皮衍生的EET都会显着刺激血管生成，原发性肿瘤生长和转移。一致地，使用特定的EET抗逆邦剂或通过SEH的内皮特异性过表达来减少内源性EET，抑制了肿瘤的生长。因此，我们假设内皮中的EET是肿瘤生长和转移的有效调节剂。内皮衍生的EET可能是促进基质作用的关键旁分泌介质。这是一个新颖的概念，因为它归因于促进肿瘤的营养和炎症调节功能，除了其提供血液供应的既有作用外。该项目的总体目标是阐明EET刺激肿瘤生长的机制。 AIM 1将确定促进性肿瘤的EET是否来自基质中的内皮，肿瘤细胞或巨噬细胞（所有这些都表达产生CYPS的EET和EET代谢SEH）。这将主要通过采用异种移植肿瘤模型的肿瘤与转基因宿主区室中CYP或SEH的差异过表达进行解剖。我们观察到的高EET水平触发的遥远转移的数量，大小和扩散的急剧增加是前所未有的。因此，AIM 2将确定内皮衍生的Eets是在原发性肿瘤部位（侵袭，迁移）还是在转移部位（归因，定殖，休眠，休眠逃生）促进传播。这将是使用抛物线模型（两只小鼠的手术连接）来实现的，其中携带原发性肿瘤的供体小鼠的内皮中具有高EET，并且受体小鼠的EET水平正常。将转移到肿瘤的供体的器官的速率与受体（跨副作用连接）的供体的器官的速率将揭示EET的作用部位。最后，AIM 3将通过确定Eets的小分子拮抗剂是否抑制肿瘤生长，并将开始探索其作用机理，来测试EET是否可以作为癌症治疗的药理靶标。了解EET在肿瘤发生中的作用是直接临床相关性的，原因有两个。 （1）增加EET的药物是心脏保护性的，并且在II期临床试验中进行高血压；鉴于我们的初步结果，必须仔细评估癌症风险的潜力。 （2）包括EET在内的药理学上可访问的自闭症系统可能为癌症治疗中的抗块状和抗血管生成策略提供了一个全新的靶标。 公共卫生相关性：了解已被称为炎症介质的环氧钠酸癌（EET）中的精确作用至关重要，因为增加EET的药物在II期临床试验中的高血压试验；但是，我们的试点研究表明，升高的Eets促进了癌症和转移的生长。相反，阻止EET途径可能会提供一种新的策略来阻止肿瘤血管，从而有助于对抗癌症。因此，将在临床前试验中测试阻止EET的新型药物以确认其活性。