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.

Public Health Relevance

Incidence and negative prognosis of several cancers are associated with diabetes, but the molecular mechanisms of this association are unknown. Surprisingly, incidence of other cancers (prostate) is negatively associated with diabetes. In this application, we propose the hypothesis that tissue-specific regulation of cancer angiogenesis by hyperglycemia controls the growth of cancers in diabetics. We have discovered a novel microRNA-dependent tissue-specific mechanism activated by hyperglycemia and regulating angiogenesis. We propose to demonstrate the mechanism and its molecular details in cultured cells, in animal cancer models and in human diabetic tissues and to explore a breakthrough therapeutic approach, which will target cancer angiogenesis in a tissue-specific manner without affecting physiological angiogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Arya, Suresh
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Stenina-Adognravi, Olga; Plow, Edward F (2017) Thrombospondin-4 in tissue remodeling. Matrix Biol :
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Muppala, Santoshi; Frolova, Ella; Xiao, Roy et al. (2015) Proangiogenic Properties of Thrombospondin-4. Arterioscler Thromb Vasc Biol 35:1975-86
Duncan, Andra E; Kateby Kashy, Babak; Sarwar, Sheryar et al. (2015) Hyperinsulinemic Normoglycemia Does Not Meaningfully Improve Myocardial Performance during Cardiac Surgery: A Randomized Trial. Anesthesiology 123:272-87
Krukovets, Irene; Legerski, Matthew; Sul, Pavel et al. (2015) Inhibition of hyperglycemia-induced angiogenesis and breast cancer tumor growth by systemic injection of microRNA-467 antagonist. FASEB J 29:3726-36
Stenina-Adognravi, Olga (2014) Invoking the power of thrombospondins: regulation of thrombospondins expression. Matrix Biol 37:69-82
Frolova, Ella G; Drazba, Judith; Krukovets, Irene et al. (2014) Control of organization and function of muscle and tendon by thrombospondin-4. Matrix Biol 37:35-48