Stem-like Cancer Cells in Breast Tumorigenesis

乳腺肿瘤发生中的干细胞样癌细胞

• 批准号: 7047943
• 负责人: ROBERT Y TSAI
• 金额: $ 25.25万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047943
• 关键词: breast neoplasms; drug resistance; flow cytometry; gene expression; genetically modified animals; laboratory mouse; metastasis; neoplasm /cancer genetics; neoplastic cell; neoplastic growth; stem cells

DESCRIPTION (provided by applicant): The long-range goal of my research is to uncover the nature of the cancer stem cells, and to design therapeutic approaches that can specifically target these cells for the treatment of breast cancers. The objective of this application is to establish the expression pattern of NS and Ngp1 in breast cancer cells, determine the growth phenotype and gene expression profile of NS- and Ngp1-expressing cells, and provide experimental evidence that demonstrates the role of NS+ cells in breast tumorigenesis. The central hypothesis is that NS and Ngp1 are preferentially expressed by the stem-like cells in breast tumors, and that these cells are responsible for the rapid growth, drug resistance, and high metastasis of malignant breast cancers. The rationale is that cancer stem cells, which are responsible for the high growth rate and drug resistance of malignant breast cancers, share common molecules such as NS and Ngp1 with somatic stem cells to drive the self-renewing machinery. Therefore, eliminating NS-expressing breast cancer cells will inhibit tumor initiation and progression. To accomplish the overall objective of this proposal, three specific aims will be pursued. The first aim is to establish the expression pattern of NS and Ngp1 in normal breast tissues and breast cancer cells. The second aim is to determine the cellular and molecular properties of those NS- and Ngp1-expressing cells by genetically marking these cells with living color proteins and purifying them by flow cytometry. The third aim is to determine the role of NS+ cells in the development, progression, and recurrence of breast tumors by evaluating the consequences of their elimination. An inducible cell ablation system will be employed to target the NS+ cells in transgenic animals. These results will provide the much-needed justification for the use of stem cell-targeting therapy in cancer treatment, and valuable information for developing new pharmacological and genetic therapies that can specifically target these cancer stem cells in order to cure advanced breast carcinomas.

描述（由申请人提供）：我的研究的长期目标是揭示癌症干细胞的本质，并设计可以专门针对这些细胞来治疗乳腺癌的治疗方法。 本申请的目的是建立乳腺癌细胞中 NS 和 Ngp1 的表达模式，确定 NS 和 Ngp1 表达细胞的生长表型和基因表达谱，并提供实验证据来证明 NS+ 细胞在乳腺癌中的作用肿瘤发生。 中心假设是NS和Ngp1优先由乳腺肿瘤中的干细胞样细胞表达，并且这些细胞是恶性乳腺癌的快速生长、耐药性和高转移的原因。 其基本原理是，负责恶性乳腺癌高生长率和耐药性的癌症干细胞与体干细胞共享 NS 和 Ngp1 等共同分子来驱动自我更新机制。 因此，消除表达 NS 的乳腺癌细胞将抑制肿瘤的发生和进展。 为了实现本提案的总体目标，将实现三个具体目标。 第一个目标是建立 NS 和 Ngp1 在正常乳腺组织和乳腺癌细胞中的表达模式。 第二个目标是通过用活颜色蛋白对这些细胞进行基因标记并通过流式细胞术纯化它们来确定这些表达 NS 和 Ngp1 的细胞的细胞和分子特性。 第三个目标是通过评估消除 NS+ 细胞的后果来确定 NS+ 细胞在乳腺肿瘤发生、进展和复发中的作用。 将采用诱导型细胞消融系统来靶向转基因动物中的 NS+ 细胞。 这些结果将为在癌症治疗中使用干细胞靶向疗法提供急需的理由，并为开发可特异性靶向这些癌症干细胞以治愈晚期乳腺癌的新药理学和基因疗法提供宝贵的信息。