Lung Epithelial-Mesenchymal Interactions in Adenocarcinoma Invasion

腺癌侵袭中的肺上皮-间质相互作用

基本信息

批准号：
7213198
负责人：
Charles A. Powell
金额：
$ 38.73万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213198
关键词：
Address Adenocarcinoma Adenoviruses Alleles Alveolar wall Animal Model Apoptosis Applications Grants Basement membrane Bioinformatics Biological Biological Assay Breast Bronchiolo-Alveolar Adenocarcinoma CCR5 gene CXC Chemokines Cancer Histology Cell surface Cell-Cell Adhesion Cells Cellular Morphology Characteristics Clinical Coculture Techniques Codon Nucleotides Development Disease Down-Regulation End Point Epithelial Epithelial Cells Epithelial-Stromal Communication Epithelium Event Fibroblasts Frequencies Gene Expression Gene Expression Profiling Genes Genetic Models Genetic Transcription Goals Growth Growth Factor Receptors Heterogeneity Histology Human In Vitro Incidence Individual Invaded Invasive Knock-out Lung Lung Adenocarcinoma Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Mesenchymal Microarray Analysis Modeling Molecular Molecular Profiling Morphology Mucins Mus Mutant Strains Mice Mutation Neoplasm Metastasis Nodal Oncogenic Outcome Pathological Staging Pathway interactions Patients Pattern Phenotype Principal Investigator Process Production Proteins RANTES Relative (related person)Repression Research Personnel Risk Role Signal Transduction Specimen Staging Staining method Stains Stromal Cells Stromal Neoplasm Survival Rate System TGFB1 gene TGFBR2 gene Testing Tissue Microarray Tissues Transforming Growth Factors Week Wild Animals World Health Organization angiogenesis base cell motility cell stroma clinically significant cohort expectation follow-up human data in vivo inhibitor/antagonist interest knock-down lung Carcinoma matrigel mouse model mutant neoplastic cell novel prevent programs receptor recombinase research study size tumor

项目摘要

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.

描述（由申请人提供）：在肺腺癌中，组织学是异质的，并且与组织入侵和临床结局有关。腺癌中肿瘤内组织学异质性的光谱表明，Nvasivessives是疾病的连续性，从非侵入性支气管性支气管瘤癌（BAG）到腺癌的疾病连续性，再到腺癌将亚型与袋子成分与纯净的腺癌混合。目前未知的肺部过渡所必需的分子事件。在这项研究中，我们专注于侵袭，这是癌症的重要生物学和形态学特征，在转移和结果方面具有直接的临床意义。在初步的基因表达分析实验中，我们鉴定了II型TGFB受体（TGFBRII），在侵入性肿瘤中，该实验在肺部入侵分类器中获得的1个最有趣的基因中的1个。我们假设抑制肺腺癌中TGFBRII的抑制是为了介导在肺腺癌中获得侵入性之前的肿瘤/基质相互作用。在此赠款建议中，我们将在以下具体目的中解决主要假设：目标1是使用鼠肺腺癌的遗传模型来确定TGFBR2抑制对体内腺癌侵入性的直接作用。我们将创建一种新型的动物模型，以肺部靶向TGFBR2和K-RAS突变的小鼠中浸润性肺腺癌。在AIM 2中，我们将确定CCL5（RANTES）的需求，用于介导肿瘤 - 块状相互作用，这对于侵袭TGFBRII敲低细胞很重要。 CCL5被确定为浸润性肿瘤中TGFB信号传导的潜在下游介体。在AIM 3中，我们将创建一个大型腺癌肿瘤微阵列，以检查人类肺腺癌中TGFBRII免疫染色的临床意义。在这些研究中，我们将证明TGFBRII途径在调节肿瘤上皮/基质相互作用中对获得肺腺癌中侵入性很重要的重要性，我们希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，这些目标将开发临床上可用的测定，以预测腺癌组织标本的侵入性倾向，并开发和测试药理学剂，以降低肺癌患者的侵入性或预防肺癌高风险中侵入性肿瘤的发育。