Oral Cancer Initiating Cells: Characterization

口腔癌起始细胞：表征

• 批准号: 8891405
• 负责人: LORRAINE J GUDAS
• 金额: $ 43.86万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891405
• 关键词: Area; Carcinogens; Cell Lineage; Cell Survival; Cell model; Cells; Chimeric Proteins; Chromatin; Clinical Treatment; Clinical Trials; Complex; Development; Doxycycline; Drug Targeting; Dysplasia; Epithelial; Epithelium; Faculty; Failure; Functional disorder; Funding; Galactosidase; Genes; Head and Neck Squamous Cell Carcinoma; Head and Neck Surgery; Health; Human; Hyperplasia; Internal Ribosome Entry Site; Knowledge; Laboratories; LacZ Genes; Learning; Lesion; Leukoplakia; Malignant Neoplasms; Mesenchymal; Modeling; Mus; Nitroquinolines; Oral Leukoplakia; Oral cavity; Otolaryngology; Oxides; Papilloma; Pathology; Patients; Pharmaceutical Preparations; Play; Polycomb; Positioning Attribute; Process; Proteins; Publishing; Quality of life; Radiation therapy; Radiosurgery; Recruitment Activity; Regimen; Regulation; Reporter; Research; Research Personnel; Role; Small Interfering RNA; Smoking; Squamous cell carcinoma; Stem cells; Stratum Basale; Study models; Survival Rate; Tamoxifen; Techniques; Testing; Tetanus Helper Peptide; Time; Tongue; Transgenic Mice; United States National Institutes of Health; Universities; cancer cell; cancer stem cell; carcinogenesis; chemotherapy; conventional therapy; drinking water; effective therapy; experience; expression vector; fluidity; malignant mouth neoplasm; medical schools; meetings; member; molecular marker; mouth squamous cell carcinoma; neoplastic; neoplastic cell; offspring; oral carcinogenesis; oral cavity epithelium; orofacial; promoter; self-renewal; success; targeted cancer therapy; theories; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): Despite intensive treatment that generally combines surgery, radiation, and chemotherapy, oral squamous cell carcinomas (OSCCs) have a long-term survival rate of only 15-50%. Thus, there is a great need for improvements in pharmacologic treatments/chemotherapeutics for OSCCs. One current theory is that conventional treatment fails because it does not adequately treat cancer-initiating cells (CICs), also called cancer stem cells (CSCs). Our laboratory developed the 4-NQO (4-nitroquinoline oxide) carcinogenesis model of oral cancer for mice, now the most widely used murine model for the study of the development of OSCC. When we provide 4-NQO, a carcinogen and a surrogate for the neoplastic lesions caused by smoking, in the drinking water, mice develop lesions in their oral cavities that mimic those in humans, including hyperplasia, dysplasia, leukoplakia, papilloma, and invasive squamous cell carcinomas (SCCs); moreover, the molecular markers of OSCC in this murine model are the same as many of those in human OSCCs. Here we propose to use a cell lineage-tracing approach in this 4-NQO oral carcinogenesis model to test the hypothesis that certain Polycomb proteins which are involved in chromatin regulation, specifically Bmi1, also play a major role in putative CICs in the oral cavity. Bmi1-expressing cells will be permanently marked at the time of tamoxifen addition by using transgenic mice that have a tamoxifen-regulated, creER(TAM) fusion protein gene driven by the Bmi1 promoter, and crossing them with Rosa26 "confetti" reporter transgenic mice. These mice will be followed during the carcinogenesis process to determine the Bmi1-expressing cell progeny and the expression of Bmi1+ marked cells in OSCCs that develop over time. We will also characterize the functions of Bmi1 in OSCC by over- expressing Bmi1, specifically in the oral cavity epithelium and in a regulated manner, through the use of a doxycycline-regulated expression vector in mice during oral cavity carcinogenesis. Completion of these aims will provide us with much new information about the Bmi1 gene, which is thought to be a key gene required for formation of CICs in human OSCCs. Moreover, the techniques used and further developed in this proposed research will provide us with useful, powerful tools with which to identify and study CICs in OSCC, including their ability to self-renew, their abilityto differentiate, and their phenotypic fluidity. This knowledge is essential to discover new therapies and to screen for drugs that target CICs in human OSCCs.

描述（由申请人提供）：尽管通常结合手术、放疗和化疗的强化治疗，口腔鳞状细胞癌 (OSCC) 的长期生存率仅为 15-50%。因此，非常需要改进 OSCC 的药物治疗/化疗。目前的一种理论认为，传统治疗失败是因为它不能充分治疗癌症起始细胞（CIC），也称为癌症干细胞（CSC）。我们实验室开发了4-NQO（4-硝基喹啉氧化物）小鼠口腔癌致癌模型，是目前研究口腔癌发生发展最广泛使用的小鼠模型。当我们在饮用水中提供 4-NQO（一种致癌物质，也是吸烟引起的肿瘤病变的替代品）时，小鼠的口腔会出现类似于人类的病变，包括增生、异型增生、白斑、乳头状瘤和侵袭性鳞状上皮瘤。细胞癌（SCC）；此外，该小鼠模型中 OSCC 的分子标记与人类 OSCC 中的许多分子标记相同。在这里，我们建议在 4-NQO 口腔癌发生模型中使用细胞谱系追踪方法来检验以下假设：某些参与染色质调节的 Polycomb 蛋白（特别是 Bmi1）也在口腔中假定的 CIC 中发挥重要作用。通过使用具有由 Bmi1 启动子驱动的他莫昔芬调节的 creER(TAM) 融合蛋白基因的转基因小鼠，并将其与 Rosa26“五彩纸屑”报告基因转基因小鼠杂交，在添加他莫昔芬时，Bmi1 表达细胞将被永久标记。在致癌过程中对这些小鼠进行跟踪，以确定表达 Bmi1 的细胞后代以及随时间发展的 OSCC 中 Bmi1+ 标记细胞的表达。我们还将通过在口腔癌发生过程中在小鼠体内使用多西环素调节的表达载体以调节的方式过度表达Bmi1（特别是在口腔上皮中）来表征Bmi1在OSCC中的功能。这些目标的完成将为我们提供有关 Bmi1 基因的许多新信息，该基因被认为是人类 OSCC 中 CIC 形成所需的关键基因。此外，本研究中使用和进一步开发的技术将为我们提供有用、强大的工具来识别和研究 OSCC 中的 CIC，包括它们的自我更新能力、分化能力和表型流动性。这些知识对于发现新疗法至关重要 并筛选针对人类 OSCC 中 CIC 的药物。