Tissue Specific Regulation of Diabetes-Associated Cancer Growth

糖尿病相关癌症生长的组织特异性调节

• 批准号: 9070628
• 负责人: OLGA I STENINA
• 金额: $ 32.89万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070628
• 关键词: Affect; Angiogenic Proteins; Animal Cancer Model; Animals; Antineoplastic Agents; Bladder; Breast; Breeding; Cancer Model; Cardiomyopathies; Cells; Colon Carcinoma; Cultured Cells; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Endometrial Carcinoma; Goals; Growth; Health; Hepatic; Human; Hyperglycemia; Incidence; Ischemia; Kidney; Kidney Diseases; Liver; Long-Term Effects; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; MicroRNAs; Microvascular Dysfunction; Modeling; Molecular; Morphology; Myocardium; Neuropathy; Organ; Pancreas; Pathway interactions; Patients; Physiologic Neovascularization; Prevention; Production; Prostate; Regulation; Retina; Retinal Diseases; Skin; Specificity; Testing; Therapeutic; Therapeutic Intervention; Thrombospondin 1; Tissues; Up-Regulation; Wound Healing; angiogenesis; cancer cell; cancer therapy; diabetic; diabetic patient; in vivo; malignant breast neoplasm; mouse model; neovascularization; novel; outcome forecast; prevent; prostate cancer model; research study; response; tumor; tumor growth; tumor progression; type I and type II diabetes

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.

描述（由申请人提供）：糖尿病与多种癌症（例如乳腺癌、膀胱癌、胰腺癌、肝癌）发病率增加以及其他癌症（例如前列腺癌）发病率降低相关。我们认为，与癌症的组织特异性关联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，糖尿病的异常血管生成（某些组织（例如视网膜和肾脏）中的新生血管增多，而血管生成不足导致其他组织（例如皮肤和心肌）缺血）多年来已被认识到，并且是糖尿病微血管并发症的原因。视网膜病、神经病、心肌病和肾病）。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型组织特异性机制：microRNA-467 (miR-467) 的水平因高血糖而上调，miR-467 抑制强效抗血管生成蛋白血小板反应蛋白-1 (TSP) 的产生-1)，结果，血管生成以组织特异性方式增加。我们的初步数据确定 miR-467 是高血糖下 TSP-1 产生和血管生成的调节剂，建立了高血糖诱导的肿瘤生长与体内 miR-467 和 TSP-1 之间的相关性，证实了 miR-467 对高血糖的影响。体内血管生成以及 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) 表征由高血糖激活的新型组织特异性途径，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癌症生长；2) 证明 miR-467 是关键该途径的调节因子，可以有针对性地控制高血糖诱导的肿瘤生长。假设高血糖对癌症生长的组织特异性刺激是通过 miR-467 的组织特异性上调和 TSP-1 产生的沉默介导的，并且可以通过以下方式以组织特异性方式预防高血糖诱导的肿瘤生长： miR-467 的中和作用将在三个具体目标中进行测试： 1. 证明 miR-467、TSP-1 与人类糖尿病癌症组织中癌症血管生成之间的相关性。 2. 使用 antagomiR-467 的全身递送来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已有充分记录但知之甚少的关联提供了突破性的解释，并为预防和治疗糖尿病患者的癌症提出了新的靶点。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证明这一通路，并将评估 miR-467 拮抗剂在预防高血糖诱导的癌症生长方面的功效。