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

基本信息

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
项目类别：
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

项目摘要

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）：在乳腺癌化学预防方面，很少有药物能够破坏自分泌/旁分泌信号通路，而自分泌/旁分泌信号通路通过 PGE2（前列腺素 E2）和促炎细胞因子维持肿瘤支持性微环境，发挥着重要作用。抗糖尿病药物二甲双胍通过促进癌细胞增殖来介导肿瘤进展，与降低乳腺癌发病率有关，具有抗增殖、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。肿瘤微环境中的炎症信号传导以及 PGE2、膜联蛋白 A2 和生长和分化因子 15 (GDF15) 都是在肿瘤进展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 PGE2/膜联蛋白 A2/GDF15 信号轴来破坏乳腺癌中的促肿瘤自分泌/旁分泌炎症信号。研究包括：目标 1 将检验二甲双胍调节导致 BCC 细胞内在和细胞外在抑制的假设目标 2 将检验二甲双胍通过抑制 PGE2 和膜联蛋白 A2 的产生以及诱导 GDF15 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。通过识别抗塑料作用中涉及的关键信号元件，为二甲双胍和类似的“代谢修复药物”作为治疗/化学预防药物的开发做出贡献。从根本上说，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。