INVOLVEMENT OF STEM-LIKE CELLS IN MODELS OF SPONTANEOUS TRANSFORMATION

类干细胞参与自发转化模型

• 批准号: 8359717
• 负责人: DAVID MILLS
• 金额: $ 6.08万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359717
• 关键词: Agar; Aging-Related Process; Anchorage-Independent Growth; Aneuploidy; Bile Duct Epithelium; Biological Assay; Cell Adhesion; Cell physiology; Cells; Centers of Research Excellence; Characteristics; Data; Epithelial Cells; Exhibits; Funding; Gene Mutation; Goals; Grant; Growth; Growth Factor; Human; Laboratories; Liver; Malignant neoplasm of liver; MicroRNAs; Modeling; Morphology; NCI Center for Cancer Research; National Center for Research Resources; Normal Cell; Population Heterogeneity; Principal Investigator; Property; Proteins; Rattus; Research; Research Infrastructure; Resources; Rodent; Role; Solid Neoplasm; Source; Stem cells; Transplantation; Tumor Stem Cells; Tumorigenicity; Tyrosine; United States National Institutes of Health; base; cancer stem cell; cholangiocyte; cost; daughter cell; neoplastic; research and development; self-renewal; stem; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite extensive study of human and rodent liver cancer, liver cancer stem cells remain difficult to identify. Increasingly, evidence supports a model where tumor stem cells arise from normal stem cells during the aging process through genetic mutations that contribute to dysregulation of normal cell processes. The resulting cancer stem cell in turn acquires a unique set of characteristics including the ability to self-renew and give rise to heterogeneous populations of daughter cells, properties needed for tumor survival and propagation. In previous studies, we have shown that with continued passage (p), rat bile duct epithelial cells (BDEC) accumulated neoplastic characteristics, some or all of which were required for the induction of anchorage independent growth and tumorigenicity by activated ErbB-2/Neu. Briefly, by mid-passage (p31-84), BDEC showed alterations in morphology, onset of aneuploidy, increased growth rate with growth factor independence, decreased cell adhesion and loss of cholangiocyte markers expressed at low passage (p85), an increasing number of BDEC expressed activated, tyrosine phosphorylated ErbB-2/Neu and exhibited anchorage independent growth on soft agar. Based on data generated in our laboratory using the BDEC and PEC models, we hypothesize that the soft agar invasion assay selects for a subpopulation of chemoresistant cells with high self-renewal, a characteristic that enables these cells to sustain and expand solid tumor progression. To accomplish this goal we will examine these cells for chemoresistance, tumorigenicity, and the ability to differentiate along an endodermal lineage when transplanted into rat liver. We will also investigate the role of soft agar invasive-derived microvesicle shedding, as horizontal transfer of microvesicle cargo (e.g., proteins, microRNA) to neighboring cells may impart a selective survival advantage to the originating tumor.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 尽管对人类和啮齿动物肝癌进行了广泛的研究，但肝癌干细胞仍然难以识别。越来越多的证据支持这样一种模型：肿瘤干细胞是在衰老过程中通过导致正常细胞过程失调的基因突变从正常干细胞产生的。由此产生的癌症干细胞反过来获得了一组独特的特征，包括自我更新和产生异质子细胞群的能力、肿瘤存活和增殖所需的特性。在之前的研究中，我们已经表明，随着继续传代（p），大鼠胆管上皮细胞（BDEC）积累了肿瘤特征，其中部分或全部是激活的 ErbB-2/Neu 诱导贴壁不依赖生长和致瘤性所必需的。 。简而言之，到传代中期（p31-84），BDEC 显示出形态学的改变、非整倍性的开始、生长因子独立性增加的生长速率、细胞粘附减少和低传代（p85）表达的胆管细胞标记物的丢失、数量增加。 BDEC 表达活化的酪氨酸磷酸化 ErbB-2/Neu，并在软琼脂上表现出贴壁独立生长。 根据我们实验室使用 BDEC 和 PEC 模型生成的数据，我们假设软琼脂侵袭试验选择了具有高度自我更新能力的化疗耐药细胞亚群，这一特征使这些细胞能够维持和扩大实体瘤进展。为了实现这一目标，我们将检查这些细胞的化疗耐药性、致瘤性以及移植到大鼠肝脏中时沿内胚层谱系分化的能力。我们还将研究软琼脂侵入衍生的微泡脱落的作用，因为微泡货物（例如蛋白质、微小RNA）水平转移到邻近细胞可能会给原始肿瘤带来选择性生存优势。