Year: 2009
Type: editorial
Abstract: There is a fundamental difference between science and medicine: scientists can afford to spend many years trying to understand molecular mechanisms that may eventually be of therapeutic use (or not); clinicians are faced with waiting rooms full of patients that need treating now and therefore must use the therapy of the day. Yet at times, the years spent by scientists working on topics that may not be immediately or even predictably useful comes to fruition with an insight that presents new therapeutic opportunities. In this respect, one of the greatest challenges in modern biology is to harness the power of stem cells for therapeutic use. To do this will require an in depth understanding of what drives stem cell quiescence, activation and differentiation of their transit amplifying progeny. Melanocyte stem cells are located in the bulge region of the hair follicle and since their discovery by the group of Shin-ichi Nishikawa, substantial progress has been made in their characterisation. Unlike differentiated melanocytes, they do not express markers of pigmentation and are negative for the expression of Mitf and Sox10, two key melanocyte transcription factors. What drives their quiescence is most likely Notch signalling since the stem cells express high levels of downstream targets for Notch. Intriguingly, Notch is also known to suppress the activity of the stress signalling p38 kinase cascade that plays a key role in UV-mediated induction of pigmentation. The knowledge outlined here means that the melanocyte stem cells are perhaps ripe for exploitation for therapeutic purposes. One immediate application would be in the treatment of vitiligo, a multifactorial disease characterised by the destruction of mature differentiated melanocytes. While differentiated melanocytes are missing in vitiligo skin, the stem cells escape destruction and therefore represent a potential source of new differentiated melanocytes that would re-populate and re-pigment the skin. One of the major therapeutic approaches to vitiligo is UV-based therapy that can lead to varying degrees of repigmentation. However, UV irradiation can also lead to DNA damage and while partially effective is not necessarily ideal. Now, in a series of papers culminating in one published in this issue from Saha et al, the Bhadra group have followed an alternative therapeutic approach in which they have isolated and purified a bioactive lipid that stimulates melanocyte stem cells to proliferate. The mechanism appears to be via lipid-mediated activation of p38 stress signalling that in turn would activate expression of Mitf and consequently lead to both stimulation of stem cell division and increased expression of the Mitf target genes implicated in pigmentation. As reported in the paper and discussed in the News and Views from Mauro Picardo, the results of treatment of mouse skin with a sphingolipid purified from placental extract are striking. The lipid not only stimulates melanocyte stem cells but also leads to increased numbers of hair follicles suggesting that it activates more than one stem cell type. Although it will be some time before the full therapeutic implications of lipid-based therapies are realised, this results reported by Saha et al provide a major step in the right direction. The work from the Bhadra group has identified a lipid that will operate to activate normal melanocyte stem cells and presumably overrides the signals provided by the microenvironment in the niche that maintains stem cell quiescence. The microenvironment also plays a critical role in melanocyte development as it directs the migration of melanoblasts from the neural crest to the epidermis and hair follicles and instructs the programme of differentiation. In melanoma, the role of the microenvironment is also being recognised as increasingly important and several factors including interactions with the stroma and fibroblasts, nutrient deprivation, hypoxia and the impact of chemokines play a major role in tumour progression. In this issue, a review from Ann Richmond et al. highlights the critical influence of chemokines on melanoma behaviour and points out how understanding the impact of chemokines can offer therapeutic possibilities. A second review from Barbara Bedogni and Marianne Broome Powell explores the impact on melanoma of tissue oxygenation that regulates a wide variety of cellular processes ranging from survival and death to cellular metabolism, angiogenesis and senescence. While covering melanoma, the review also examines the role of oxygenation in normal skin and how hypoxic melanocytes are more prone to oncogenic transformation. Intriguingly, the effect on transformation of activation of AKT a signalling molecule implicated in survival lying downstream from the PI3kinase pathway is enhanced under hypoxic conditions. This may be relevant to another paper published in this issue from Ze’ev Ronai’s lab, which shows that a novel AKT-inhibitor has a dramatic effect on the growth of melanomas in a xenograft model.
Source: Pigment Cell & Melanoma Research
Author: Colin Goding
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2008928469