The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy

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 mechanism(s) of each phase. Prevention of each phase could reduce the risk to cancer. Because reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion phase. 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 agents. A hypothesis will be proposed that involves stem cells, which lack gap junctional intercellular communication (GJIC-) or their early progenitor daughter 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. Chemopreventing agents to each of these two types of initiated cells must have different mechanisms of action. Assuming stem cells are target cells for carcinogenesis, an alternative method of chemoprevention would be to reduce the stem cell pool. Anti-tumor promoter chemopreventive agents, such as green tea components, resveratrol, caffeic acid phenethylene ester, that either up-regulate GJIC in stem cells or prevent the down regulation of GJlC by tumor promoters in early progenitor cells, will be provided. Human pluri-potent stem cell systems, that can be induced to form 3-dimensional "organoid" structures, will be discussed as a more realistic model system to screen for relevant chemopreventive agents. (c) 2005 Elsevier SAS. All rights reserved.