Molecular Programs for Stem Cells of Hematological Malignancies

描述(申请人提供)：有人提出，人类癌症含有负责启动和维持肿瘤生长的癌症干细胞(CSC)，而且这些细胞对治疗具有抵抗力。然而，CSC的概念最近一直受到围攻。一些人认为这个概念是使用异种模型的产物，因为随着越来越多的免疫缺陷宿主的使用，启动癌症的细胞的频率似乎急剧增加。也许CSC概念的一个更根本的挑战是CSC的分子程序不一定与大多数癌细胞不同。例如Wnt、Hedgehog和Bmi-1，它们是已知的CSC自我更新的调节者，通常也参与细胞增殖的调节。为了克服这些警告，我们一直在使用自发性小鼠淋巴瘤模型来确定CSC功能的分子程序。在CSC的自我更新和维持这两个开创性的功能中，我们最近的研究建立了CSC维持的分子程序设计，该研究已被《细胞干细胞》杂志接受发表。在这些进展的基础上，我们建议确定驱动CSC自我更新的编程，并进一步确定我们是否可以使用这些自我更新和维护程序将癌细胞重新编程回CSC。 与公共卫生相关：有人提出，人类癌症含有负责启动和维持肿瘤生长的癌症干细胞(CSC)，而且这些干细胞对治疗具有抵抗力。CSC概念的一个更根本的挑战是，CSC的分子程序不一定与大多数癌细胞不同。为了克服这些警告，我们一直在使用自发性小鼠淋巴瘤模型来确定CSC功能的分子程序。在CSC的自我更新和维持这两个开创性的功能中，我们最近的研究建立了CSC维持的分子程序设计，该研究已被《细胞干细胞》杂志接受发表。在这些进展的基础上，我们建议确定驱动CSC自我更新的编程，并进一步确定我们是否可以使用这些自我更新和维护程序将癌细胞重新编程回CSC。

DESCRIPTION (provided by applicant): It has been proposed that human cancers contain cancer stem cells (CSC) that are responsible for initiating and maintaining tumor growth and also, these are resistant to therapy. However, the concept of CSC has been under siege recently. Some have argued that the concept is an artifact of using xenogeneic models, as the frequency of cancer-initiating cells appears to increase dramatically with the use of increasingly immune-deficient hosts. Perhaps a more fundamental challenge of the CSC concept is that the molecular program of CSC is not necessarily distinct from the bulk of cancer cells. For instance Wnt, Hedgehog and Bmi- 1, which are known regulators for self-renewal of CSC, are also involved in regulation of cell proliferation in general. To overcome these caveats, we have been using a spontaneous mouse lymphoma model to determine the molecular program underlying CSC functions. Of the two seminal functions of CSC, namely, self-renewal and maintenance of CSC, our recent study, which was accepted for publication in Cell Stem Cell, has established the molecular programming underlying CSC maintenance. Building on these advances, we propose to identify the programming driving CSC self-renewal and further, determine if we can use these self- renewal and maintenance programs to reprogram cancer cells back into CSC. PUBLIC HEALTH RELEVANCE: It has been proposed that human cancers contain cancer stem cells (CSC) that are responsible for initiating and maintaining tumor growth and also, these are resistant to therapy. A more fundamental challenge of the CSC concept is that the molecular program of CSC is not necessarily distinct from the bulk of cancer cells. To overcome these caveats, we have been using a spontaneous mouse lymphoma model to determine the molecular program underlying CSC functions. Of the two seminal functions of CSC, namely, self-renewal and maintenance of CSC, our recent study, which was accepted for publication in Cell Stem Cell, has established the molecular programming underlying CSC maintenance. Building on these advances, we propose to identify the programming driving CSC self-renewal and further, determine if we can use these self- renewal and maintenance programs to reprogram cancer cells back into CSC.