Endothelial cell insulin and increased intestinal tumor formation in obesity

肥胖症中内皮细胞胰岛素与肠道肿瘤形成增加

• 批准号: 8838069
• 负责人: Christian Rask-Madsen
• 金额: $ 18万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838069
• 关键词: Abbreviations; Adhesions; Adult; Advanced Malignant Neoplasm; Animal Model; Animals; ApcMin/+ mice; Area; Back; Binding; Biology; Blocking Antibodies; Blood Vessels; Breeding; Cancer Control; Cells; Child; Colon Carcinoma; Data; Development; Diet; Employee Strikes; Endothelial Cells; Endothelium; Fatty acid glycerol esters; Gene Deletion; Genetic Recombination; Genotype; Growth; Health; Human; Hyperinsulinism; Immune; Infiltration; Insulin; Insulin Receptor; Insulin Resistance; Integrin alpha4; Integrins; Intervention; Intestinal Neoplasms; Intestines; Knock-out; Knockout Mice; Knowledge; Laboratories; Leukocyte Rolling; Leukocytes; Malignant Neoplasms; Measures; Mediating; Mesentery; Metabolic Diseases; Microscopy; Mission; Modeling; Mus; Mutant Strains Mice; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathway interactions; Phenotype; Play; Population; Positioning Attribute; Prevalence; Prevention; Public Health; Publishing; Receptor Gene; Research; Risk; Role; Small Intestines; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Angiogenesis; Tumor Burden; Tumor Suppressor Genes; United States; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; adenoma; anticancer research; base; cancer cell; cancer prevention; cancer risk; cancer type; endothelial dysfunction; feeding; field study; improved; in vivo; inhibitor/antagonist; innovation; insight; insulin receptor substrate 1 protein; insulin signaling; mouse model; novel; overexpression; prevent; research study; small molecule; tumor; tumor progression; tumorigenesis; vascular inflammation; venule

DESCRIPTION (provided by applicant): More than one-third of the US population is now obese. Obesity is associated with colon cancer and other malignancies, and the increased prevalence of obesity threatens to set back advances made in cancer control. It has been proposed that this association could be due to growth- promoting effects of hyperinsulinemia. We propose an alternative in which hyperinsulinemia and cancer risk is both mediated by insulin resistance. We have previously published a striking phenotype of mice with endothelial cell knockout of the insulin receptor gene (Insr), an important aspect of endothelial dysfunction in obese humans. These animals have 4-fold increased leukocyte adhesion to endothelial cells because of endothelial cell upregulation of vascular cell adhesion molecule-1 (VCAM-1). Preliminary data from my lab now show that tumor-prone Apc (Min/+) mice with endothelial cell Insr knockout (IRKO/M mice) have increased tumor numbers in the small intestine compared with controls. They also have increased immune cell infiltration in small intestinal tissue. We therefore hypothesize that obesity-associated insulin resistance in endothelial cells promotes immune cell recruitment to the gut which in turn promote tumor development. With Aim 1, we will quantitate endothelial cell rolling and adhesion to endothelium in intestinal venules using in vivo microscopy. We will also determine whether treatment with an alpha4 integrin inhibitor, which blocks binding of leukocytes to VCAM-1, prevents the accelerated tumorigenesis in IRKO/M mice. With Aim 2, we will use Apc(Min/+) mice with transgenic overexpression of insulin receptor substrate-1 (IRS-1) in endothelial cells (Tg/M mice) or their controls (wt/M) after feeding them a high-fat or control diet. We will determine whether tumor burden and lekocyte rolling/adhesion in intestinal wall venules in vivo are improved in obese Tg/M mice compared to obese wt/M mice. The genetically modified mice described for both aims are available in our laboratory. This proposal is highly innovative because insulin resistance in cancer target tissues has not previously been thought to be the cause of the association between hyperinsulinemia and cancer risk in obesity. In addition, we introduce mouse tumor models with loss and gain of insulin signaling targeted to endothelial cells which allows us to study insulin resistance independent from hyperinsulinemia, thereby overcoming the problem that these two factors cannot be separated in humans or most animal models. The proposed research is significant because it will provide a target pathway for prevention of cancer in obesity.

描述（由申请人提供）：现在，超过三分之一的美国人口肥胖。肥胖症与结肠癌和其他恶性肿瘤有关，肥胖症的患病率增加有可能使癌症控制的进展恢复。已经提出，这种关联可能是由于增长促进高胰岛素血症的作用。我们提出了一种替代方法，其中高胰岛素血症和癌症风险均由胰岛素抵抗介导。我们以前已经发表了一种具有胰岛素受体基因（INSR）内皮细胞敲除小鼠的惊人表型，这是肥胖人内皮功能障碍的重要方面。由于血管细胞粘附分子-1（VCAM-1）的内皮细胞上调，这些动物对内皮细胞的白细胞粘附增加了4倍。现在，我的实验室的初步数据表明，与对照组相比，小肠内肿瘤（Min/+）小鼠具有内皮细胞INSR敲除（IRKO/M小鼠）的肿瘤数量增加。它们还增加了小肠组织中的免疫细胞浸润。因此，我们假设内皮细胞中与肥胖相关的胰岛素抵抗会促进肠道的免疫细胞募集，从而促进肿瘤的发育。使用AIM 1，我们将使用IN中的内皮细胞滚动和粘附到内皮 体内显微镜。我们还将确定用α4整联蛋白抑制剂（阻断白细胞与VCAM-1结合）的治疗是否可以防止IRKO/M小鼠的加速肿瘤发生。使用AIM 2，我们将在内皮细胞（TG/M小鼠）中使用胰岛素受体底物-1（IRS-1）的转基因过表达APC（Min/+）小鼠，或者在给它们喂养高脂或对照饮食后，或其对照（WT/M）。我们将确定与肥胖的WT/M小鼠相比，肥胖的TG/M小鼠的体内肠道壁静脉的肿瘤负担和肠道滚动/粘附是否得到改善。我们的实验室都可以使用这两个目标的转基因小鼠。该提案具有很高的创新性，因为癌症靶组织中的胰岛素抵抗力以前并不是肥胖症高胰岛素血症与癌症风险之间关联的原因。此外，我们引入了靶向内皮细胞的胰岛素信号传导损失和增益的小鼠肿瘤模型，这使我们能够研究独立于高胰岛素血症的胰岛素抵抗，从而克服了这两个因素在人类或大多数动物模型中无法分离的问题。拟议的研究很重要，因为它将为预防肥胖症预防癌症提供目标途径。