Retinoids in Oncology: Conclusions and Future Directions

Abstract

Cancer is overall the net result of disturbances in normal processes of cellular growth and differentiation, processes in which natural retinoids play a major homeostatic role. The authors of this monograph have provided an overview of the current understanding of retinoid biology with particular reference to the use of this class of agents in the prevention and treatment of malignancy. It is clear from the discussions in this book that, although there have been dramatic increases both in our understanding of these agents and in our experience with their use in therapeutics, much remains to be learned. As discussed by Arthur Zelent, many of the molecular components of the retinoid signalling pathways have been identified. Still to be defined, however, is the extent of the interactions between retinoid and other nuclear receptors, and the nature and importance of differences in expression of different retinoid receptors in different tissues. The complexities of this system will continue to present challenges in predicting the net biological effects of particular therapeutic interventions in the clinical setting. The recent demonstrations of the negative regulation by all-trans retinoic acid of AP-1-responsive genes, the role of retinoid nuclear receptor phosphorylation in receptor activation, and interactions between retinoid receptors and other nuclear receptors, including proto-oncogenes such as v-erbA, are probably only the beginning of increased appreciation of the linkage between retinoid signalling pathways and other critical cellular pathways involved in growth and differentiation. A further complexity relates to the possibility that retinoid-mediated effects can be induced through mechanisms other than the retinoid receptors, for example through direct retinoylation of intracellular proteins. Understanding of retinoid biology continues to increase at a remarkable rate, and it is clear that this improved basic understanding of the biology of this class of agents will continue to affect our estimation of their potential uses and limitations in cancer therapy.