A mouse model of stem cell deregulation and lung cancer

干细胞失调和肺癌的小鼠模型

• 批准号: 7891197
• 负责人: JOSEPH D LOCKER
• 金额: $ 26.49万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891197
• 关键词: A Mouse; Abnormal Cell; Acceleration; Adult; Basal Cell; Birth; Bronchi; Bronchogenic Carcinoma; Cell Count; Cell Fraction; Cell Maintenance; Cells; Development; Differentiation Antigens; Distal; Dysplasia; Epithelial; Epithelium; Flow Cytometry; Funding; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Goals; Heterozygote; Histopathology; Human; Hyperplasia; Incidence; Knockout Mice; Label; LacZ Genes; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular Profiling; Mus; Mutation; Pathogenesis; Pathology; Peripheral; Population; Predisposition; Primary Cell Cultures; Property; Regulation; Regulatory Pathway; Reporter Genes; Research; Role; Staging; Stem cells; Suppressor Genes; TP53 gene; Testing; Trachea; Tracheobronchial; Transcription Repressor/Corepressor; Tumor Stem Cells; Tumor Suppression; aged; bronchial epithelium; cancer cell; cancer stem cell; carcinogenesis; falls; human disease; imprint; mouse model; novel; null mutation; progression marker; promoter; reconstitution; research study; tumor; tumor progression

DESCRIPTION (provided by applicant): During the previous funding period, we established an Nkx2.8-null mouse, in which the gene was replaced by a LacZ reporter gene under control of the intact Nkx2.8 promoter. In large airways of adult mice, reporter gene expression was confined to a subset of basal cells, and the number of expressing cells was significantly expanded in the Nkx2.8-/- mouse compared to Nkx2.8 heterozygotes. This cell expansion led to wide- spread bronchial dysplasia and aged mice had a high incidence of lung cancer. In development, Nkx2.8-expressing cells appeared relatively late, after the lungs had formed. First apparent in the distal lung buds, the cells spread upward throughout the bronchi and trachea, and eventually formed separate cell populations in the tracheo- bronchial and bronchioloalveolar regions. Both populations show properties of local stem cells. However, the null mutation deregulates only the tracheobronchial population. Increased LacZ-positive cells were associated with bronchial hyperplasia from birth, and labeling studies demonstrated that increased proliferation persisted in adults. Nkx2.8 therefore appears to act as a negative regulator that limits the number of tracheobron- chial stem cells. We propose new studies to accelerate the development of spontaneous bronchial cancer (Aim 1). The experiments will test the role of genetic background and suppressor-gene mutations on bronchial tumor progression. Other studies (Aim 2) will exploit the marker gene to analyze the dynamics of stem cell maintenance and differentiation, and their perturbation by the null-mutation. Histopathology and flow cytometry will correlate proliferation and differentiation markers in LacZ-expressing cells, which will also be isolated to characterize expression profiles, and differentiation properties in primary cell culture. Aim 3 will analyze tumor suppressive properties of induced Nkx2.8 expression in human lung cancer cells. Expression profiles from these cells will be com- pared to those obtained from mouse bronchial cell fractions, to determine specific relationships between tumor and stem cell regulation.

描述（由申请人提供）：在上一个融资期间，我们建立了NKX2.8-NULL小鼠，其中该基因被完整的NKX2.8启动子控制的LACZ报告基因代替。在成年小鼠的大型气道中，报告基因表达仅限于基底细胞的一部分，与NKX2.8杂合子相比，NKX2.8 - / - 小鼠在NKX2.8 - / - 小鼠中显着扩展。这种细胞的扩张导致广泛的支气管增生症，老年小鼠的肺癌发生率很高。在发育中，肺形成后，表达NKX2.8的细胞显得相对较晚。首先是远端肺芽，细胞向上散布在整个支气管和气管中，并最终在气管支气管和支气管肺泡区域中形成单独的细胞群。两个种群都显示出局部干细胞的特性。然而，无效突变仅消除气管支出人群。 LACZ阳性细胞增加与从出生开始的支气管增生有关，标记研究表明，成人的增殖持续增加。因此，NKX2.8似乎充当负调节剂，它限制了气管干细胞的数量。我们提出了新的研究，以加快自发支气管癌的发展（AIM 1）。实验将测试遗传背景和抑制 - 基因突变对支气管肿瘤进展的作用。其他研究（AIM 2）将利用标记基因来分析干细胞维持和分化的动力学及其对无效的扰动。组织病理学和流式细胞仪将在表达LACZ的细胞中相关联的增殖和分化标记，这也将被分离以表征表达谱以及原代细胞培养中的分化特性。 AIM 3将分析人类肺癌细胞中诱导NKX2.8表达的肿瘤抑制特性。这些细胞中的表达谱将与从小鼠支气管细胞部分获得的表达谱合并，以确定肿瘤和干细胞调节之间的特定关系。

项目成果

Breast cancer: the matrix is the message.

• DOI: 10.1016/j.ajpath.2010.12.013
• 发表时间: 2011-03
• 期刊: The American journal of pathology
• 作者: J. Locker;J. Segall

Both gene amplification and allelic loss occur at 14q13.3 in lung cancer.

• DOI: 10.1158/1078-0432.ccr-10-1892
• 发表时间: 2011-02-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Harris T;Pan Q;Sironi J;Lutz D;Tian J;Sapkar J;Perez-Soler R;Keller S;Locker J
• 通讯作者: Locker J