Year: 2005
Type: editorial
Abstract: Back in 1988 the first paper of my laboratory published on pigment cells reported the presence of a novel DNA-binding activity in melanomas that turned out to be the Brn-2 transcription factor. At that time the incidence of melanoma in the UK was something like 3500 new cases per year. By last year that number had increased to more than 7000, while in the US the lifetime risk of melanoma is around 1/75. Despite increased public awareness of the disease, the incidence of melanoma is anticipated to rise inexorably in the coming decades. Over recent years attention has been focussed on identification of many of the genetic lesions that underpin the disease which include gain of function mutations in the MAP kinase signalling pathway, through activation of BRAF or NRAS for example and loss of function in the Rb and p53 pathways though mutations in INK4a/ARF or amplification of cyclin D. However, given that metastatic melanoma is notoriously unresponsive to current therapies, there is clearly an urgent need for the increased understanding of the disease at the molecular level to translate into more effective and targeted therapies. One promising recent addition to the repertoire of anti-cancer drugs is the family of compounds that act to inhibit histone deacetylases, enzymes that are intimately involved in the regulation of gene expression through their ability to reverse the acetylation of histone tails and most likely also non-histone proteins. The review by Boyle et al. focuses on the potential for HDAC inhibitors in the treatment of melanoma, while the paper from Peltonen et al. examines the ability of the HDAC inhibitor TSA to induce p53-independent apoptosis in melanoma cells. The ability to grow cells in defined culture conditions underpins much of what we now know of how cells integrate extracellular cues with the cell cycle and differentiation. Most of us tend to do our experiments using cell lines and try as best we can to avoid contamination with cells of any other type. While the use of cell lines grown as monolayers is convenient, it doesn't reflect accurately the situation in vivo where melanocytes and melanoma cells interact intimately with both keratinocytes and fibroblasts. In their review on p. 150, Haass et al. discuss the importance of cell–cell interactions in adhesion, migration and inter cell-communication in melanocytes and melanoma. This is an increasingly important area of research, and is critical if we are to understand how melanoma develops. The Wnt signalling pathway, acting via β-catenin, is deregulated in a substantial minority of melanomas, but is also critical for melanocyte development where it is required for activation of Mitf expression. Although Wnt1 and Wnt3a have been described as having redundant roles in melanocyte development, Dunn et al. now show that the two factors have distinct mode of action, with Wnt1 increasing neural crest-derived melanocytes numbers via a paracrine effect, while Wnt3a can act on melanoblasts to maintain Mitf expression and consequently promote cells to adopt a melanocyte fate. The results presented provide a new insight into the roles of Wnts in the origin of melanoblasts from the neural crest.
Source: Pigment Cell Research
Author: Colin Goding
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2117025469