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: 7538365
• 负责人: Charles A. Powell
• 金额: $ 40.11万
• 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/7538365
• 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; Genetic Transcription; 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; 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，组织学是异质性的，并且与组织浸润和临床表现相关。 结果。腺癌的肿瘤内组织学异质性表明 侵袭性代表了从非侵袭性细支气管肺泡癌（BAG）到 腺癌混合亚型与BAG成分的纯浸润腺癌。分子 肺中这种转变所必需的事件目前尚不清楚。在这项研究中，我们重点关注入侵， 具有直接临床意义癌症的重要生物学和形态学特征， 转移和结果。在初步的基因表达谱实验中，我们鉴定了II型TGF-β 1。 /?受体（TGF/SRII），在浸润性肿瘤中表达水平显著降低，作为一种 在肺侵袭性分类器的获取中最有趣的基因。我们假设， 肺腺癌中的TGFBRII需要介导肿瘤/间质相互作用， 肺腺癌侵袭性的获得。在这份拨款申请中，我们将讨论主要的 假设在以下具体目标：1.确定Tgfbr 2抑制对 使用小鼠肺腺癌的遗传模型研究腺癌的体内侵袭性。我们将创建一个 肺靶向缺失Tgfbr 2的小鼠侵袭性肺腺癌的新动物模型 K-Ras突变。在目标2中，我们将确定CCL 5（Rantes）在介导肿瘤中的需求。 基质相互作用对于TGFBRII敲低细胞的侵袭是重要的。CCL 5被鉴定为 在侵袭性肿瘤中TGFB信号传导的潜在下游介质。在目标3中，我们将创建一个大型 腺癌肿瘤微阵列检测人TGF β R Ⅱ免疫染色的临床意义 肺腺癌在这些研究中，我们将证明TGFBR 2通路在 调节肿瘤上皮/间质相互作用对获得肺中的侵袭性很重要 腺癌，我们希望确定这种活性的机制。这些研究的结果将 促进长期目标的实现，即开发临床可用的检测方法来预测 腺癌组织标本中的侵袭倾向，并开发和测试药理学试剂， 将减少肺癌患者的侵袭性或预防侵袭性肿瘤的发展， 肺癌的高危人群