Tissue Specific Regulation of Diabetes-Associated Cancer Growth

描述（由申请人提供）：糖尿病与几种癌症（例如，乳腺、膀胱、胰腺、肝脏）和其他疾病（例如，前列腺）。我们认为，糖尿病患者血管生成的组织特异性调节与癌症的组织特异性关联。众所周知的糖尿病的异常血管生成（在一些组织中增加的新血管形成，例如，视网膜和肾脏，以及在其他组织中引起局部缺血的血管生成不足，例如，皮肤和心肌）已经被认识多年，并且是糖尿病微血管并发症（视网膜病、神经病、心肌病和肾病）的原因。然而，组织特异性糖尿病血管生成的分子机制尚不清楚。我们发现了一种由高血糖激活的新的组织特异性机制：microRNA-467（miR-467）的水平在高血糖时上调，miR-467抑制有效的抗血管生成蛋白血小板反应蛋白-1（TSP-1）的产生，因此，血管生成以组织特异性方式增加。我们的初步数据确定了miR-467作为响应高血糖的TSP-1产生和血管生成的调节剂，建立了体内高血糖诱导的肿瘤生长与miR-467和TSP-1之间的相关性，证实了miR-467对体内血管生成的影响以及miR-467拮抗剂对高血糖诱导的肿瘤生长的影响。本项目的总体目标是：1）在体内糖尿病小鼠模型和人类糖尿病癌症组织中表征由高血糖激活的新组织特异性途径并控制血管生成和癌症生长; 2）证明miR-467是该途径的关键调节因子，并且可以靶向控制高血糖诱导的肿瘤生长。高血糖症对癌症生长的组织特异性刺激是由miR-467的组织特异性上调和TSP-1产生的沉默介导的，并且高血糖症诱导的肿瘤生长可以通过中和miR-467以组织特异性方式预防的假设将在三个特定目的中进行测试：1.证明miR-467、TSP-1与人糖尿病癌组织中癌血管生成的相关性。2.使用全身性递送EscheromiR-467预防体内高血糖诱导的乳腺癌生长。3.证明miR-467拮抗剂作用的组织特异性。我们发现的高血糖诱导血管生成的组织特异性机制为高血糖与几种癌症之间的关系提供了突破性的解释，并为糖尿病患者癌症的预防和治疗提供了新的靶点。该机制可以以组织特异性方式靶向，而不影响生理性血管生成。拟议的计划将在动物糖尿病和癌症模型以及人类癌症组织中体内证明这一途径，并将评估miR-467拮抗剂在预防高血糖诱导的癌症生长中的疗效。

DESCRIPTION (provided by applicant): Diabetes is associated with increased incidence of several cancers (e.g., breast, bladder, pancreas, liver) and decreased incidence of others (e.g., prostate). We suggest that the tissue-specific association with cancers is caused by a tissue-specific regulation of angiogenesis in diabetic patients. A well-known aberrant angiogenesis of diabetes (increased neovascularization in some tissues, e.g., retina and kidney, and deficient angiogenesis causing ischemia in others, e.g., skin and myocardium) has been recognized for many years and is the cause of diabetic microvascular complications (retinopathy, neuropathy, cardiomyopathy, and nephropathy). However, the molecular mechanisms of the tissue-specific diabetic angiogenesis are unknown. We have discovered a novel tissue-specific mechanism that is activated by hyperglycemia: the levels of microRNA-467 (miR-467) are upregulated in response to hyperglycemia, miR-467 inhibits production of a potent anti-angiogenic protein thrombospondin-1 (TSP-1), and, as a result, angiogenesis is increased in a tissue-specific manner. Our preliminary data identified miR-467 as a regulator of TSP-1 production and angiogenesis in response to hyperglycemia, established a correlation between hyperglycemia-induced tumor growth and miR-467 and TSP-1 in vivo, confirmed the effect of miR-467 on angiogenesis in vivo and the effect of miR-467 antagonist on hyperglycemia-induced tumor growth. The overall goals of this project are: 1) characterizing the novel tissue-specific pathway activated by hyperglycemia and controlling angiogenesis and cancer growth in the in vivo diabetic mouse models and in human diabetic cancer tissues and 2) demonstrating that miR-467 is a key regulator of this pathway and can be targeted to control the hyperglycemia-induced tumor growth. The hypothesis that the tissue-specific stimulation of cancer growth by hyperglycemia is mediated by a tissue-specific upregulation of miR-467 and silencing of TSP-1 production and that the hyperglycemia-induced tumor growth can be prevented in a tissue-specific manner by neutralizing of miR-467 will be tested in three Specific Aims: 1. To demonstrate the correlation between miR-467, TSP-1 and cancer angiogenesis in human diabetic cancer tissues. 2. To prevent hyperglycemia-induced breast cancer growth in vivo using systemic delivery of antagomiR-467. 3. To demonstrate the tissue-specificity of the effects of miR-467 antagonist. The tissue-specific mechanism of hyperglycemia-induced angiogenesis that we have discovered provides a breakthrough explanation for the well-documented but poorly understood association between hyperglycemia and several cancers and suggests a new target for the prevention and treatment of cancers in diabetic patients. This mechanism can be targeted in a tissue-specific manner without affecting the physiological angiogenesis. The proposed plan will demonstrate this pathway in vivo in animal diabetes and cancer models and in human cancer tissues and will assess the efficacy of miR-467 antagonist in preventing hyperglycemia-induced cancer growth.