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：
8855851
负责人：
Christopher Williams
金额：
$ 10.56万
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/8855851
关键词：
ANXA2 gene 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 In Vitro Incidence Inflammation Inflammatory Malignant Neoplasms Mammary Neoplasms Mediating Meta-Analysis Metabolic Metabolism Metformin Mind Modeling Myocardial Infarction Neoplasm Metastasis PLAB Protein PTGS1 gene 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 public health relevance 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（应用程序提供）：关于乳腺癌化学预防，很少开发出破坏维持肿瘤支持性微环境的自分泌/旁分泌信号传导电路的药物。通过PGE2（前列腺素E2）和促炎细胞因子通过促进癌细胞增殖在介导肿瘤进展中起着重要作用。抗糖尿病药物二甲双胍与乳腺癌的发病率降低有关，在实验模型中表现出抗增殖，抗炎的作用。但是，很少有研究研究二甲双胍是否可以减弱肿瘤，从而促进乳腺癌微环境的自分泌/旁分泌炎症信号。在这项研究中，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。 PGE2，ANNEXIN A2以及生长和分化因子15（GDF15）是每个分子在癌症和炎症中在细胞超支信号中起独特的作用。因此，总体假设是二甲双胍通过破坏PGE2/Annexin A2/GDF15信号传导轴来破坏乳腺癌中促肿瘤的自分泌/旁分泌信号传导。因此，这项研究的具体目的包括：AIM 1将检验以下假设：二甲双胍调节导致细胞内在和细胞外部抑制BCC 体外和体内的增殖和侵入性。 AIM 2将检验二甲双胍通过反映PGE2和膜联蛋白A2产生以及诱导GDF15表达来调节乳腺癌微环境中肿瘤支持性信号传导的假设。这些研究的长期目标将有助于二甲双胍和类似的“代谢再现药物”作为治疗/化学预防剂的发展，通过识别其抗肿瘤作用所涉及的关键信号元素。从根本上讲，这些研究将为肿瘤疾病中代谢和感染的交集提供宝贵的见解。