Catalytic Subunit of the Telomerase Gene Hest2

描述（由申请人提供）：这里提出的研究源于当前癌症研究的两个领域的意外融合。一个领域描述了这样一个事实，即癌细胞利用某些通常在正常胚胎发育和功能中起作用的细胞生物学程序，将上皮细胞转化为具有更多间充质（类似结缔组织）外观和行为的细胞。这种转化通常被称为上皮-间质转化（epithelial-mesenchymal transition， EMT），当被癌细胞利用时，可以赋予这些细胞关键的能力，如侵袭性和运动性，这两者都是癌细胞转移所必需的。第二个研究领域已经解决了存在于肿瘤内大量非自我更新癌细胞中的少数自我更新癌细胞。少数细胞，通常被称为癌症干细胞（CSCs），能够形成新的肿瘤，而在肿瘤内形成大多数细胞的癌细胞缺乏这种能力。这些CSCs反映了正常组织中干细胞的行为，这些干细胞也构成了这些组织中总细胞群的一小部分，并且由于它们的自我更新能力，也负责这些正常组织的再生能力。最近的研究表明，当正常乳腺上皮细胞（MECs）被诱导进行EMT时，它们获得了正常上皮干细胞的自我更新能力。类似地，当肿瘤细胞被迫经历EMT时，它们获得了更大的肿瘤启动能力，因此很可能是csc。这些最近发现的后果将在拟议的研究中加以探讨。例如，有理由相信EMT足以将癌细胞从原发肿瘤转移到远处转移部位。其中一些研究将检验在经历了EMT后所产生的播散性细胞，现在是否获得了形成宏观转移的能力。这项研究还将揭示干细胞是否优先从正常细胞中产生，或者它们是否可以同样有效地从正常非干细胞中形成。此外，基因改造的小鼠将被构建，如果它们激活了几个已知的编程EMT的转录因子之一，其细胞就会发出荧光。这些小鼠的细胞将使筛选诱导上皮细胞经历EMT和诱导非干细胞成为干细胞的细胞间信号成为可能。

DESCRIPTION (provided by applicant): The research proposed here derives from an unexpected convergence of two areas of current cancer research. One area describes the fact that carcinoma cells exploit certain cell-biological programs that are usually operative in normal embryonic development and function to convert epithelial cells to cells that have a more mesenchymal (connective tissue-like) appearance and behavior. This conversion is often termed an epithelial-mesenchymal transition (EMT) and, when appropriated by carcinoma cells, serves to impart to these cells critical powers, such as invasiveness and motility, both of which are essential for cancer cell metastasis. A second research area has addressed the existence of small minorities of self-renewing cancer cells that exist amid far larger numbers of non-self-renewing cancer cells within tumors. The minority cells, often termed cancer stem cells (CSCs), are capable of seeding new tumors, while the cancer cells forming the majority of cells within a tumor lack this ability. These CSCs mirror the behavior of the stem cells in normal tissues, which also constitute small minorities of the total cell populations in such tissues and, because of their self-renewing abilities, are also responsible for the regenerative abilities of these normal tissues. Recent research has revealed that when normal mammary epithelial cells (MECs) are induced to undergo an EMT, they acquire the self-renewing powers of normal epithelial stem cells. Analogously, when tumor cells are forced to undergo an EMT, they acquire far greater tumor-initiating ability and thus are likely to be CSCs. The ramifications of these recent findings will be explored in the proposed research. For example, there is reason to believe that an EMT suffices to convey carcinoma cells from a primary tumor to a site of distant metastasis. Some of this research will examine whether the resulting disseminated cells, having experienced an EMT, now gain the ability to form macroscopic metastases. This research will also reveal whether CSCs arise preferentially from normal cells, or whether they can be formed equally efficiently from normal non-stem cells. In addition, genetically altered mice will be constructed whose cells fluoresce in the event that they activate one of the several transcription factors that are known to program the EMT. The cells of these mice will make it possible to screen for the cell-to-cell signals that induce epithelial cells to undergo the EMT and induce non-stem cells to become stem cells.