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: 8255616
• 负责人: Jonathan M Kurie
• 金额: $ 18.95万
• 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/8255616
• 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 原癌基因的激活突变发生在大约 30% 的肺腺癌中，肺腺癌是非小细胞肺癌 (NSCLC) 最常见的亚型。 K-ras 是一种膜相关 GTP 酶，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 的这些下游介质中哪些有助于肺部肿瘤的发生尚未完全阐明。此外，尚无有效的方法可用于治疗 K-ras 突变 NSCLC。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存在的反应驱动的。这些细胞源自支气管肺泡干细胞（BASC），分泌趋化因子，招募宿主炎症细胞和内皮细胞，而内皮细胞反过来又分泌趋化因子和生长因子，促进肺肿瘤发生。我们建议通过完成两个具体目标来检验这一假设。第一个具体目标是检查炎症细胞中 CXCR2 的缺失是否足以抑制致癌 K-ras 诱导的肺部肿瘤发生。我们将通过创建两种新的致癌 K-ras 驱动的肺癌小鼠模型来实现这一目标，其中一种模型的趋化因子受体 CXCR2 在整体上被耗尽，以证实我们的发现，即用 CXCR2 中和抗体治疗 KrasLA1 小鼠可阻止肺癌发生，另一种模型中的 CXCR2 在炎症细胞中被特异性地耗尽。我们研究了这些小鼠模型中肺部肿瘤的发生是否被消除。第二个具体目标是在体外共培养模型中检查肿瘤/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）的明确终点来检查肺基质细胞（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 KrasLA1 小鼠的肺腺癌细胞系）。 增殖、迁移和内皮管形成）。我们将研究 CXCR2 在这些双向相互作用中的作用，并且我们将通过对条件培养基样品进行蛋白质组分析来鉴定体外模型中的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肿瘤发生的机制，并为测试 CXCR2 作为肺癌预防和治疗的靶点奠定基础。