Regulation of cancer stem cell quiescence: Implications to tumor recurrence and t

描述（由申请方提供）：细胞毒性药物治疗后的临床复发对大量癌症患者来说是一个危及生命的问题。据推测，这种形式的治疗抗性是由一小群生长停滞的癌症干细胞介导的，这些干细胞在治疗中存活并引发复发。虽然有趣，但由于技术限制，该假设尚未得到验证，无法直接检测完整肿瘤内的这些生长停滞癌细胞。我们已经克服了这个问题，开发了一个双荧光报告系统，永久标记所有癌细胞的红色荧光蛋白的表达，而它区分慢循环从快速增殖的癌细胞，通过他们的保留强力霉素抑制组蛋白2B绿色荧光融合蛋白（H2 BGFP）在脉冲追踪实验。使用鳞状细胞癌作为分级组织肿瘤的范例，我们能够检测具有肿瘤启动潜力的快速循环和生长停滞的癌细胞。此应用程序旨在测试 假设：（1.）鳞状细胞癌含有通过响应性适应机制在快循环状态和慢循环状态之间相互转化的癌症干细胞;（2.）快和慢循环癌症干细胞由控制其增殖行为的特征性分子标记定义;和（3.）慢循环癌症干细胞对细胞毒性药物是惰性的，并且能够在治疗后引发复发。我们的研究结果有望得到积极的发展。 影响癌症患者的疗法和治疗的设计，因为鉴定静止的癌症干细胞和控制其行为的机制是鉴定预测哪些癌症将抵抗细胞毒性疗法的预后标志物的第一步，它还将促进特异性刺激静止的癌症干细胞增殖以增加其对细胞毒性疗法的脆弱性的新型组合疗法的开发。药物，而不影响正常的，成体干细胞的静止。

DESCRIPTION (provided by applicant): Clinical recurrence after therapy with cytotoxic agents presents a life threatening problem for a large number of cancer patients. It has been hypothesized that this form of therapy resistance is mediated by a small population of growth arrested cancer stem cells that survive treatment and initiate recurrence. Although intriguing, this hypothesis remains untested due to technical limitations that preclude direct detection of these growth arrested cancer cells within intact tumors. We have overcome this problem with the development of a dual fluorescent reporter system that permanently marks all cancer cells with the expression of a red fluorescent protein, while it distinguishes slow-cycling from rapidly proliferating cancer cells by their retention of a doxycycline repressible Histone 2B green fluorescent fusion protein (H2BGFP) in pulse-chase experiments. Using squamous cell carcinoma as a paradigm for hierarchically organized tumors, we are able to detect fast cycling and growth arrested cancer cells with tumor initiating potential. This application aims to test the hypothesis that: (1.) squamous cell carcinomas contain cancer stem cells that interconvert between fast and slow cycling states by responsive adaptation mechanisms; (2.) fast and slow cycling cancer stem cells are defined by characteristic molecular signatures that govern their proliferative behavior; and (3.) slow cycling cancer stem cells are inert to cytotoxic drugs and able to initiate recurrence after treatment. The results of our research are expected to positively impact the design of therapies and treatment of cancer patients as the identification of quiescent cancer stem cells and the mechanisms that govern their behavior presents a first step towards the identification of prognostic markers that predict which cancers will resist cytotoxic therapies It will also promote the development of novel combination therapies that specifically stimulate proliferation of quiescent cancer stem cells to increase their vulnerability to cytotoxic drugs, without affecting quiescence of normal, adult stem cells.