Lung Epithelial-Mesenchymal Interactions in Adenocarcinoma Invasion

描述（由申请方提供）：在肺腺癌中，组织学是异质性的，与组织浸润和临床结局相关。腺癌的肿瘤内组织学异质性谱表明，侵袭性代表了从非侵袭性细支气管肺泡癌（BAG）到具有BAG组分的腺癌混合亚型再到纯侵袭性腺癌的疾病连续体。肺中这种转变所必需的分子事件目前尚不清楚。在这项研究中，我们专注于侵袭，这是癌症的一个重要生物学和形态学特征，在转移和结局方面具有直接的临床意义。在初步的基因表达谱实验中，我们确定了II型TGF β受体（TGF β R Ⅱ），这是在侵袭性肿瘤中表达水平显着较低，作为一个最有趣的基因在收购肺侵袭性分类。我们假设肺腺癌中TGFBRII的抑制是介导肿瘤/间质相互作用所必需的，而这种相互作用先于肺腺癌的侵袭性获得。在这项资助计划中，我们将解决以下具体目标的主要假设：目的1是确定TGFBR 2抑制对腺癌侵袭性的直接作用，在体内使用小鼠肺腺癌的遗传模型。我们将通过肺靶向TGFBR 2基因缺失和K-Ras基因突变，建立一种新的小鼠侵袭性肺腺癌动物模型。在目标2中，我们将确定CCL 5（Rantes）在介导肿瘤-基质相互作用中的需求，这些相互作用对于TGFBRII敲低细胞的侵袭是重要的。CCL 5被鉴定为侵袭性肿瘤中TGFB信号传导的潜在下游介质。目的3：建立一个大型腺癌肿瘤微阵列，以检测TGF β R Ⅱ免疫染色在人肺腺癌中的临床意义。在这些研究中，我们将证明TGFBRII途径在调节肿瘤上皮/间质相互作用中的重要性，这种相互作用对于肺腺癌侵袭性的获得很重要，我们期望确定这种活性的机制。这些研究的结果将有助于实现长期目标，即开发临床可用的检测方法，以预测腺癌组织标本的侵袭倾向，并开发和测试降低肺癌患者侵袭性或预防肺癌高危个体侵袭性肿瘤发展的药理学药物。

DESCRIPTION (provided by applicant): Within lung adenocarcinoma, histology is heterogeneous and associated with tissue invasion and clinical outcomes. The spectrum of intra-tumoral histological heterogeneity in adenocarcinoma suggests nvasiveness represents a continuum of disease from noninvasive bronchioloalveolar carcinoma (BAG) to adenocarcinoma mixed subtype with BAG component to pure invasive adenocarcinoma. The molecular events essential to this transition in the lung are presently unknown. In this study, we focus on invasion, a significant biological and morphological characteristic of cancer with direct clinical implications in terms of metastasis and outcome. In preliminary gene expression profiling experiments, we identified the type II TGFB receptor (TGFBRII), which was expressed at significantly lower levels in invasive tumors, as 1 of the most interesting genes in the acquisition of lung invasiveness classifiers. We hypothesize that repression of TGFBRII in lung adenocarcinoma is required to mediate tumor/stromal interactions that precede the acquisition of invasiveness in lung adenocarcinoma. In this grant proposal, we will address the main hypothesis in the following specific aims: Aim 1 is to determine the direct role of TGFBR2 repression on adenocarcinoma invasiveness in vivo using genetic model of murine lung adenocarcinoma. We will create a novel animal model of invasive lung adenocarcinoma in mice with pulmonary targeted deletion of TGFBR2 and mutation of K-Ras. In Aim 2, we will determine the requirement for CCL5 (Rantes) in mediating tumor-stromal interactions that are important for invasion of TGFBRII knock-down cells. CCL5 was identified as a potential downstream mediator of TGFB signaling in invasive tumors. In Aim 3, we will create a large adenocarcinoma tumor microarray to examine the clinical significance of TGFBRII immunostaining in human lung adenocarcinoma. In these studies, we will demonstrate the importance of TGFBRII pathways in modulating tumor epithelial/stromal interactions important for the acquisition of invasiveness in lung adenocarcinoma and we expect to identify the mechanisms of this activity. The results of these studies will facilitate the attainment of the long-term goals, which are to develop clinically available assays to predict invasive propensity in adenocarcinoma tissue specimens and to develop and test pharmacologic agents that will reduce invasiveness in patients with lung cancer or prevent the development of invasive tumors in individuals at high risk for lung cancer.