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

描述(申请人提供)：肥胖已被明确地确定为几种癌症，特别是乳腺癌的一个重要的风险和预后因素，但 肺癌中的肥胖症仍然存在争议，需要澄清。据报道，体重指数(BMI)和肺癌风险之间存在负相关(1，2)。然而，这些可能是由于吸烟造成的残留混杂。此外，几项关注饮食因素而不是BMI的流行病学研究表明，高饮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个潜在机制涉及通过增加芳香酶活性改变雌激素代谢，以及通过炎症介质核因子-kappaB(NF-：B)介导的雌激素受体信号改变(7)。是否在肺中发生类似的机制还没有被研究，但雌激素信号在肺癌发生和发展中的作用现在已经确定。肺癌表达雌激素受体和芳香化酶，无性别差异(8)。这些标记物在肺癌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癌的发生有关，并证明了抗雌激素治疗在预防肺癌中的保护作用(9，10)。我们最近发现芳香化酶抑制剂阿那曲唑可以抑制烟草诱导的小鼠肺肿瘤的发生，并且激素信号标志物在该模型系统中浸润性小鼠肺癌和肿瘤的肺炎性细胞中表达，提示肺癌中也存在炎症-芳香化酶联系。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-雌激素信号轴可能也是肥胖和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释放而增加肺癌风险。这项建议的目的是阐明肥胖、炎症和雌激素信号在肺癌发生中的机制联系，从而促进我们对肥胖影响肺癌风险的分子机制的理解。这一假说将通过临床前动物模型和实验中的人群研究来解决，具体目的如下：1)确定饮食诱导的肥胖在烟草致癌物暴露引起的肺癌发生中的促进作用，以及雌激素途径抑制剂和/或炎症抑制剂减少这种影响的能力；以及2)确定炎症和/或肥胖的标记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 在肺癌发生中发挥作用的炎症信号通路、激素调控策略和/或在选定的高危人群中进行抗炎治疗可能有利于肺癌的预防。

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.