Molecular and Functional Characterization of Colon Tumor Cancer Stem Cells and St

结肠肿瘤干细胞和 St 的分子和功能表征

• 批准号: 7915640
• 负责人: MICHAEL CLARKE
• 金额: $ 92.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915640
• 关键词: Molecular; Functional; Characterization; Colon; Tumor

Cancer trails only cardiovascular disease as the leading cause of mortality in the US. Cancers of the lung, colon, breast and prostate, all derived from epithelium, account for the majority of cancer-related deaths. Recently, our group has made two important discoveries about the various populations of normal and cancer cells in tumors. First, we find that in tumors arising in the breast, colon and head and neck only a subset of the cancer cells, called cancer stem cells, drive the growth and spread of the tumor and are ultimately responsible for patient morbidity and mortality. Next, compared to normal tissue fibroblasts, tumor stroma fibroblasts are "activated" and make high levels of growth factors implicated in carcinogenesis. The goal of this proposal which is to understand the mechanisms by which colon cancer stem cells interact with the tumor stroma, addresses the central theme of this RFA. As envisioned by the RFA, the investigators are a highly collaborative, multi-disciplinary group drawn from several departments and schools of Stanford University including members from the Departments of Bioengineering, Biochemistry, Statistics, Health Research Policy, Surgery, Medicine and the Stanford Institute of Stem Cell Biology. The team is developing novel, cutting edge technology to understand at the molecular and cellular level how the cancer stem cells interact with the tumor stroma. The grant consists of 2 highly interactive projects as well as an administrative core and a bioinformatics core. Project 1 will obtain gene expression profiles from tumor components including cancer stem cells and normal stromal cells. The gene expression data will be used to identify stromal factors that drive cancer stem cell growth in novel high throughput assays. Project 2 has two parts. We will use microfluidic devices to do single cell gene expression arrays to determine whether there is cellular heterogeneity of the markers described in Project 1 to enrich cancer stem cells. If so, each cell population will be analyzed in Project 1 to determine whether we can further enrich cancer stem cells. The second part will use microfluidic devices to identify stromal cell factors that drive proliferation of colon cancer stem cells. Any factors identified in Project 2 that drive proliferation of the cancer stem cells will be tested in Project 1 to see if the factors cause expansion of cancer stem cells or if they drive them to differentiate into cancer cells that no longer can form a tumor.

在美国，癌症仅次于心血管疾病，成为导致死亡的首要原因。肺癌、结肠癌、乳腺癌和前列腺癌都源于上皮细胞，占与癌症相关的死亡人数的大部分。最近，我们的团队对肿瘤中正常细胞和癌细胞的不同群体有了两个重要的发现。首先，我们发现，在乳房、结肠和头颈部发生的肿瘤中，只有一种称为癌症干细胞的癌细胞子集驱动肿瘤的生长和扩散，并最终导致患者的发病率和死亡率。其次，与正常组织成纤维细胞相比，肿瘤间质成纤维细胞被“激活”，并产生与致癌有关的高水平生长因子。这项建议的目标是了解结肠癌干细胞与肿瘤间质相互作用的机制，解决了这一RFA的中心主题。按照RFA的设想，调查人员是一个高度合作的多学科小组，来自斯坦福大学的几个系和学院，包括来自生物工程、生物化学、统计学、卫生研究政策、外科、医学和斯坦福干细胞生物学研究所的成员。这个团队正在开发 新的尖端技术，在分子和细胞水平上了解癌症干细胞如何与肿瘤间质相互作用。这笔赠款包括两个高度互动的项目以及一个行政核心和一个生物信息学核心。项目1将获得肿瘤成分的基因表达谱，包括癌症干细胞和正常基质细胞。基因表达数据将用于在新的高通量分析中识别推动癌症干细胞生长的基质因子。项目2由两部分组成。我们将使用微流控设备进行单细胞基因表达阵列，以确定项目1中描述的标记是否存在细胞异质性，以丰富癌症干细胞。如果是这样的话，将在项目1中分析每个细胞群，以确定我们是否可以进一步丰富癌症干细胞。第二部分将使用微流控设备来识别驱动结肠癌干细胞增殖的基质细胞因子。项目2中确定的任何推动癌症干细胞增殖的因素都将在项目1中进行测试，以确定这些因素是否会导致癌症干细胞的扩张，或者是否会促使它们分化为不再形成肿瘤的癌细胞。

项目成果

Single-cell dissection of transcriptional heterogeneity in human colon tumors.

• DOI: 10.1038/nbt.2038
• 发表时间: 2011-11-13
• 期刊: Nature biotechnology
• 影响因子: 46.9

Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting.

通过细胞分选从人鼠乳腺肿瘤异种移植物中去除乳酸脱氢酶升高病毒。

• DOI: 10.1016/j.jviromet.2011.02.015
• 发表时间: 2011
• 期刊: Journal of virological methods
• 影响因子: 3.1
• 作者: Liu,Huiping;Bockhorn,Jessica;Dalton,Rachel;Chang,Ya-Fang;Qian,Dalong;Zitzow,LoisA;Clarke,MichaelF;Greene,GeoffreyL
• 通讯作者: Greene,GeoffreyL

Therapeutic implications of the cancer stem cell hypothesis.

• DOI: 10.1016/j.semradonc.2008.11.002
• 发表时间: 2009-04
• 期刊: SEMINARS IN RADIATION ONCOLOGY
• 影响因子: 3.5
• 作者: Diehn, Maximilian;Cho, Robert W.;Clarke, Michael F.
• 通讯作者: Clarke, Michael F.