Mechanisms of survival of liver cancer stem cells

肝癌干细胞的存活机制

• 批准号: 8049761
• 负责人: Carl Barth Rountree
• 金额: $ 7.68万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049761
• 关键词: Accounting; Apoptosis; Apoptotic; Area; Award; Biological; CD44 gene; CXCR4 gene; Carcinoma; Cell Cycle Regulation; Cell Line; Cell Survival; Cell surface; Cells; Chemotherapy-Oncologic Procedure; Cholangiocarcinoma; Chronic; Coupled; Critical Pathways; Data; Epithelial; Failure; Funding; Goals; Growth Factor; Hepatocyte; Host Defense; Human; Injury; Investigation; Link; Liver; Liver Stem Cell; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Mus; Neoplasms; Outcome; PI3K/AKT; Pathway Analysis; Pathway interactions; Patients; Phenotype; Population; Premalignant; Primary carcinoma of the liver cells; Proliferating; Proteins; Publishing; Regulatory Pathway; Reporting; Research; Resistance; Signal Pathway; Signal Transduction; Stem cells; Study Section; TACSTD2 gene; TNFSF10 gene; Testing; Time; Tissues; Transforming Growth Factors; Work; base; cancer stem cell; cancer therapy; chemotherapy; cholangiocyte; innovation; novel therapeutic intervention; outcome forecast; oval cell; public health relevance; response; stem cell population; therapy development; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The broad goal of this project is to understand the mechanism of liver cancer stem cell survival and resistance to chemotherapy. Accumulating evidence indicates that liver cancer stem cells (CSC) are the origin of a subset of hepatocellular carcinomas (HCC). HCC patients with a stem cell based tumor have a significantly worse prognosis compared to patients with more differentiated HCC. The central hypothesis is that deregulated growth factor signaling allows stem cells to escape normal apoptotic mechanisms and become CSCs. We have identified liver CSC phenotypes in two pre-tumor chronic liver injury models using CD133 expression. These CD133+ CSCs are resistant to Transforming Growth Factor-( (TGF-()- induced apoptosis. To date, no one has reported an unbiased analysis to identify the strongest liver cancer stem cell immuno-phenotype identified from the many published markers. By identifying the most reliable immuno-phenotype of liver CSC, we can further dissect the factors that influence the loss of cell cycle control and resistance to apoptosis critical to liver cancer progression and chemotherapy resistance. The rationale for the proposed research is that new therapeutic approaches for liver cancer can be developed to target liver CSCs, which maintain the larger neoplasia and account for a significant proportion of chemotherapy failures. We will utilize multiple human hepatocellular carcinoma and cholangiocarcinoma cell lines to investigate the single best cancer stem cell marker linked to deregulation of critical pathways known to influence liver carcinoma progression. Aim 1 Determine the liver cancer stem cell surface marker highly correlated with resistance to chemotherapy and to biologically induced apoptosis. Hypothesis: Resistance to signal mediated apoptosis and chemotherapy agents provides CSCs a mechanism of survival. Aim 2 Test regulatory pathways within specific cancer stem cell populations. Hypothesis: Deregulation of key pathways known to influence HCC progression (RAS/MAPK, PI3K/AKT, (-catenin) will provide a mechanism of survival and apoptosis resistance to liver CSCs. The proposed work is innovative because we propose an unbiased analysis of CSC surface markers coupled with an investigation of mechanisms of survival. The work proposed in Aim 1 will provide us with a more complete understanding of the best liver CSC surface marker. Furthermore, we anticipate that Aim 2 will allow us to understand how specific deregulation of key signaling pathways provides liver CSCs with a survival mechanism. PUBLIC HEALTH RELEVANCE: The broad goal of this project is to understand the mechanism of liver cancer stem cell survival and resistance to chemotherapy. We seek to understand the relationship between liver stem cells and cancer stem cells during chronic liver injury and tumorigenesis. If successful, the potential impact of this award will be realized in the area of liver cancer therapy development.

描述（由申请人提供）：该项目的主要目标是了解肝癌干细胞存活和耐化疗的机制。越来越多的证据表明，肝癌干细胞（CSC）是肝细胞癌（HCC）的起源。与分化程度更高的HCC患者相比，具有干细胞肿瘤的HCC患者的预后显著更差。中心假设是，去调节的生长因子信号传导允许干细胞逃避正常的凋亡机制并成为CSC。我们已经在两个肿瘤前慢性肝损伤模型中使用CD 133表达鉴定了肝CSC表型。这些CD 133 + CSC对转化生长因子-（TGF-β）诱导的凋亡具有抗性。到目前为止，还没有人报道一个公正的分析，以确定最强的肝癌干细胞免疫表型从许多已发表的标志物。通过鉴定肝CSC最可靠的免疫表型，我们可以进一步剖析影响细胞周期控制丧失和细胞凋亡抵抗的因素，这些因素对肝癌进展和化疗抵抗至关重要。这项研究的基本原理是，可以开发新的肝癌治疗方法来靶向肝CSC，肝CSC维持较大的肿瘤形成，并占化疗失败的很大一部分。我们将利用多种人肝细胞癌和胆管癌细胞系来研究与已知影响肝癌进展的关键途径失调相关的单一最佳癌症干细胞标志物。 目的1确定与化疗耐药和生物诱导凋亡高度相关的肝癌干细胞表面标志物。 假设：对信号介导的凋亡和化疗药物的抗性为CSC提供了存活机制。 目的2检测特定癌症干细胞群中的调控通路。 假设：已知影响HCC进展的关键途径（RAS/MAPK、PI 3 K/AKT、β-连环蛋白）的失调将提供肝CSC的存活和凋亡抗性机制。 拟议的工作是创新的，因为我们提出了一个公正的分析CSC表面标记加上生存机制的调查。目标1中提出的工作将为我们提供对最佳肝脏CSC表面标记物的更完整的理解。此外，我们预计Aim 2将使我们能够了解关键信号通路的特异性失调如何为肝脏CSC提供存活机制。 公共卫生相关性：该项目的广泛目标是了解肝癌干细胞存活和耐化疗的机制。我们试图了解慢性肝损伤和肿瘤发生过程中肝干细胞和肿瘤干细胞之间的关系。如果成功，该奖项的潜在影响将在肝癌治疗开发领域实现。

项目成果

miR-200b restoration and DNA methyltransferase inhibitor block lung metastasis of mesenchymal-phenotype hepatocellular carcinoma.

• DOI: 10.1038/oncsis.2012.15
• 发表时间: 2012-06-11
• 期刊: ONCOGENESIS
• 影响因子: 6.2
• 作者: Ding, W.;Dang, H.;You, H.;Steinway, S.;Takahashi, Y.;Wang, H-G;Liao, J.;Stiles, B.;Albert, R.;Rountree, C. B.
• 通讯作者: Rountree, C. B.

Induction of tumor initiation is dependent on CD44s in c-Met⁺ hepatocellular carcinoma.

• DOI: 10.1186/s12885-015-1166-4
• 发表时间: 2015-03-21
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Dang H;Steinway SN;Ding W;Rountree CB
• 通讯作者: Rountree CB

The EGFR/ErbB3 Pathway Acts as a Compensatory Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma.

• DOI: 10.1371/journal.pone.0128159
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Steinway SN;Dang H;You H;Rountree CB;Ding W
• 通讯作者: Ding W