Cancer, retrodifferentiation, and the myth of Faust.

The close relationship at the molecular level between cellular differentiation and neoplasia has been evidenced by the discovery in adult individuals of fetospecific antigens and fetal type isozymes associated with many spontaneous and experimentally induced malignant tumors. One question in relation with this finding is whether cancerous tumors develop from the differentiation of a tissue reserve of stem cells or by a process of retrodifferentiation, i.e., the nucleocytoplasmic stepwise reversion of cells toward stationary states with simplified structure and less information content. The question is not merely academic; elucidation of the nature of the target cells from which neoplastic growth emerges has obviously physiopathological and therapeutic implications. This contribution is an analysis of the nature and the mechanism of cellular retrodifferentiation and a discussion of its possible role in regeneration and metaplasia, as well as in neoplastic development. Throughout living systems, retrodifferentiation appears as a common adaptive process for the maintenance of cell integrity against deleterious agents of varied etiology (physical, chemical,and viral). While preserving the entire information encoded on its genome, cells undergoing retrodifferentiation lose morphological and functional complexity by virtue of a process of self-deletion of cytoplasmic structures and the transition to a more juvenile pattern of gene expression. This results in a progressive uniformization of originally distinct cell phenotypes and to a decrease of responsiveness to regulatory signals operational in adult cells. Retrodifferentiation is normally counterbalanced by a process of reontogeny that tends to restore the terminal phenotypes from where the reversion started. This explains why retrodifferentiation remains invariably associated to cell regeneration and tissue repair. There is an ever growing evidence that neoplastic transformation in vivo and in vitro is frequently preceded and/or accompanied by biochemical, morphological, and behavioral transitions characteristic of a cell undergoing retrodifferentiation. Contrary to what occurs in regenerating tissues, the "unbalanced" character of tumor-associated retrodifferentiation seems to be a property linked to cancer. The question arises why a unique mechanism of cell rejuvenation is in physiological conditions (regeneration), followed by a process of reontogeny, while in neoplasia the process remains incomplete or does not occur and leads to the emergence of a population of persistently dividing cells. It is to be hoped that a careful study of retrodifferentiation in physiological and tumoral models will help to distinguish that which in neoplastic development can be relevant to an adaptive cell behavior from that which might eventually be the result of specific or constitutive alterations.