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）：尽管经过强化治疗通常结合了手术，放射和化学疗法，但口服鳞状细胞癌（OSCC）的长期存活率仅为15-50％。因此，非常需要改善OSCC的药理学治疗/化学治疗药。当前的一种理论是，常规治疗失败，因为它不能充分处理癌症引发细胞（CICS），也称为癌症干细胞（CSC）。我们的实验室开发了小鼠口腔癌的4-NQO（4-硝酸氧化物）癌变模型，这是目前最广泛使用的鼠模型，用于研究OSCC的发展。当我们提供4-NQO，一种致癌物和替代物来为吸烟引起的肿瘤病变，在饮用水中，小鼠在其口腔中出现病变，这些病变模仿了人类的人，包括增生，发育不良，白细胞瘤，毛细血管瘤，毛细血管瘤和入侵性的粪便型细胞carcinomas（SCCS）（SCCS）；此外，在此鼠模型中，OSCC的分子标记与人类OSCC中的许多相同。在这里，我们建议在这个4-NQO口服癌变模型中使用细胞谱系追踪方法来检验以下假设：某些参与染色质蛋白调节的多肉蛋白，特别是BMI1，在口腔腔中的推定CICS中也起着重要作用。通过使用由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，将表达BMI1的细胞将在他莫昔芬添加时永久标记，并用Rosa26“ Confetti” Confetti“ conteti” cofteti“ conterti” conterter“ proseter” conterter tranger trangenic小鼠。这些小鼠将在癌变过程中遵循，以确定表达BMI1的细胞后代和随着时间的流逝而发展的OSCC中BMI1+标记细胞的表达。我们还将通过过度表达BMI1，特别是在口腔上皮和调节方式中，通过在口腔癌癌中使用强力霉素调节的表达载体来表征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，这被认为是人类OSCC中CICS形成所需的关键基因。此外，在这项拟议的研究中使用和进一步开发的技术将为我们提供有用的强大工具，可以使用这些工具来识别和研究OSCC中的CIC，包括它们自我更新的能力，分化的能力以及表型流动性。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。