Trosko James E, Chang Chia-Cheng, Upham Brad L, Tai Mei-Hui
246 National Food Safety Toxicology Center, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.
Mutat Res. 2005 Dec 11;591(1-2):187-97. doi: 10.1016/j.mrfmmm.2005.01.034. Epub 2005 Aug 5.
Since carcinogenesis is a multi-stage, multi-mechanism process, involving mutagenic, cell death and epigenetic mechanisms, during the "initiation/promotion/and progression" phases, chemoprevention must be based on understanding the underlying mechanism(s) of each phase, In principle, prevention of each of these phases could reduce the risk to cancer. However, because reducing the mutagenic/initiation phase to a zero level is impossible, the most efficacious intervention would be at the promotion phase that requires a sustained exposure to promoting conditions/agents. In addition, assuming the "target" cells for carcinogenesis are the pluri-potent stem cells and their early progenitor or transit cells, chemoprevention strategies for inhibiting the promotion of these two types of pre-malignant "initiated" cells will require different kinds of agents. A hypothesis will be proposed that involves adult stem cells, which express Oct-4 gene and lack gap junctional intercellular communication (GJIC-) or the early progenitor cells which express GJIC+ and are partially-differentiated, if initiated, will be promoted by agents that either inhibit secreted negative growth regulators or by inhibitors of GJIC. Consequently, anti-tumor promoting chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action and work on different target cells. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Many classes of anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, either up-regulate GJIC in stem cells or prevent the down regulation of GJIC by tumor promoters in early progenitor cells.
由于致癌作用是一个多阶段、多机制的过程，涉及诱变、细胞死亡和表观遗传机制，在“启动/促进/进展”阶段，化学预防必须基于对每个阶段潜在机制的理解。原则上，预防这些阶段中的每一个都可以降低患癌风险。然而，由于将诱变/启动阶段降低到零水平是不可能的，最有效的干预将是在促进阶段，这需要持续暴露于促进条件/促进剂。此外，假设致癌作用的“靶”细胞是多能干细胞及其早期祖细胞或过渡细胞，抑制这两种类型的癌前“启动”细胞促进作用的化学预防策略将需要不同类型的试剂。将提出一个假设，涉及表达Oct-4基因且缺乏间隙连接细胞间通讯（GJIC-）的成体干细胞，或者表达GJIC+且部分分化的早期祖细胞，如果被启动，将被抑制分泌性负生长调节因子的试剂或GJIC抑制剂促进。因此，针对这两种类型启动细胞的抗肿瘤促进化学预防剂必须具有不同的作用机制，并作用于不同的靶细胞。假设干细胞是致癌作用的靶细胞，化学预防的另一种方法将是减少干细胞池。许多类别的抗肿瘤促进化学预防剂，如绿茶成分、白藜芦醇、咖啡酸苯乙酯，要么上调干细胞中的GJIC，要么防止肿瘤促进剂在早期祖细胞中下调GJIC。
