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：
7738519
负责人：
Charles A. Powell
金额：
$ 34.94万
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/7738519
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 Epithelial Epithelial Cells Epithelial-Stromal Communication Epithelium Event Fibroblasts Frequencies Gene Expression Gene Expression Profiling Genes Genetic Models Goals Growth Growth Factor Receptors Heterogeneity Histology Human In Vitro Incidence Individual Invaded 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 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 Wild Animals World Health Organization adverse outcome angiogenesis base cell motility cell stroma clinically significant cohort expectation follow-up high risk human data in vivo inhibitor/antagonist interest knock-down lung Carcinoma matrigel meetings mouse model mutant neoplastic cell novel prevent programs receptor recombinase research study tumor

项目摘要

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.

在肺腺癌中，组织学是异质的，与组织入侵和临床有关结果。腺癌内肿瘤内组织学异质性的谱图表明不可证明是从非侵入性支气管瘤癌（BAG）到疾病连续的腺癌将亚型与袋子成分与纯侵入性腺癌混合。分子目前未知的肺部过渡至关重要的事件。在这项研究中，我们专注于入侵，癌症的重要生物学和形态学特征，其直接临床意义就转移和结果。在初步基因表达分析实验中，我们确定了II型TGF- /？受体（TGF/SRII），在侵入性肿瘤中以显着较低的水平表达，作为其中之一在获取肺部侵入性分类器时，最有趣的基因。我们假设对肺腺癌中的TGFBRII需要介导之前的肿瘤/基质相互作用肺腺癌中侵入性的获取。在此赠款建议中，我们将讨论主要以下特定目的中的假设：1。确定TGFBR2抑制的直接作用使用鼠肺腺癌的遗传模型，体内腺癌的侵入性。我们将创建一个具有肺靶向缺失TGFBR2和 K-Ras的突变。在AIM 2中，我们将确定介导肿瘤的CCL5（RANTES）的要求对于侵袭TGFBRII敲除细胞很重要的基质相互作用。 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检查TGFBRII免疫染色人类的临床意义肺腺癌。在这些研究中，我们将证明TGFBR2途径在调节肿瘤上皮/基质相互作用对于获得肺中的侵入性很重要腺癌，我们希望确定这种活性的机制。这些研究的结果将促进实现长期目标，这些目标将开发临床可用的测定以预测腺癌组织标本中的侵入性倾向，并开发和测试药理学剂将降低肺癌患者的侵入性或防止侵袭性肿瘤的发展患有肺癌高风险的人。