Peroxisome Proliferator-Activated Receptor (gamma) in Lung Cancer

简介(申请人提供)：肺癌是男性和女性癌症死亡的主要原因，大多数病例被归类为非小细胞肺癌(NSCLC)。由于在诊断时，大多数肺癌已经是晚期，因此需要新的策略来针对肿瘤的进展和转移。过氧化物酶体增殖物激活受体γ(PPARγ)是核激素受体超家族配体激活转录因子中的一员，在脂肪细胞活化中发挥重要作用，但也与多种癌症有关。在之前的资助期间，我们证明了PPARγ的激活对人非小细胞肺癌细胞具有多效性，包括促进分化表型，抑制转化生长和侵袭。该受体是罗格列酮和吡格列酮等噻唑烷二酮类药物的靶标。最近的回顾性研究表明，这些药物特别地降低了患者患肺癌的风险，使PPARγ成为治疗肺癌的有吸引力的靶点。肿瘤的进展和转移需要肿瘤细胞与周围肿瘤微环境(TME)之间复杂的相互作用。我们开发了一种免疫活性的小鼠肺癌细胞进展模型，在该模型中，将小鼠肺癌细胞注射到同基因小鼠的肺部。这些细胞形成原发肿瘤，转移到肺的其他叶、淋巴结以及包括肝脏和脑在内的远处器官。这个模型允许操纵肿瘤细胞或TME中的特定基因。使用这个模型，我们出人意料地表明，与对肿瘤细胞的影响相反，全身给药吡格列酮加速了肿瘤的进展并促进了转移。我们假设，PPARγ激活的这些不同效应是肿瘤细胞和TME相反作用的结果，肿瘤细胞中的激活抑制进展，而TME中的细胞激活促进进展。我们的初步数据表明，吡格列酮影响肿瘤相关巨噬细胞的分布，并可能促进肿瘤血管生成。该项目将使用体内模型和体外研究来确定每种细胞类型中PPARγ对肿瘤进展和转移的贡献。提出了三个具体目标。目的1研究肿瘤细胞中PPARγ激活在肿瘤进展中的特殊作用，并确定人和小鼠非小细胞肺癌细胞中的效应通路。目标2将使用定向基因敲除策略评估PPARγ在巨噬细胞中的作用。研究将使用体外系统来定义癌细胞和巨噬细胞之间的串扰。AIM 3将采用类似的靶向基因敲除策略来评估在吡格列酮治疗下内皮细胞中PPARγ在肿瘤进展中的作用。由于大量患者接受TZDS治疗，确定这些药物和PPARγ在癌症进展和转移中的作用至关重要。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths in both men and women, with the majority of cases being classified as non-small cell lung cancer (NSCLC). Since at time of diagnosis, the majority of lung cancers are already advanced, new strategies are required to target tumor progression and metastasis. Peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, plays a critical role in adipocyte activation, but has also been implicated in a variety of cancers. During the previous funding period we demonstrated that activation of PPARγ has pleiotropic effects on human NSCLC cells, including promotion of a differentiated phenotype and inhibition of transformed growth and invasiveness. This receptor is the target of thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone. Recent retrospective studies have suggested that these agents specifically reduce the risk of developing lung cancer in patients, making PPARγ an attractive target for treatment of lung cancer. Cancer progression and metastasis require complex interactions between tumor cells and the surrounding tumor microenvironment (TME). We have developed an immunocompetent mouse model for lung cancer cells progression, in which mouse lung cancer cells are injected into the lungs of syngeneic mice. These cells form a primary tumor which metastasizes to the other lobes of the lung, lymph nodes, and distant organs including liver and brain. This model allows manipulation of specific genes in either tumor cells or the TME. Using this model we have unexpectedly shown that in contrast to effects on tumor cells, systemic administration of pioglitazone accelerates tumor progression and promotes metastases. We hypothesize that these disparate effects of PPARγ activation are a result of opposing effects in tumor cells vs. the TME, with activation in tumor cells inhibiting progression and activation in cells of the TME contributing to progression. Our preliminary data indicate that pioglitazone affects the distribution of tumor-associated macrophages and may promote tumor angiogenesis. This project will use in vivo models and in vitro studies to define the contribution of PPARγ in each cell type to tumor progression and metastasis. Three specific aims are proposed. Aim 1 will examine the specific role of PPARγ activation in tumor cells on cancer progression, and define effector pathways in human and murine NSCLC cells. Aim 2 will assess the role of PPARγ in macrophages using a targeted knockout strategy. Studies will use in vitro systems to define cross-talk between cancer cells and macrophages. Aim 3 will employ a similar targeted knockout strategy to assess the role of PPARγ in endothelial cell on tumor progression in the setting of pioglitazone. Since large numbers of patients are treated with TZDs, defining the role of these agents and PPARγ on cancer progression and metastasis is of critical importance.