Signaling inputs that maintain the heterogeneity of colorectal cancer cells

维持结直肠癌细胞异质性的信号输入

基本信息

批准号：
7980220
负责人：
DARINA LAZAROVA
金额：
$ 39.19万
依托单位：
GEISINGER COMMONWEALTH SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7980220
关键词：
3-Dimensional Activins Agreement Antineoplastic Agents Apoptosis Apoptotic Benzamides Biological Factors Butyrates Cancer cell line Cell Culture System Cell Culture Techniques Cell Fraction Cell physiology Cells Clinical Trials Colon Colon Carcinoma Colorectal Cancer Complex Cutaneous Depsipeptides Dietary Fiber Exercise Exhibits Exposure to FDA approved Fermentation Genus Cola Heterogeneity Histone Deacetylase Inhibitor Histones Human In Vitro Lateral Ligands Maintenance Malignant - descriptor Malignant Neoplasms Marketing Mediator of activation protein Modality Mutation Names Notch and Wnt Signaling Pathway Outcome Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Population Prevention Process Proteins Radiation Regimen Reporting Resistance Role Signal Pathway Signal Transduction T-Cell Lymphoma Testing Therapeutic Therapeutic Agents Transforming Growth Factor beta Vorinostat Zolinza abstracting anti-cancer therapeutic base beta catenin cancer cell cell growth cell type cohort design good diet in vivo notch protein novel public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Signaling inputs that maintain the heterogeneity of colorectal cancer cells Abstract Butyrate, a fermentation product of dietary fiber in the colon, inhibits the activity of histone deacetylases and induces cell growth arrest, differentiation, and apoptosis in colorectal cancer (CRC) cells in vitro. Based upon these activities, butyrate is a likely mediator of the protective role of dietary fiber against colon cancer. We have established that the apoptotic levels in CRC cells exposed to butyrate depend upon the levels to which the agent hyper-activates Wnt signaling, a pathway that is abnormally activated in most CRCs. However, within each CRC cell population, only a fraction of cells acquires high levels of Wnt signaling, and the apoptotic outcome is limited to this fraction. Similar Wnt signaling heterogeneity of CRCs in vivo may contribute to their resistance to the apoptotic effects of butyrate and synthetic histone deacetylase inhibitors designed as anti-cancer agents. Based upon preliminary studies, we hypothesize that exposure to butyrate induces a process of cell-fate assignment similar to this of lateral inhibition. However, due to modified signaling inputs, this process does not result in the terminal differentiation of all cells: only cells with hyper-induced Wnt signaling undergo apoptosis; whereas, cells with moderate levels of Wnt signaling acquire more invasive phenotype supported by noncanonical TGFbeta/Activin, Notch, and Wnt signaling pathways. The aims of the project are: (1) to investigate the role for noncanonical TGFbeta/Activin signaling in CRC cells with differential sensitivity to the effects of butyrate, (2) to determine how components of Notch pathway maintain the heterogeneity in butyrate-treated CRC cell populations in terms of Wnt signaling levels, and (3) to test a bimodal approach that targets with apoptosis both low- and high-Wnt signaling CRC cells. For our analyses on the transcriptional activity and apoptotic role of the three signaling pathways we will utilize a panel of human CRC cell lines with differential sensitivity to the apoptotic effect of butyrate, as well as developed by us butyrate-resistant cells. The efficacy of a bimodal approach that targets with apoptosis both cells with low and high Wnt signaling will be tested in a 3-dimensional cell culture system. Understanding the interactions between noncanonical TGFbeta/Activin, Notch and Wnt signaling pathways may suggest approaches to overcome the CRC cell heterogeneity by targeting cells with both high and low sensitivity to the apoptotic effect of butyrate. Such strategies will be valid for an increasing cohort of synthetic histone deacetylase inhibitors, compounds that mimic the effects of butyrate on Wnt signaling and apoptosis in CRC cells and are currently in clinical trials as anti-cancer therapeutic agents. PUBLIC HEALTH RELEVANCE: Colorectal cancer cell populations in vitro and in vivo are heterogeneous in terms of Wnt signaling levels. This heterogeneity renders some of the cells more resistant to the programmed cell death induced by butyrate, a fermentation product of dietary fiber in the colon, and other anti-cancer agents, which mimic the effects of butyrate. We will analyze the mechanisms via which colorectal cancer cell heterogeneity arises, and test a novel treatment approach to overcome it.

描述（由申请人提供）：维持结直肠癌细胞异质性的信号输入抽象丁酸酯（丁酸酯）是结肠饮食纤维的发酵产物，抑制了组蛋白脱乙酰基酶的活性并诱导细胞生长的生长，分化，分化，大肠癌中的凋亡（ CRC）体外细胞。基于这些活动，丁酸酯可能是饮食纤维保护结肠癌的保护作用的介体。我们已经确定，暴露于丁酸酯的CRC细胞中的凋亡水平取决于试剂过度激活Wnt信号的水平，Wnt信号传导在大多数CRC中被异常激活的途径。但是，在每个CRC细胞群体中，只有一部分细胞获得高水平的Wnt信号传导，凋亡结果仅限于这一部分。 CRC在体内的类似Wnt信号传导异质性可能有助于它们对设计为抗癌剂的丁酸酯和合成组蛋白脱乙酰基酶抑制剂的凋亡作用。基于初步研究，我们假设暴露于丁理酸会引起类似于侧向抑制的细胞命令分配过程。但是，由于修改的信号输入，此过程并不能导致所有细胞的终末分化：只有具有高诱导的Wnt信号传导的细胞会经历凋亡；而Wnt信号中等水平的细胞可获得更多的侵入性表型，该表型由非规范的TGFBETA/AIVITIN，NOTCH和WNT信号传导途径支持。该项目的目的是：（1）研究对丁酸酯效果的敏感性差异的CRC细胞中非规范TGFBETA/激活素信号的作用，（2）确定Notch途径的组件如何保持丁酸酯处理的CRC的异质性细胞群体在Wnt信号传导水平方面以及（3）测试靶向低和高Wnt信号CRC细胞的双峰方法。对于我们对三种信号通路的转录活性和凋亡作用的分析，我们将利用一组对丁酸酯凋亡效应差异的人CRC细胞系，以及美国抗逆转肌酸酯抗性细胞的发展。在三维细胞培养系统中，将测试具有低Wnt信号传导的双峰方法的双峰方法的功效。了解非规范性TGFBETA/活化素，Notch和Wnt信号通路之间的相互作用可能表明通过靶向对Butyrate的凋亡作用的高灵敏度和低灵敏度来克服CRC细胞异质性的方法。此类策略对于越来越多的合成组蛋白脱乙酰基酶抑制剂有效，这些化合物模仿丁酸酯对CRC细胞中Wnt信号和凋亡的影响，目前正在临床试验中作为抗癌治疗剂。公共卫生相关性：在WNT信号水平方面，体外和体内结直肠癌细胞种群是异质的。这种异质性使一些细胞对丁酸酯诱导的程序性细胞死亡具有更大的耐药性，丁酸酯是结肠中饮食纤维的发酵产物和其他抗癌药，它们模仿了丁酸酯的作用。我们将分析发生结直肠癌细胞异质性的机制，并测试一种克服它的新型治疗方法。