Finding a niche

Abstract

One of the wonders of development is the long migration undertaken by cells of the neural crest to their final destinations where they undergo differentiation. For cells of the melanocyte lineage, migration is driven by the ability of melanoblasts to receive and interpret extracellular cues that control their rate of proliferation and give directional signals so that they take the correct route. This intrinsic capacity of neural crest cells for long-distance movement may be one reason why melanomas are so aggressive; oncogene-mediated deregulation of key developmental signal transduction pathways coupled with microenvironmental stress may be sufficient to reactivate the embryonic migratory potential without the need for acquisition of pro-metastasis mutations. The processes underpinning development and those implicated in melanoma genesis and progression are intimately related, and the lessons from one system are likely to be applicable to the other. One key concern is the origin of melanoma: do the initial mutational events that lead to malignant transformation occur in differentiated melanocytes or their stem cells? Given that differentiated cells most likely have heterochromatinized the genes required for proliferation, the melanocyte stem cell might represent an attractive candidate. Moreover, there is increasing evidence that the heterogeneity observed within a melanoma may in part reflect the presence of ‘melanoma stem cells’ that would provide a reservoir of potentially drug-resistant cells with a capacity to form new tumours. Understanding how such a population of melanoma stem cells might be generated, and how the microenvironment might control the switch from proliferation to quiescence and vice versa is a key issue in the field. Presumably the tumour microenvironment will provide a ‘niche’ that is permissive for the generation and maintenance of the melanoma stem cell population. However, the dynamic nature of melanoma provides major challenges to understanding the nature of the putative melanoma stem cell niche. By contrast, understanding the molecular mechanisms that lead to the generation, maintenance and re-activation of normal melanocyte stem cells is tractable. Advances made over recent years, particularly by the Nishikawa laboratory, first identified melanocyte stem cells in the hair follicle bulge region and subsequently led to the molecular characterization of the hair follicle melanocyte stem cells in terms of their gene expression characteristics. The results obtained provide the basis for addressing a key question in stem cell biology: what determines a stem cell niche? The review from Masatake Osawa and Shin-Ichi Nishikawa in this issue summarizes the progress made to date on the characterization of melanocyte stem cells and proposes a model to describe the events that lead to the generation of a melanocyte stem cell. Although there is yet a long way to go, it is clear that unlike most other stem cell systems, the melanocyte lineage provides an excellent model for defining what is required for a stem cell niche. Importantly, the answers obtained to date suggest that melanocyte and melanoma stem cells may have a great deal in common. While melanoma represents a potentially fatal disease of the melanocyte lineage, it is relatively well characterized at the molecular level compared with vitiligo, a disease in which there is loss of melanocytes in the skin. While not life threatening, vitiligo nevertheless represents a major challenge to our understanding of pigment cell biology and as pointed out by Alain Taieb in his News and Views article, there is no obvious angle of attack. Although there is evidence that one component of the disease is stress sensitivity, one aspect that is undoubted is that vitiligo is characterized by a cell-based immune response against differentiated melanocytes and that this is underpinned by a genetic component. The current status of the genetics of vitiligo is reviewed by Rich Spritz, who not only highlights specific candidate genes for the disease, but also points out several candidates that appear to have fallen by the wayside. Progress in understanding vitiligo is likely to require a very broad approach in multiple disciplines, but rigorous application of statistics to genetic analysis will be critical if any progress in identifying true vitiligo-associated genes is to be made. Moreover, while understanding the molecular basis of vitiligo is clearly important, there is an urgent need for more effective treatment now. In that respect, while the immune response may eliminate differentiated melanocytes, the melanocyte stem cells in their niche do not express melanocyte markers and therefore will escape destruction. Understanding the mechanisms that lead to reactivation of the stem cell population and consequent repopulation of de-pigmented skin with new melanocytes represents the most viable approach for an effective anti-vitiligo therapy. Again, the review from Osawa and Nishikawa in this issue provides a sound basis for studies directed towards stem cell-based vitiligo therapy.