The gluttonous side of malignant melanoma: basic and clinical implications of macroautophagy.

Abstract

True to their inherent aggressive behavior, melanomas keep impressing the melanoma community with their ability to bypass tumor suppressor mechanisms. Name a pathway with the potential to control cell survival and melanoma cells will likely have it potentiated by multiple genetic or epigenetic alterations. In the context of progression and chemoresistance, large efforts have been dedicated to the identification of protective mechanisms associated with or linked to apoptotic death programs. These studies have guided the design of targeted anticancer strategies. Still, the promise for pro-apoptotic inducers as lead compounds for drug development has yet to come to fruition. It was then a question of time to identify alternative modulators of cell viability. An ideal candidate that is raising great expectations in the oncology field is autophagy, a catabolic process with multiple roles in cell homeostasis. Here we review the incipient literature on autophagy markers in melanocytic lesions. Intriguingly, histopathological studies are unveiling an intrinsic inter- and intratumor variability in the expression of autophagy modulators. Nonetheless, functional studies support a key role of autopaphagy programs in the response to a variety of stress factors. These include adaptive responses to nutrient deprivation, hypoxia and many anticancer agents, among other stimuli. Strategies are being also developed to mobilize the endocytic machinery and shift autolysosomes into death effectors. The opportunities that lie ahead in this field are exciting. Various authophagy mediators are potentially druggable. Moreover, animal models and the development of sophisticated screening methods offer a platform for multilevel academic-industrial collaborations. These efforts are expected to open avenues of research and, hopefully, lead to a more rational approach to melanoma treatment.