Induction of a tumor-hostile breast cancer microenvironment by metformin

 描述(申请人提供)：关于乳腺癌的化学预防，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。前列腺素E_2(PGE2)的慢性炎症信号和促炎细胞因子通过促进癌细胞增殖，在调节肿瘤进展中发挥重要作用。抗糖尿病药物二甲双胍与乳腺癌发病率的降低有关，在实验模型中显示出抗增殖、抗炎的作用。然而，很少有研究研究二甲双胍是否可以减弱肿瘤刺激的自分泌/旁分泌炎症信号，而这些炎症信号是乳腺癌微环境的条件。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。PGE2、Annexin A2和生长与分化因子15(GDF15)都是在癌症和炎症的细胞外源信号中发挥不同作用的分子。因此，总体假设是二甲双胍通过破坏PGE2/Annexin A2/GDF15信号轴来干扰乳腺癌的促肿瘤自分泌/旁分泌炎症信号。因此，本研究的具体目的包括：目标1将检验二甲双胍调节导致细胞内源性和细胞外源性抑制基底细胞癌的假设 体外和体内的增殖和侵袭能力。目的2验证二甲双胍通过抑制PGE2和Annexin A2的产生以及通过诱导GDF15的表达来调节乳腺癌微环境中的肿瘤支持性炎症信号的假说。这些研究的长期目标将通过确定与其抗肿瘤作用有关的关键信号元素，为开发二甲双胍和类似的作为治疗/化学预防药物的“代谢修复药物”做出贡献。更根本的是，这些研究将为肿瘤疾病中新陈代谢和炎症的交集提供有价值的见解。

 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.