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: 8319725
• 负责人: Charles A. Powell
• 金额: $ 3.8万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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/8319725
• 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; 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 growth; 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，组织学是异质的，并且与组织侵袭和临床相关。 结果。腺癌瘤内组织学异质性谱表明 侵袭性代表从非侵袭性细支气管肺泡癌 (BAG) 到 具有BAG成分的腺癌混合亚型到纯浸润性腺癌。分子 目前尚不清楚肺部这种转变所必需的事件。在这项研究中，我们关注的是入侵， 癌症的重要生物学和形态学特征，具有直接的临床意义 转移和结果。在初步的基因表达谱实验中，我们鉴定出 II 型 TGF- /?受体（TGF/SRII），其在侵袭性肿瘤中的表达水平显着较低，是一种 获取肺侵袭性分类器中最有趣的基因。我们假设压制 肺腺癌中的 TGFBRII 需要介导肿瘤/基质相互作用， 肺腺癌获得侵袭性。在本拨款提案中，我们将解决主要问题 具体目标如下： 1. 确定 Tgfbr2 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 肺靶向删除Tgfbr2和小鼠的侵袭性肺腺癌新动物模型 K-Ras 突变。在目标 2 中，我们将确定 CCL5 (Rantes) 在介导肿瘤中的需求 基质相互作用对于 TGFBRII 敲低细胞的侵袭很重要。 CCL5 被鉴定为 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/基质相互作用对于获得肺部侵袭性很重要 腺癌，我们希望确定这种活性的机制。这些研究的结果将 促进实现长期目标，即开发临床可用的检测方法来预测 腺癌组织标本的侵袭倾向，并开发和测试药物 将减少肺癌患者的侵袭性或预防侵袭性肿瘤的发展 肺癌高危人群。

项目成果

Tgf-beta signaling pathway in lung adenocarcinoma invasion.

• DOI: 10.1097/jto.0b013e3181c8cc0c
• 发表时间: 2010-02
• 期刊: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
• 作者: Toonkel RL;Borczuk AC;Powell CA
• 通讯作者: Powell CA

Waiting to exhale.

等待呼气。

• DOI: 10.1164/rccm.200710-1604ed
• 发表时间: 2008
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Powell,CharlesAndrew

Do all lung adenocarcinomas follow a stepwise progression?

• DOI: 10.1016/j.lungcan.2011.05.021
• 发表时间: 2011-10
• 期刊: LUNG CANCER
• 影响因子: 5.3
• 作者: Yatabe, Yasushi;Borczuk, Alain C.;Powell, Charles A.
• 通讯作者: Powell, Charles A.

Carcinoma of the lung and metastatic disease of the central nervous system.

肺癌和中枢神经系统转移性疾病。

• DOI: 10.1164/ajrccm.178.10.1090
• 发表时间: 2008
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Austin,JohnHM;Mujoomdar,Amol;Powell,CharlesA;Pearson,GregoryDN;Raftopoulos,Harry
• 通讯作者: Raftopoulos,Harry

Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.

• DOI: 10.1097/pas.0b013e318190157c
• 发表时间: 2009-03
• 期刊: The American journal of surgical pathology
• 作者: Borczuk AC;Qian F;Kazeros A;Eleazar J;Assaad A;Sonett JR;Ginsburg M;Gorenstein L;Powell CA
• 通讯作者: Powell CA