PATHOLOGY IN THE CONTROL OF DIFFERENTIATION IN CANCER

五年前，在这笔赠款开始时，我们提交了 假设缺陷的表达在综合控制中 对细胞分化和增殖的影响显著 在致癌过程中的作用。为了检验这一假设，我们首先提出了 研究如何建立对分化的综合控制 正常细胞中的增殖受到调节，以及什么事件 调解这些过程。接下来，我们进行了实验， 确定是否以及如何通过 化学和/或物理因素取代了综合防治 对细胞分化和增殖的影响。进步极快 在所有这些研究中都做了|我们确定 分化和增殖的综合控制被介导 在不同的细胞周期停滞状态下，特定的序列 生物事件必须作为此监管的一部分发生 机制，而且这一监管过程在两个方面都很明显 小鼠骨髓间充质干细胞和正常人表皮细胞 细胞。此外，我们在以下方面取得了重大进展 从沙门氏菌中鉴定和纯化生理调节分子 控制这些过程的人类血液。我们还建立了 引发癌症的物理和化学因素或 导致完全癌变可以导致稳定的缺陷 细胞分化和增殖的综合调控 间充质干细胞和初步结果表明 类似的情况也发生在正常的人类表皮细胞中。我们 因此，现在建议扩大这些研究的具体内容 目标是建立监管一体化的机制 细胞分化和增殖的调控及 致癌物质破坏这些关键基因的机制 监管流程。

Five years ago at the inception of this grant, we presented the hypothesis that the expression of defects in the integrated control of cellular differentiation and proliferation served a significant role in carcinogensis. To test this hypothesis we first initiated studies to establish how the integrated control of differentiation and proliferation is regulated in normal cells and what events mediate these processes. We next performed experiments to determine if and how the induction of carcinogenesis with chemical and/or physical agents abrogates the integrated control of cellular differentiation and proliferation. Excellent progress has been made in all these studies| We established that the integrated control of differentiation and proliferation is mediated at a distinct cell cycle arrest state, that a specific sequence of biological events must occur as part of this regulatory mechanism, and that this regulatory process is evident both in murine mesenchymal stem cells and in normal human epidermal cells. In addition, we have made significant progress in identifying and purifying physiological regulatory molecules from human blood that control these processes. We also established that physical and chemical agents that initiate carcinogenesis or cause complete carcinogenesis can induce stable defects in the integrated control of cellular differentiation and proliferation in mesenchymal stem cells and preliminary results suggest that comparable events occur in normal human epidermal cells. We therefore now propose to expand these studies with the specific goal to establish the mechanisms that regulate the integrated control of cellular differentiation and proliferation and the mechanisms by which carcinogenic agents disrupt these critical regulatory processes.