Differentiation: an encouraging approach to anticancer therapy

Differentiation is a complex multistep process of cell specialization that begins with the installation of a genetic programme, named determination, specific for a cell lineage. Development of the differentiation programme includes the cell-type specific silencing of some genes and the expression of other genes, that regulate the biological functions associated with the cellular type and that distinguish the specialized cells. Terminal differentiation is the end stage of this process where the cells irreversibly lose their proliferative capacity and which represents a form of negative control of growing. Regulating molecules interact to produce the correct balance between cellular multiplication and differentiation during embryogenesis and the normal behaviour of an adult. Cancer is a process in which changes in regulating circuits are produced, such as proliferation control, the balance between cellular survival and programmed cellular death (apoptosis), the communication with neighbouring cells and with the extracellular matrix, angiogenesis, and finally, the migration of the tumoural cell, the invasion and metastasic dissemination. This process implies the progressive development of a more malign phenotype with an increase of genetic alterations involving genes at several levels of expression during long periods of time. These genetic changes uncouple the normal balance between multiplication and cellular differentiation with an increase in the rate of proliferating cells. Classic chemotherapeutical agents have been very important; nevertheless, as the mechanism of action of these drugs depends on the cytodestruction of the neoplastic cells, their beneficial effects are normally accompanied by a notable morbidity, cytotoxicity and multidrug resistance. The knowledge of the mechanisms involved in differentiation and malignant transformation has allowed the search of alternative routes for antitumoural therapy that does not imply cellular death. Differentiation therapy focuses on the development and use of specific agents designed to selectively attract the terminal differentiation process, making the elimination of tumoural cells feasible together with the establishment of normal cellular homeostasis.