Lung Epithelial-Mesenchymal Interactions in Adenocarcinoma Invasion

腺癌侵袭中的肺上皮-间质相互作用

• 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
• 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

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，组织学是不均匀的，与组织侵袭和临床有关