Ignored hallmarks of carcinogenesis: stem cells and cell-cell communication.

Hanahan and Weinberg (2000, Cell 100: 57-70) listed "hallmarks" of cancer that must be considered in order to understand the underlying determinants of carcinogenesis: (a) self-sufficiency in growth signals; (b) insensitivity to growth-inhibitory (antigrowth) signals; (c) evasion of programmed cell death (apoptosis); (d) limitedless replicative potential; (e) sustained angiogenesis; and (f) tissue invasion and metastasis. While these are important phenotypic markers, important concepts--the role of pluripotent stem cells and gap junctional intercellular communication (GJIC)--must be brought into this analysis of carcinogenesis. Carcinogenesis is a multistage, multimechanism process consisting of a single cell that has been irreversibly blocked from terminal differentiation (the initiation stage). The promotion phase is a potentially reversible or interruptible clonal expansion of the initiated cell by a combination of growth stimulation and inhibition of apoptosis. When the expanded initiated cells accrue sufficient mutations and epigenetic alterations to become growth stimulus independent and resistant to growth inhibitors and apoptosis, to have unlimited replicative potential and invasive and metastatic phenotypes, then the progression phase has been achieved. The hypothesis that integrates these hallmarks is that the stem cell and its early progenitor cell are the target cells for the initiation event. These cells are naturally immortal and become mortal only when they are induced to terminally differentiate and lose their telomerase activity. These two types of initiated cells are suppressed by either secreted negative growth regulators (the stem cells) or GJIC (the early initiated progenitor cells). Promoters inhibit either the secreted growth inhibitor to initiated stem cells or GJIC between the initiated progenitor cells and the normal progenitor cells. When a stable resistance to the secreted negative growth regulator or permanent downregulation of GJIC has occurred, the cell has entered the progression phase. These two new concepts contradict the current paradigm that the first phase of carcinogenesis is the immortalization of a normal cell followed by its neoplastic transformation. Our hypothesis is that the first stage of carcinogenesis must prevent the "mortalization" or terminal differentiation of a naturally immortal cell. Chemoprevention and chemotherapeutic implications suggest that one must induce connexin genes in initiated stem cells and restore GJIC in initiated early progenitor cells.