Isolation and characterization of the normal and cancer stem cells of the tongue.

描述(申请人提供)：口腔上皮癌是一种常见的恶性肿瘤，每年在美国新增加4万名患者。由于远处转移的发展和出现耐药的局部和区域复发，这种疾病的死亡率仍然很高。头颈部鳞状细胞癌(HNSCC)的诊断年龄中位数在传统上和历史上都被设定为60岁。然而，在40岁的年轻人中，起源于口腔和口咽部的肿瘤的发病率一直在稳步和迅速地上升。此外，舌癌似乎是发病率增加的主要原因，现在已成为口腔第二常见的恶性肿瘤。最近的研究表明，肿瘤的形成可能是癌症干细胞发展的结果。根据这一假设，肿瘤中有一小部分肿瘤干细胞(CSC)，这些干细胞负责肿瘤治疗失败后的重新生长和转移的建立。消除癌症的成功治疗需要考虑到CSC亚群的不寻常特性。发展这样一种治疗策略的一个主要问题是，仍然缺乏能够容易地区分CSCs与其分化后代以及与正常组织对应的方法。从人类肿瘤中提纯肿瘤干细胞受到患者异质性和新鲜且相当大的肿瘤样本可用性的限制。此外，目前的标志物丰富，但不允许完全纯化的人类干细胞。基于我们的初步观察，我们提出了一种利用小鼠模型获取和鉴定口腔上皮细胞、正常细胞和肿瘤干细胞的替代方法。本研究获得的正常舌上皮干细胞与肿瘤干细胞的基因表达谱可用于鉴定CSC群体中丰富的细胞表面或分泌蛋白，这可能用于指导人类癌症的鉴定、进一步纯化和血液检测。实验分离的CSC也可以用于药物筛选，以识别专门针对癌症干细胞的化合物。此外，癌症研究的一个关键目标是确定癌症干细胞产生和自我更新的机制。定义了CSC的小鼠模型提供了解剖这些过程的时间和功能动力学的可能性。 公共卫生相关性：口腔上皮癌是一种常见的恶性肿瘤，死亡率仍然很高。最近的研究表明，肿瘤中有一小部分癌症干细胞(CSC)，这些干细胞负责肿瘤在治疗失败后重新生长。为了改进目前的治疗，我们需要考虑到CSC亚群的不同寻常的特性。我们的总体目标是分离和鉴定正常和癌症舌上皮干细胞，并鉴定舌上皮癌干细胞与其分化后代和正常干细胞的不同之处。这可能允许选择性地靶向和消除CSC，从而改善治疗结果。

DESCRIPTION (provided by applicant): Oral epithelium cancer is a common malignancy that affects 40,000 new patients in the United States each year. Mortality from this disease remains high because of the development of distant metastases and the emergence of therapy-resistant local and regional recurrences. The median age at diagnosis for head and neck squamous cell carcinoma (HNSCC) has classically and historically been set at 60 years. The incidence of a subset of neoplasms originating from the oral cavity and the oropharynx, however, in young adults, age <40, has been steadily and rapidly increasing. Furthermore, carcinoma of the tongue appears to account for the majority of this increase in incidence and has now become the second most common malignancy in the oral cavity. Recent research suggests that tumor formation may result from the development of cancer stem cells. According to this hypothesis tumors harbor a small population of cancer stem cells (CSC) that are responsible for re-growth of a tumor following unsuccessful treatment and for the establishment of metastases. The successful treatment to eliminate cancer need to take into account the unusual properties of the CSC subpopulation. A major problem to the development of such a treatment strategy is that methods are still lacking that can readily distinguish CSCs from their differentiating progeny and from their normal tissue counterparts. Purification of cancer stem cells from human tumors is limited by patient heterogeneity and availability of fresh and sizable tumor samples. Moreover, current markers enrich for but do not allow complete purification of human CSCs. Based on our preliminary observations we propose an alternative route to obtain and characterize oral epithelia normal and cancer stem cells using mouse model. Obtained in our study gene expression profiles of normal tongue epithelium stem cells versus cancer stem cells could be used to identify cell surface or secreted proteins enriched in CSC population, which may be used to guide the identification, further purification, and blood-based detection of human cancer. Experimentally isolated CSC may also be used for drug screening to identify compounds that specifically target cancer stem cells. Further, a key goal in cancer research is to identify the mechanism by which cancer stem cells arise and self- renew. Mouse models with defined CSC offer the possibility of dissecting the temporal and functional dynamics of these processes. PUBLIC HEALTH RELEVANCE: Oral epithelium cancer is a common malignancy with still high mortality rate. Recent studies suggest that tumors harbor a small population of cancer stem cells (CSC) that are responsible for re-growth of a tumor following unsuccessful treatment. To improve the current treatment we need to take into account the unusual properties of the CSC subpopulation. Our overall goal is to isolate and characterize normal and cancer tongue epithelium stem cells and characterize how the tongue epithelium cancer stem cells differ from their differentiating progeny and from normal stem cells. This might allow to target selectively and eliminate CSC, thus improving therapeutic outcome.