Peroxisome Proliferator-Activated Receptor (gamma) in Lung Cancer

描述（由申请人提供）：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靶向肿瘤进展和转移。 过氧化物酶体增殖物激活受体-γ（过氧化物酶体增殖物激活受体γ）是配体激活转录因子核激素受体超家族的成员，在脂肪细胞活化中起关键作用，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NSCLC细胞具有多效性作用，包括促进分化表型和抑制转化生长和侵袭性。 该受体是噻唑烷二酮类（TZD）（如罗格列酮和吡格列酮）的靶点。 最近的回顾性研究表明，这些药物可以特异性降低患者发生肺癌的风险，使PPARγ成为治疗肺癌的有吸引力的靶点。 癌症进展和转移需要肿瘤细胞与周围肿瘤微环境（TME）之间的复杂相互作用。 我们已经开发了一种肺癌细胞进展的免疫活性小鼠模型，其中小鼠肺癌细胞被注射到同基因小鼠的肺中。 这些细胞形成原发性肿瘤，其转移到肺的其他叶、淋巴结和包括肝和脑的远端器官。 该模型允许操纵肿瘤细胞或TME中的特定基因。 使用该模型，我们意外地发现，与对肿瘤细胞的作用相反，吡格列酮的全身给药加速了肿瘤进展并促进了转移。 我们假设，这些不同的PPARγ激活效应是肿瘤细胞与TME中相反效应的结果，肿瘤细胞中的激活抑制进展，TME细胞中的激活促进进展。 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的PPARγ对肿瘤进展和转移的贡献。 提出了三个具体目标。 目的1将研究肿瘤细胞中PPARγ激活对癌症进展的特定作用，并定义人和小鼠非小细胞肺癌细胞中的效应途径。 目的2将使用靶向敲除策略评估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。 目的3将采用类似的靶向敲除策略，以评估在吡格列酮背景下内皮细胞中的PPARγ在肿瘤进展中的作用。 由于大量患者接受TZD治疗，因此确定这些药物和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.