Endothelial cell insulin and increased intestinal tumor formation in obesity

描述（由申请人提供）：超过三分之一的美国人口现在肥胖。肥胖与结肠癌和其他恶性肿瘤有关，肥胖的流行率增加有可能阻碍癌症控制方面取得的进展。有人提出这种关联可能是由于高胰岛素血症的生长促进作用。我们提出了一种替代方案，其中高胰岛素血症和癌症风险都是由胰岛素抵抗介导的。我们以前已经发表了一个惊人的表型小鼠内皮细胞敲除胰岛素受体基因（Insr），一个重要方面的内皮功能障碍，在肥胖的人。由于血管细胞粘附分子-1（VCAM-1）的内皮细胞上调，这些动物的白细胞与内皮细胞的粘附增加了4倍。我实验室的初步数据显示，与对照组相比，内皮细胞Insr敲除的肿瘤易感Apc（Min/+）小鼠（IRKO/M小鼠）小肠中的肿瘤数量增加。它们还增加了小肠组织中的免疫细胞浸润。因此，我们假设，肥胖相关的胰岛素抵抗的内皮细胞促进免疫细胞招募到肠道，这反过来又促进肿瘤的发展。有了目标1，我们将定量内皮细胞滚动和粘附到内皮细胞在肠微静脉使用在 活体显微镜我们还将确定用α 4整联蛋白抑制剂治疗是否能阻止白细胞与VCAM-1的结合，从而防止IRKO/M小鼠的加速肿瘤发生。在目标2中，我们将使用在内皮细胞中胰岛素受体底物-1（IRS-1）转基因过表达的Apc（Min/+）小鼠（Tg/M小鼠）或其对照（wt/M），在给它们喂食高脂肪或对照饮食后。我们将确定与肥胖wt/M小鼠相比，肥胖Tg/M小鼠体内肠壁微静脉中的肿瘤负荷和白细胞滚动/粘附是否得到改善。我们的实验室中可获得针对这两个目的描述的遗传修饰小鼠。这一建议具有高度创新性，因为癌症靶组织中的胰岛素抵抗以前并不被认为是高胰岛素血症和肥胖症癌症风险之间关联的原因。此外，我们引入了小鼠肿瘤模型，靶向内皮细胞的胰岛素信号的损失和增益，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不能分离的问题。这项拟议的研究意义重大，因为它将为预防肥胖症中的癌症提供一种靶向途径。

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.