Human adult stem cell markers: lack of gap junctional communication and Oct 4 expression as ‘hallmarks’ in the cause, prevention and treatment of cancers
Dept. Pediatrics and Human Development, College of Human Medicine, National Food Safety & Toxicology Center, Michigan State University, E. Lansing, Michigan, United States
AIM: To present evidence that adult human stem cells are target cells for initiating the carcinogenesis process and the inhibition of gap junctional intercellular communication (GJIC) by chemicals and oncogene lead to the promotion / progression phases of carcinogenesis, while the prevention of this inhibition in pre-malignant cells is the basis for chemoprevention and the reversal of inhibited GJIC by tumor promoters or oncogenes is the basis for chemotherapy. METHODS: Adult human stem cells isolated from the kidney, breast, pancreas, liver and the adipose (mesenchymal) tissues were characterized for two markers found in these cells (absence of GJIC function and the expression of Oct 4 gene). GJIC function was measured in normal, tumor promoter-treated cells, in cells treated with both tumor promoters and chemopreventive agents, in oncogene-activated cells and in oncogene-chemotherapeutic agent-treated cells. RESULTS: Normal human adult stem cells showed no GJIC and expressed the Oct 4 transcription factor gene, whereas the normal derivative, differentiated progenitor cells showed functional GJIC and no expressed Oct 4. In addition, immortalized but non-tumorigenic cells, as well as the tumorigenic cells, showed Oct 4 expression, with or without expressed connexin genes but with no functional heterologous GJIC. CONCLUSIONS: Expression of connexins and their function in gap junctions are needed for the differentiation of stem cells in tissues. If during the carcinogenic process the expression of connexins is inhibited or the expressed connexins are inhibited, signals needed for terminal differentiation in either type of the GJIC-deficient cell will be lacking. This will lead to tumor cells that are either very “stem cell- or embryonic-like” or that are “partially differentiated”, as predicted by Van R. Potter when he stated: “ Oncogeny as partially blocked ontogeny”. The results support the “stem cell” theory of carcinogenesis and that the absence of functional GJIC, either due to no expressed connexins or expressed connexins that are non-functional, and the expression of Oct 4 appear to be common markers for adult human stem cells and tumor cells.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 701 (Molecular oncogenesis).