Stem Cells and Skin Cancer Prevention and Angiogenesis

干细胞和皮肤癌的预防和血管生成

• 批准号: 9248258
• 负责人: Richard L. Eckert
• 金额: $ 37.4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-03 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248258
• 关键词: Address; Alpha Cell; Angiogenic Factor; Attenuated; Blood Vessels; Broccoli - dietary; Cancer Etiology; Cell Maintenance; Cell Survival; Cells; Development; Diet; Endothelial Cells; Engineering; Excision; Frequencies; Gene Expression; Gene Targeting; Goals; Growth; Growth Factor; Human; In Vitro; Injectable; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Monitor; Mus; Operative Surgical Procedures; Polycomb; Population; Prevention; Preventive; Production; Property; Proteins; Recurrence; Regulation; Role; Skin Cancer; Squamous cell carcinoma; Stem cells; Sulforaphane; System; Testing; Tumor Expansion; Tumor Stem Cells; Vascular Endothelial Cell; Vascularization; angiogenesis; cancer prevention; cancer stem cell; in vivo; interest; knock-down; neoplastic cell; protein biomarkers; protein expression; protein function; public health relevance; response; self-renewal; skin cancer prevention; stem; tumor

 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.

 描述（由申请人提供）：表皮癌干（ECS）细胞是饮食癌症预防剂的重要潜在靶标。我们开发了体外和体内培养系统，可以从鳞状细胞癌中增殖人类 ECS 细胞。使用该系统，我们发现与非干癌细胞相比，ECS 细胞对膳食癌症预防剂萝卜硫素 (SFN) 治疗的敏感性显着增强。我们提出萝卜硫素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 的表达在 ECS 细胞群中显着升高，并且 SFN 治疗可抑制该调节因子的水平。我们假设，与非干癌细胞相比，ECS 细胞对 SFN 超级敏感，并且 SFN 降低 Ezh2 蛋白水平和功能，从而改变下游靶基因表达，从而降低 ECS 细胞存活率。我们进一步假设 Ezh2 控制肿瘤细胞产生血管生成因子，从而驱动肿瘤血管化，从而允许肿瘤快速扩张，而 SFN 会抑制这一过程。然而，我们对这一规定并没有很好的理解。首先，Ezh2 作为增强干细胞对 SFN 敏感性的介质的作用是什么？抑制 Ezh2 蛋白功能是否是 SFN 依赖性抑制癌症干细胞存活所必需的？其次，我们不知道 ECS 细胞是否会在体内表现出类似的增强的 SFN 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​​动内皮细胞依赖性肿瘤血管化的机制。我们的目标是表征萝卜硫素抗干细胞作用机制，最终目标是将萝卜硫素开发为表皮干细胞导向的癌症预防剂。