Lung Epithelial-Mesenchymal Interactions in Adenocarcinoma Invasion

在肺腺癌中，组织学是异质性的，与组织侵袭和临床相关。 结果。腺癌中肿瘤内组织学异质性的光谱提示 无转移性代表从非侵袭性细支气管肺泡癌(BAG)到 腺癌以BAG成分混合亚型为主，为单纯浸润性腺癌。分子 肺部这种转变所必需的事件目前尚不清楚。在这项研究中，我们关注的是入侵，一个 癌症的显著生物学和形态特征，在以下方面具有直接临床意义 转移和转归。在初步的基因表达谱实验中，我们鉴定了II型转化生长因子- /?受体(TGF/SRII)，它在侵袭性肿瘤中表达水平显著降低，作为一种 肺侵袭性分类器获得过程中最有趣的基因。我们假设，对中国的压制 肺腺癌中需要TGFBRII来介导肿瘤/间质之间的相互作用 肺腺癌侵袭性的获得。在这项拨款建议中，我们将解决主要的 假说的具体目的如下：1.确定TGFBR2的直接抑制作用 用小鼠肺腺癌遗传模型研究肺腺癌体内侵袭性。我们将创建一个 肺靶向缺失TGFBR2和TGFBR2基因的小鼠侵袭性肺腺癌动物模型 K-RAS基因突变。在目标2中，我们将确定CCL5(RANTES)在介导肿瘤- 基质相互作用对TGFBRII基因敲除细胞的侵袭非常重要。CCL5被确定为 侵袭性肿瘤中TGFb信号的潜在下游介体。在目标3中，我们将创建一个大型 腺癌肿瘤基因芯片检测人TGFBRII免疫染色的临床意义 肺腺癌。在这些研究中，我们将证明TGFBR2通路在 调节肿瘤上皮/间质间的相互作用对获得肺侵袭力具有重要意义 腺癌，我们希望确定这种活动的机制。这些研究的结果将 促进长期目标的实现，即开发可用于临床预测的分析方法 腺癌组织标本的侵袭倾向，并开发和测试 将降低肺癌患者的侵袭力或防止侵袭性肿瘤的发展 肺癌高危人群。

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 TGF- /? receptor (TGF/SRII), which was expressed at significantly lower levels in invasive tumors, as one 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: 1. 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 human lung adenocarcinoma. In these studies, we will demonstrate the importance of TGFBR2 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.