Stem Cells and Skin Cancer Prevention and Angiogenesis

 描述（由申请人提供）：表皮癌干细胞（ECS）是膳食癌症预防剂的重要潜在靶点。我们已经开发了体外和体内培养系统，允许从鳞状细胞癌增殖人ECS细胞。使用这个系统，我们表明，ECS细胞显示出显着增强的敏感性与饮食癌症预防剂，萝卜硫素（SFN）的治疗相比，非干细胞癌细胞。我们提出，肿瘤细胞的ECS细胞亚群被萝卜硫素选择性地靶向。我们进一步表明，表达的polycomb组（PcG）干细胞维持蛋白，Ezh2，是显着升高的ECS细胞群和SFN治疗抑制这种调节剂的水平。我们假设与非干细胞癌细胞相比，ECS细胞对SFN超敏感，并且SFN降低Ezh2蛋白水平和功能，从而改变下游靶基因表达以降低ECS细胞存活。我们进一步假设Ezh2控制肿瘤细胞产生血管生成因子，这些因子驱动肿瘤血管形成以允许肿瘤快速扩张，而SFN抑制了这一点。但是，我们对这项规定并没有很好的理解。首先，Ezh2作为增强干细胞对SFN敏感性的介体的作用是什么？Ezh2蛋白功能的抑制是否是癌症干细胞存活的SFN依赖性抑制所必需的？其次，我们不知道ECS细胞是否会在体内显示出类似的增强的SFN敏感性，因此重要的是， test.第三，我们不知道Ezh2和SFN影响肿瘤细胞产生血管生成剂以驱动内皮细胞依赖性肿瘤血管形成的机制。我们的目标是表征萝卜硫素抗干细胞作用机制，最终目标是开发萝卜硫素作为表皮干细胞导向的癌症预防剂。

 DESCRIPTION (provided by applicant): Epidermal cancer stem (ECS) cells are important potential targets of dietary cancer prevention agents. We have developed in vitro and in vivo cultivation systems that allow propagation of human ECS cells from squamous cell carcinoma. Using this system, we show that ECS cells display markedly enhanced sensitivity to treatment with dietary cancer prevention agent, sulforaphane (SFN), as compared to non-stem cancer cells. We propose that ECS cell subpopulation of tumor cells is selectively targeted by sulforaphane. We further show that expression of the polycomb group (PcG) stem cell maintenance protein, Ezh2, is markedly elevated in the ECS cell population and that SFN treatment suppresses the level of this regulator. We hypothesize that ECS cells are ultra-sensitive to SFN, compared to non-stem cancer cells, and that SFN reduces Ezh2 protein level and function thereby altering downstream target gene expression to reduce ECS cell survival. We further hypothesize that Ezh2 controls tumor cell production of angiogenic factors that drive tumor vascularization to permit rapid tumor expansion, and that SFN inhibits this. However, we do not have a good understanding of this regulation. First, what is the role of Ezh2 as a mediator of enhanced stem cell sensitivity to SFN and is suppression of Ezh2 protein function required for SFN-dependent suppression of cancer stem cell survival? Second, we do not know if ECS cells will display a similar enhanced SFN sensitivity in vivo and so it will be important to test. Third, we do not know the mechanism whereby Ezh2 and SFN influence tumor cell production of angiogenic agents to drive endothelial cell-dependent tumor vascularization. Our goal is to characterize the sulforaphane anti-stem cell mechanism of action with an ultimate goal of developing sulforaphane as an epidermal stem cell-directed cancer prevention agent.