Inflammation in Oncogenic K-ras-induced Lung Tumorigenesis

致癌 K-ras 诱导的肺肿瘤发生中的炎症

• 批准号: 8052822
• 负责人: Jonathan M Kurie
• 金额: $ 25.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052822
• 关键词: Address; Adenocarcinoma Cell; Affect; Alleles; Alveolar; Alveolar Cell Type I; Alveolar Macrophages; Antibodies; Cell Communication; Cell Line; Cell Proliferation; Cell model; Cells; Coculture Techniques; Conditioned Culture Media; Endothelial Cells; Epithelial; Epithelial Cells; Fibroblasts; Genes; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Hyperplasia; IL8RB gene; Immune response; In Vitro; Inflammation; Inflammatory; Introns; Investigation; Killer Cells; Lesion; Ligands; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Mediator of activation protein; Membrane; Modeling; Muramidase; Mus; Mutation; Neoplasms; Non-Small-Cell Lung Carcinoma; Oncogenic; Partner in relationship; Pathway interactions; Phosphotransferases; Process; Proteomics; Proto-Oncogenes; Recombinants; Recruitment Activity; Role; Sampling; Site; Staging; Stem cells; Stromal Cells; Structure of parenchyma of lung; Testing; Tube; Vascular Endothelial Cell; adenoma; cancer therapy; cell motility; cell type; chemokine; chemokine receptor; in vitro Model; lung cancer prevention; lung tumorigenesis; macrophage; matrigel; migration; monocyte; mouse model; mutant; neoplastic cell; neutralizing antibody; neutrophil; novel; promoter; response; stem cell differentiation; tumor

DESCRIPTION (provided by applicant): Activating mutations in the K-ras proto-oncogene occur in approximately 30% of lung adenocarcinomas, the most common subtype of non-small cell lung cancer (NSCLC). K-ras is a membrane-associated GTPase that activates multiple kinase pathways, several of which have transforming activity in cellular models. Which of these downstream mediators of K-ras contribute to lung tumorigenesis has not been fully elucidated. Moreover, no effective approaches are available for the treatment of K-ras-mutant NSCLC. Our global hypothesis is that oncogenic K-ras-induced lung tumorigenesis is driven in part by a host response to the presence of transformed alveolar epithelial cells. These cells arise from bronchioalveolar stem cells (BASCs) and secrete chemokines that recruit host inflammatory cells and endothelial cells, which, in turn, secrete chemokines and growth factors that promote lung tumorigenesis. We propose to test this hypothesis by the completion of two Specific Aims. The first Specific Aim is to examine whether CXCR2 loss in inflammatory cells is sufficient to inhibit lung tumorigenesis induced by oncogenic K-ras. We will achieve this by creating two new oncogenic K-ras-driven mouse models of lung cancer, one in which the chemokine receptor CXCR2 is depleted globally to confirm our finding that treatment of KrasLA1 mice with a CXCR2 neutralizing antibody blocks lung tumorigenesis, and the other in which CXCR2 is depleted specifically in inflammatory cells. We investigate whether lung tumorigenesis is abrogated in these mouse models. The second Specific Aim is to examine the mechanisms by which tumor/stromal cell interactions promote lung tumorigenesis in an in vitro co-culture model. We will examine whether lung stromal cells (fibroblasts, endothelial cells, and macrophages) affect lung tumor cells (BASCs and a lung adenocarcinoma cell line derived from KrasLA1 mice) in a bi-directional manner using well-defined endpoints for tumor cells (cell proliferation, migration, and invasion), BASCs (proliferation and differentiation), and stromal cells (cell proliferation, migration, and endothelial tube formation). We will investigate the role of CXCR2 in these bi-directional interactions, and we will identify novel chemokines and growth factors in the in vitro model by performing proteomic analysis on conditioned media samples. We hope to better understand the mechanisms by which tumor/stromal cell interactions promote lung tumorigenesis and to build a rationale to test CXCR2 as a target for lung cancer prevention and therapy.

描述（由申请人提供）：K-ras原癌基因激活突变发生在约30%的肺腺癌中，肺腺癌是非小细胞肺癌（NSCLC）的最常见亚型。K-ras是一种膜相关的GT3，可激活多种激酶途径，其中几种在细胞模型中具有转化活性。K-ras的这些下游介质中的哪一个有助于肺肿瘤发生尚未完全阐明。此外，目前还没有有效的方法来治疗K-ras突变型非小细胞肺癌。我们的总体假设是致癌K-ras诱导的肺肿瘤发生部分是由宿主对转化的肺泡上皮细胞的反应驱动的。这些细胞来自细支气管肺泡干细胞（BASC），并分泌趋化因子，这些趋化因子招募宿主炎性细胞和内皮细胞，而宿主炎性细胞和内皮细胞又分泌促进肺肿瘤发生的趋化因子和生长因子。我们建议通过完成两个具体目标来检验这一假设。第一个具体目的是检查炎症细胞中CXCR 2的丢失是否足以抑制致癌K-ras诱导的肺肿瘤发生。我们将通过创建两个新的致癌K-ras驱动的肺癌小鼠模型来实现这一目标，其中一个模型中趋化因子受体CXCR 2在全球范围内被耗尽，以证实我们的发现，即用CXCR 2中和抗体治疗KrasLA 1小鼠可以阻断肺肿瘤发生，另一个模型中CXCR 2在炎症细胞中特异性耗尽。我们调查是否肺肿瘤发生是废除在这些小鼠模型。第二个具体目标是在体外共培养模型中研究肿瘤/基质细胞相互作用促进肺肿瘤发生的机制。我们将使用肿瘤细胞（细胞增殖、迁移和侵袭）、BASC（增殖和分化）和基质细胞（细胞增殖、迁移和内皮管形成）的明确终点，检查肺基质细胞（成纤维细胞、内皮细胞和巨噬细胞）是否以双向方式影响肺肿瘤细胞（BASC和源自KrasLA 1小鼠的肺腺癌细胞系）。我们将研究CXCR 2在这些双向相互作用中的作用，并通过对条件培养基样品进行蛋白质组学分析，在体外模型中鉴定新型趋化因子和生长因子。我们希望更好地了解肿瘤/基质细胞相互作用促进肺癌发生的机制，并建立一个基本原理来测试CXCR 2作为肺癌预防和治疗的靶点。