Physiologic Correlates of Malignancy

The essential features of cancer are uncontrolled growth, overcoming of replicative senescence, invasiveness, and tumor- or organ-specific neoplasm- host interactions. This raises the question whether all cells have the potential to transform into malignant tumors. The physiologic barriers preventing uncontrolled cell division are higher in differentiated cells than in undifferentiated ones. Stem cells have the potential to proliferate, whereas terminally differentiated cells typically have exited the cell division cycle. Stem cells also are not subject to replicative senescence, because they may still express Telomerase, thus preventing the shortening of the chromosome ends with every cell division. In contrast, Telomerase activity is typically absent from differentiated cells. Tumors derived from them would stop growing after a limited number of population doublings. Most importantly, tissue-specific cells would have to redifferentiate in order to adopt the genetic programs for metastasis formation, which are physiologically used for homing by lymphocytes and macrophages, but not by parenchymal cells in solid organs. The association between growth factor signaling and acquisition of invasiveness is preserved in precursor cells, because it is part of the genetic programs of stress responses. Stem cell expansion and activation are induced by tissue damage. After wounding, there is an accumulation of dividing precursor cells in the affected tissues [Flemming 1885]. Growth factor-dependent signal transduction in precursor cells, but not in differentiated cells, induces transcription factors that activate stress response genes [Witt et al. 2001; Laprise et al. 2002; Nollen and Morimoto 2002]. These characteristics raise the possibility that malignant transformation is not a condition of differentiated cells but rather of tissue-resident precursor cells or stem cells [Sell and Pierce 1994; Reya et al. 2001]. This possibility, referred to as “vitium primae formationis,” was alluded to in 1875 in a study of a congenital myosarcoma of the kidneys [Cohnheim 1875]. Alterations in the cellular microenvironment, such as injury or carcinogens, may induce marked differentiative changes in tissue-resident precursor cells. In cancer, this mechanism accounts for the histologic appearance of dedifferentiation, in actuality reflecting the accumulation of stem cells that have become unresponsive to physiologic growth control mechanisms. Differentiation is an anticarcinogenic process.