Stem Cells and Skin Cancer Prevention and Angiogenesis

 描述(申请人提供)：表皮癌症干细胞(ECS)是饮食防癌药物的重要潜在靶点。我们已经开发了体外和体内培养系统，允许从鳞状细胞癌中繁殖人类ECS细胞。使用该系统，我们发现，与非干细胞癌细胞相比，ECS细胞对膳食防癌药物萝卜硫素(SFN)治疗的敏感性显著增强。我们认为萝卜硫素可以选择性地靶向肿瘤细胞的ECS细胞亚群。我们进一步表明，多梳组(PcG)干细胞维持蛋白Ezh2在ECS细胞群中的表达显著升高，SFN处理抑制了这一调节因子的水平。我们假设，与非干细胞癌细胞相比，内皮细胞对SFN超敏感，SFN降低Ezh2蛋白水平和功能，从而改变下游靶基因的表达，从而降低ECS细胞的存活率。我们进一步假设，Ezh2控制肿瘤细胞产生血管生成因子，而血管生成因子驱动肿瘤血管形成，从而允许肿瘤快速扩张，而SFN抑制这一过程。但是，我们对这一规定并没有很好的理解。首先，作为增强干细胞对SFN敏感性的媒介，Ezh2的作用是什么？抑制Ezh2蛋白的功能是否需要依赖SFN来抑制癌症干细胞的存活？其次，我们不知道ECS细胞在体内是否会表现出类似的SFN增强敏感性，因此重要的是 测试。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的肿瘤血管形成的机制。我们的目标是表征萝卜硫素的抗干细胞作用机制，最终目标是开发萝卜硫素作为一种表皮干细胞导向的癌症预防药物。

 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.