Design of Therapeutic Strategies Specific for Breast Cancer Initiating Cells

针对乳腺癌起始细胞的治疗策略的设计

基本信息

批准号：
8011483
负责人：
GERMANA RAPPA
金额：
$ 21.13万
依托单位：
NEVADA CANCER INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-10 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011483
关键词：
Biocompatible Materials Biological Biological Assay Breast Cancer Cell Breast Cancer Treatment Breast Carcinoma Cancer cell line Cell Line Cell model Cells Clone Cells Data Development Drug Delivery Systems Drug resistance Female Gene Expression Gene Expression Profile Gene Expression Profiling Gene Silencing Genes Glioblastoma Goals Growth Human In Vitro MCF7 cell Malignant Epithelial Cell Malignant Neoplasms Medical Melanoma Cell Microarray Analysis Molecular Mus Names Neoplasm Metastasis Outcome Outcome Study Pathway interactions Pattern Phenotype Population Property Proteins Public Health Reverse Transcriptase Polymerase Chain Reaction Specificity Specimen Stem cells Surface Therapeutic Time Treatment Protocols Tumorigenicity Validation angiogenesis base cancer cell cancer stem cell cancer therapy design gene function in vivo malignant breast neoplasm neoplastic cell research study self renewing cell small hairpin RNA therapeutic target therapy design tool treatment strategy tumor growth tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most common malignant tumor of females in the western hemisphere, with 178,500 new cases expected for 2007 in the U.S. alone. A growing body of evidence suggests that breast cancer growth is sustained by rare self-renewing cells, named breast cancer stem cells or breast cancer-initiating cells (BCIC), which are biologically distinct from their more numerous differentiated progeny. Although the design of therapies that eradicate BCIC has the potential to revolutionize the treatment of breast cancer, the identification of molecular therapeutic targets in BCIC isolated from human primary breast cancer specimens is an extremely difficult task. Several groups, including ours, have recently identified a sub-population of cancer-initiating cells (CIC) in several cell lines, including human breast carcinoma cell lines, opening the possibility to study BCIC in a readily available and abundant biological material. Specifically, we have found that mammary carcinoma, glioblastoma, melanoma cell lines and their single-cell clones contain cells capable of forming spheroids upon in vitro growth under stem cell-like conditions. Spheroid-forming cells displayed a gene expression profile consistent with CIC, increased tumorigenicity, and an altered pattern of chemosensitivity. We have also isolated by limiting dilution from the human breast carcinoma cell line MCF-7 the highly tumorigenic MCF-7/1-eGFP clone that expresses BCIC-associated surface markers. Based on these findings, we propose the long-term goal to design therapeutic strategies that preferentially target BCIC. The specific hypothesis is that we can design specific anti-BCIC therapeutic strategies directed against the products of genes over-expressed in human BCIC- enriched cell lines. First, we will develop BCIC models from human breast cancer cell lines. Then, we will identify genes over-expressed in BCIC by gene expression profiling. Finally, we will validate genes over-expressed in BCIC as breast cancer therapeutic targets. PUBLIC HEALTH REVELANCE: Breast cancer is the most common malignant tumor of females in the western hemisphere, with 178,500 new cases expected for 2007 in the U.S. alone. A growing body of evidence suggests that breast cancer growth is sustained by rare self-renewing cells, named breast cancer stem cells or breast cancer-initiating cells (BCIC), which are biologically distinct from their more numerous differentiated progeny. We propose to identify genes preferentially expressed in BCIC and to validate them as potential specific targets for breast cancer therapy.

描述（由申请人提供）：乳腺癌是西半球最常见的女性恶性肿瘤，仅在美国，预计2007年就预计有178,500例新病例。越来越多的证据表明，乳腺癌的生长是由罕见的自我更新细胞（称为乳腺癌干细胞或乳腺癌引起的细胞（BCIC））所维持的，这些细胞在生物学上与其众多分化后代不同。尽管根除BCIC的疗法的设计有可能彻底改变乳腺癌的治疗，但从人类原发性乳腺癌标本中分离出的BCIC中分子治疗靶标的鉴定是一项极其艰巨的任务。包括我们的几个组，包括我们的几个小组，在包括人类乳腺癌细胞系在内的几个细胞系中鉴定出癌症引发细胞（CIC）的亚群，开放了在易于可用且丰富的生物学材料中研究BCIC的可能性。具体而言，我们发现乳腺癌，胶质母细胞瘤，黑色素瘤细胞系及其单细胞克隆包含在干细胞样条件下体外生长时能够形成球体的细胞。球体形成的细胞显示出与CIC一致的基因表达谱，肿瘤性增加以及化学敏感性的改变。我们还通过限制了从人类乳腺癌细胞系MCF-7稀释的稀释度，即表达与BCIC相关的表面标记物的高度肿瘤MCF-7/1-EGFP克隆。根据这些发现，我们提出了设计优先针对BCIC的治疗策略的长期目标。具体的假设是，我们可以设计针对人类BCIC富集细胞系中过表达的基因产物的特定抗BCIC治疗策略。首先，我们将开发来自人类乳腺癌细胞系的BCIC模型。然后，我们将通过基因表达分析确定在BCIC中过表达的基因。最后，我们将验证BCIC中过表达的基因作为乳腺癌治疗靶标。公共卫生的启示：乳腺癌是西半球最常见的女性恶性肿瘤，仅在美国就预计2007年预计有178,500例新病例。越来越多的证据表明，乳腺癌的生长是由罕见的自我更新细胞（称为乳腺癌干细胞或乳腺癌引起的细胞（BCIC））所维持的，这些细胞在生物学上与其众多分化后代不同。我们建议鉴定在BCIC中优先表达的基因，并将其验证为乳腺癌治疗的潜在特定靶标。