Induction of a tumor-hostile breast cancer microenvironment by metformin

二甲双胍诱导肿瘤不利的乳腺癌微环境

• 批准号: 9058123
• 负责人: Christopher Williams
• 金额: $ 10.67万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058123
• 关键词: Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Antidiabetic Drugs; Antineoplastic Agents; Attenuated; Breast; Breast Cancer Cell; Breast Cancer Prevention; Calcium-Binding Proteins; Cardiovascular system; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemopreventive Agent; Chronic; Coculture Techniques; Coxibs; Data; Development; Diabetes Mellitus; Dinoprostone; Disease; Elements; Endometrial Carcinoma; Estrogens; Exhibits; Experimental Models; FDA approved; Fibroblasts; GDF15 gene; Genes; Goals; Health; Hyperplasia; In Vitro; Incidence; Inflammation; Inflammatory; Malignant Neoplasms; Mammary Neoplasms; Mediating; Meta-Analysis; Metabolic; Metabolism; Metformin; Mind; Modeling; Myocardial Infarction; Neoplasm Metastasis; PLAB Protein; Paracrine Communication; Pharmaceutical Preparations; Phenotype; Play; Preventive; Production; Property; Repression; Risk; Role; Signal Transduction; Source; Stroke; Testing; Therapeutic; Thromboembolism; Tumorigenicity; Woman; angiogenesis; autocrine; cancer cell; cancer chemoprevention; conditioning; cytokine; diabetic patient; in vivo; insight; mRNA Expression; malignant breast neoplasm; neoplastic; overexpression; paracrine; prevent; tumor; tumor microenvironment; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): With regard to breast cancer chemoprevention, few drugs have been developed to disrupt the autocrine/paracrine signaling circuits which maintain the tumor-supportive microenvironment. Chronic inflammatory signaling through PGE2 (prostaglandin E2) and proinflammatory cytokines play significant roles in mediating tumor progression by promoting cancer cell proliferation. The anti-diabetic drug metformin is associated with decreased incidence of breast cancer, exhibits anti-proliferative, anti-inflammatory, effects in experimental models. However, there are few studies investigating if metformin exposure can attenuate tumor promoting autocrine/paracrine inflammatory signals which condition the breast cancer microenvironment. For this study, the goal is to ascertain the impact of metformin-modulated inflammatory signaling in the tumor microenvironment and consequently on tumor progression. PGE2, Annexin A2, and growth and Differentiation Factor 15(GDF15) are each molecules which play a distinct role in cell-extrinsic signaling in cancer and inflammation. As such, the overall hypothesis is that metformin disrupts pro-neoplastic autocrine/paracrine inflammatory signaling in breast cancer by disrupting the PGE2/annexin A2/GDF15 signaling axis. As such, the specific aims of this study include: Aim 1 will test the hypothesis that metformin-conditioning leads to cell intrinsic and cell extrinsic inhibition of BCC proliferation and invasiveness in vitro and in vivo. Aim 2 will test the hypothesis that metformin modulates tumor-supportive inflammatory signaling in breast cancer microenvironment by repressing PGE2 and annexin A2 production, and by inducing of GDF15 expression. The long term goal of these studies will contribute to the development of metformin and similar "metabolic reconditioning drugs" as therapeutic/chemo-preventive agents by identifying the key signaling elements involved in their antineoplastic effects. More fundamentally, these studies will provide valuable insight into the intersection of metabolism and inflammation in neoplastic disease.

 描述（由申请人提供）：关于乳腺癌化学预防，很少有药物被开发出来破坏维持肿瘤支持微环境的自分泌/旁分泌信号通路。通过PGE 2（前列腺素E2）和促炎细胞因子的慢性炎症信号传导通过促进癌细胞增殖在介导肿瘤进展中起重要作用。抗糖尿病药物二甲双胍与乳腺癌发病率降低相关，在实验模型中表现出抗增殖、抗炎作用。然而，很少有研究调查二甲双胍暴露是否可以减弱调节乳腺癌微环境的肿瘤促进自分泌/旁分泌炎症信号。对于这项研究，目标是确定二甲双胍调节的炎症信号在肿瘤微环境中的影响，从而对肿瘤进展的影响。PGE 2、膜联蛋白A2和生长和分化因子15（GDF 15）各自是在癌症和炎症中的细胞外源性信号传导中发挥独特作用的分子。因此，总体假设是二甲双胍通过破坏PGE 2/膜联蛋白A2/GDF 15信号传导轴来破坏乳腺癌中的促肿瘤自分泌/旁分泌炎症信号传导。因此，本研究的具体目的包括：目的1将检验二甲双胍条件化导致BCC的细胞内在和细胞外在抑制的假设 体外和体内的增殖和侵袭性。目的2将检验二甲双胍通过抑制PGE 2和膜联蛋白A2的产生以及诱导GDF 15表达来调节乳腺癌微环境中肿瘤支持性炎症信号传导的假设。这些研究的长期目标将有助于二甲双胍和类似的“代谢重建药物”作为治疗/化学预防剂的开发，方法是确定其抑制作用中涉及的关键信号传导元件。更重要的是，这些研究将为肿瘤疾病中代谢和炎症的交叉提供有价值的见解。