Tissue Specific Regulation of Diabetes-Associated Cancer Growth

描述(申请人提供)：糖尿病与几种癌症(如乳腺癌、膀胱癌、胰腺癌、肝癌)的发病率增加和其他癌症(如前列腺癌)的发病率降低有关。我们认为，组织特异性与癌症的相关性是由糖尿病患者血管生成的组织特异性调节引起的。众所周知，糖尿病的一种异常血管生成(某些组织，如视网膜和肾脏的新生血管增加，以及其他组织，如皮肤和心肌的血管生成不足，导致缺血)已被认识多年，是糖尿病微血管并发症(视网膜病变、神经病变、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抑制一种强大的抗血管生成蛋白血栓反应蛋白-1(TSP-1)的产生，结果是，血管生成以组织特异性的方式增加。我们的初步数据证实miR-467是高血糖反应中TSP-1生成和血管生成的调节因子，建立了高血糖诱导的肿瘤生长与miR-467和TSP-1在体内的相关性，证实了miR-467在体内对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。该项目的总体目标是：1)表征高血糖激活的新的组织特异性途径，并在体内糖尿病小鼠模型和人类糖尿病癌症组织中控制血管生成和肿瘤生长；2)证明miR-467是这一途径的关键调节因子，可以靶向控制高血糖诱导的肿瘤生长。高血糖对肿瘤生长的组织特异性刺激是通过组织特异性上调miR-467和沉默TSP-1产生来实现的，通过中和miR-467可以以组织特异性的方式阻止高血糖诱导的肿瘤生长，这一假说将在三个特定的目的中得到验证：1.论证miR-467、TSP-1与人糖尿病癌组织中肿瘤血管生成的相关性。2.利用系统递送的antagomiR-467预防高血糖诱导的乳腺癌体内生长。3.验证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相关性提供了一个突破性的解释，并为糖尿病患者癌症的预防和治疗提供了一个新的靶点。这种机制可以在不影响生理性血管生成的情况下以组织特异性的方式进行靶向。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展示这一途径，并将评估miR-467拮抗剂在防止高血糖诱导的癌症生长方面的效果。

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.