Cell-of-origin effects on development of colon cancer

起源细胞对结肠癌发展的影响

• 批准号: 8403775
• 负责人: Robert J. Coffey
• 金额: $ 35.41万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403775
• 关键词: Address; Affect; Age-Months; Alleles; Animals; Cell physiology; Cell surface; Cells; Chromosomal Stability; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complementary DNA; Development; Digoxigenin; Dose; Elements; Environment; Epidermal Growth Factor Receptor; Epithelial; Event; Exhibits; Genes; Genetic; Genetically Engineered Mouse; Growth; Hour; In Vitro; Injection of therapeutic agent; Internal Ribosome Entry Site; KRAS2 gene; Label; Leucine; Leucine-Rich Repeat; Malignant Neoplasms; Mus; Neoplasms; Neoplastic Processes; Pattern; Phenotype; Population; Property; RNA Probes; Regulation; Signal Transduction; Sorting - Cell Movement; Stem cells; Tamoxifen; Tertiary Protein Structure; Testing; Tumor Stem Cell Assay; Xenograft procedure; cancer cell; cancer initiation; cancer stem cell; cell motility; colonic crypt; human CCXCR1 receptor; in vivo; loss of function; mutant; neoplastic cell; novel; novel therapeutics; progenitor; public health relevance; recombinase; research study; selective expression; stem cell population; tumor; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): It remains generally accepted that colorectal cancer (CRC) results from the accumulation of genetic events within the epithelial compartment. Unresolved issues include (1) whether the order of these genetic events matter (e.g., APC vs KRAS), (2) whether cancers can initiate from multiple distinct cells of origin, (3) the relationship between the normal colonic stem cell and the cells that function to maintain the tumor and (4) the contribution of the local environment to the neoplastic process. We hypothesize that colonic tumor initiation and progression is highly dependent upon the origin of the cell that incurs the relevant mutagenic events, as well as the regulation of growth and clonal selection of particular progeny that emanate from tumor-initiating cells. We have demonstrated that there are distinct normal colonic progenitor populations marked by expression of two specific cell surface markers, Lrig1 and Lgr5. Although the precise relationship between cells expressing these two markers is unknown, these two bona fide stem cell markers exhibit overlapping, yet distinct, expression patterns in both normal colon and in ApcMin/+ tumors. Of note, Lrig1 is induced by EGFR signaling and acts to negatively regulate EGFR signaling, whereas Lgr5 is a canonical Wnt target of unknown function. We have generated inducible Lrig1-CreERT2 mice, and our collaborator Hans Clevers has provided us with inducible Lgr5-EGFP-IRES-CreERT2 animals that allow for the specific activation of Cre recombinase within distinct colonic stem cell populations. We will use these mice to determine the importance of cell-of-origin in colon cancer initiation and progression. In addition, we have identified a gene, Slc26a3, that is selectively expressed in the differentiated compartment of the colon, and we have generated Slc26a3-CreERT2 mice that will allow us to resolve whether colonic tumors arise from the "top down" or "bottom up."

描述（由申请人提供）：通常认为结直肠癌（CRC）是由于遗传事件在上皮室内的积累而产生的。未解决的问题包括（1）这些遗传事件的顺序是否重要（例如，APC与KRAS），（2）癌症是否可以从多个不同的原始细胞中引发，（3）正常的结肠干细胞与维持肿瘤功能的细胞和（4）局部环境对神经胶体过程的作用。我们假设结肠肿瘤的启动和进展高度取决于造成相关诱变事件的细胞的起源，以及对从肿瘤启动细胞中散发出的特定后代的生长和克隆选择的调节。我们已经证明，有两个特定细胞表面标记LRIG1和LGR5的表达标志着明显的正常结肠祖细胞种群。尽管表达这两个标记的细胞之间的精确关系尚不清楚，但这两个真正的干细胞标记物在正常结肠和APCMIN/+肿瘤中均显示出重叠但不同的表达模式。值得注意的是，LRIG1是由EGFR信号传导诱导的，并作用于负调控EGFR信号，而LGR5是未知功能的规范WNT目标。我们已经产生了诱导的LRIG1-CREERT2小鼠，我们的合作者Hans Clevers为我们提供了诱导的LGR5-EGFP-IRES-CREERT2动物，这些动物允许在不同的结肠干细胞群体中特异性激活CRE重组酶。我们将使用这些小鼠来确定原生蛋白在结肠癌开始和进展中的重要性。此外，我们已经确定了一个基因SLC26A3，该基因在结肠的分化区室中有选择地表达，并且我们产生了SLC26A3-Creert2小鼠，该小鼠将使我们能够解决结肠肿瘤是从“上下倒下”还是“下到底”。