(PQA2) Elucidating the link between obesity, inflammation and estrogen signaling

(PQA2) 阐明肥胖、炎症和雌激素信号传导之间的联系

基本信息

批准号：
8683852
负责人：
Laura P. Stabile
金额：
$ 16.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8683852
关键词：
Address Adverse effects Affect American Animal Model Anti-Inflammatory Agents Anti-inflammatory Aromatase Aromatase Inhibitors Biological Models Body mass index Bronchoalveolar Lavage Butanones Cancer Patient Carcinogen exposure Cells Cohort Studies Communities Data Development Diagnosis Diet Dietary Factors Dietary Fats Disease Dose Epidemiologic Studies Equation Estrogen Antagonists Estrogen Metabolism Estrogen Receptors Estrogen Therapy Estrogens Fat-Restricted Diet Fatty acid glycerol esters Goals Hormonal Hormone replacement therapy Hormones IL6 gene Incidence Inflammation Inflammation Mediators Inflammatory Intake Lead Leptin Link Liquid substance Lung Lung Neoplasms Malignant neoplasm of lung Measures Mediating Modeling Molecular Mus NF-kappa B Non-Small-Cell Lung Carcinoma Obesity Pathway interactions Play Population Population Study Postmenopause Prevention Prevention strategy Prognostic Factor Receptor Signaling Reporting Research Research Project Grants Residual state Risk Factors Role Sampling Serum Sex Characteristics Signal Pathway Signal Transduction Smoker Smoking Spiral Computed Tomography Staging Structure of parenchyma of lung Survival Rate Symptoms Testing Tobacco Tobacco-Associated Carcinogen Tumor Tissue adiponectin anastrozole base cancer risk cancer type cigarette smoking cohort energy balance high risk inflammatory marker inhibitor/antagonist killings lung cancer prevention lung cancer screening lung carcinogenesis lung tumorigenesis malignant breast neoplasm mortality novel outcome forecast pre-clinical protective effect public health relevance research study statistics tumor

项目摘要

DESCRIPTION (provided by applicant): Obesity has been clearly established as an important risk and prognostic factor for several types of cancer, particularly breast cancer, but the role of obesity in lung cancer remains controversial and requires clarification. Inverse associations between body mass index (BMI) and lung cancer risk have been reported (1, 2). However, these might be due to residual confounding by smoking. Also, several epidemiological studies that focused on dietary factors instead of BMI have shown positive associations between high dietary fat intake and lung cancer risk and mortality (3-6). One potential mechanism by which obesity enhances breast cancer risk involves altered estrogen metabolism through increased aromatase activity and altered estrogen receptor signaling mediated through the inflammatory mediator nuclear factor kappa-B (NF-:B) (7). Whether a similar mechanism occurs in the lung has not yet been investigated, but the role of estrogen signaling in the development and progression of lung cancer is now firmly established. Lung tumors express estrogen receptors and aromatase with no sex difference in expression (8). High expression of these markers in lung tumors has also been correlated with poor prognosis in lung cancer patients. Furthermore, several large cohort studies have implicated the estrogen pathway in lung tumorigenesis and have demonstrated a protective effect of anti-estrogen therapy in the prevention of lung cancer (9,10). We have recently shown that the aromatase inhibitor anastrozole can inhibit tobacco-induced lung tumorigenesis in mice and that hormonal signaling markers are expressed in pulmonary inflammatory cells infiltrating murine preneoplasias and tumors in this model system, suggesting that the inflammation-aromatase link also exists in lung cancer. In addition, combined inhibition of estrogen and inflammatory pathways results in enhanced anti-tumor effects in the lungs of mice, confirming the link between these two pathways. Thus, the inflammation-estrogen signaling axis may underlie the link between obesity and lung cancer risk as well. Given these findings, we hypothesize that obesity contributes to lung cancer risk by increasing both inflammation in the lung and release of estrogen. The goal of this proposal is to elucidate the mechanistic link between obesity, inflammation and estrogen signaling in lung carcinogenesis and thereby advance our understanding of the molecular mechanisms by which obesity affects lung cancer risk. This hypothesis will be addressed using a preclinical animal model as well as a population study in the experiments of the following Specific Aims: 1) Determine the role of diet-induced obesity in promoting lung carcinogenesis caused by tobacco carcinogen exposure and the ability of estrogen pathway inhibitors and/or inflammatory inhibitors to reduce this effect; and 2) Determine the relationship between markers of inflammation and/or obesity as well as circulating hormone levels and lung cancer risk. Should this exploratory study reveal that obesity related factors are linked to the estrogen and/or inflammatory signaling pathways that play a role in lung tumorigenesis, strategies involving hormonal manipulation and/or anti-inflammatory therapies in select high-risk populations may be beneficial for lung cancer prevention.

描述（由申请人提供）：肥胖已被明确确定为多种癌症（尤其是乳腺癌）的重要风险和预后因素，但肥胖的作用肥胖与肺癌的关系仍然存在争议，需要澄清。据报道，体重指数 (BMI) 与肺癌风险之间呈负相关 (1, 2)。然而，这些可能是由于吸烟残留的混淆造成的。此外，一些关注饮食因素而不是 BMI 的流行病学研究表明，高膳食脂肪摄入量与肺癌风险和死亡率之间存在正相关 (3-6)。肥胖增加乳腺癌风险的一种潜在机制涉及通过增加芳香酶活性来改变雌激素代谢，以及改变通过炎症介质核因子 kappa-B (NF-:B) 介导的雌激素受体信号传导 (7)。类似的机制是否发生在肺部尚未得到研究，但雌激素信号在肺癌发生和进展中的作用现已确定。肺部肿瘤表达雌激素受体和芳香酶，表达没有性别差异 (8)。这些标志物在肺部肿瘤中的高表达也与肺癌患者的不良预后相关。此外，几项大型队列研究表明雌激素途径与肺部肿瘤发生有关，并证明抗雌激素治疗在预防肺癌方面具有保护作用 (9,10)。我们最近表明，芳香酶抑制剂阿那曲唑可以抑制烟草诱导的小鼠肺部肿瘤发生，并且在该模型系统中，激素信号标记物在浸润小鼠肿瘤前期和肿瘤的肺部炎症细胞中表达，这表明炎症与芳香酶的联系也存在于肺部癌症。此外，雌激素和炎症途径的联合抑制可增强小鼠肺部的抗肿瘤作用，证实了这两种途径之间的联系。因此，炎症-雌激素信号轴也可能是肥胖与肺癌风险之间联系的基础。鉴于这些发现，我们假设肥胖通过增加肺部炎症和雌激素的释放来增加肺癌风险。该提案的目的是阐明肥胖、炎症和雌激素信号在肺癌发生中的机制联系，从而增进我们对肥胖影响肺癌风险的分子机制的理解。该假设将通过临床前动物模型以及群体研究在以下具体目标的实验中得到解决：1）确定饮食引起的肥胖在促进烟草致癌物暴露引起的肺癌发生中的作用以及雌激素途径的能力抑制剂和/或炎症抑制剂以减少这种影响； 2) 确定炎症和/或肥胖标志物以及循环激素水平与肺癌风险之间的关系。这项探索性研究是否应该揭示肥胖相关因素与雌激素和/或炎症信号通路在肺部肿瘤发生中发挥作用，针对选定的高危人群进行激素调控和/或抗炎治疗的策略可能有利于肺癌的预防。