ESPCR 7th meeting
Bordeaux, 9 - 11 October 1997
by Dr. Sheila Mac Neil
This report has been compiled with input from several colleagues who kindly shared their highlights from this meeting - Dorothy Bennett, David Gawkrodger, Marco d'Ischia, Mauro Picardo and Tony Thody.
For those of you who may not have attended a European Pigment Cell Research meeting before, there are perhaps a few facts I should tell you - you will have a good time socially (and the food and drink this year were chosen with particular care - Tony Thody wishes congratulations to be passed on to Jean-Etienne Surleve-Bazeille and Alain Taieb on the excellence of both) - however, you will also need stamina and to keep your wits about you if you are to do justice to a 2½ day meeting which typically includes presentations from 6 guest lecturers, 55 oral communications and 72 posters on a range of topics which span the biochemistry of the melanins, developmental and cellular biology of the melanocytes, their genetics through to their behaviour in vitiligo and melanoma. There are no simultaneous sessions at these meetings and it is tough being a member of the audience at a European Society for Pigment Cell Research meeting.
So, is it worth listening to talks in areas outside of your own field or speciality? The answer is a clear 'yes'. If you are willing to listen and learn, the chances of setting up collaborations to extend and broaden your research are excellent. Many scientific friendships have been forged at these meetings and continue to flourish. A lot of the presentations at the meeting were visible fruit of such collaborations. Not that I am biased, of course, but as the new Secretary for the ESPCR, I would say that this meeting (more than any other that I know of) has just the right chemistry (Professor Prota) to set up enjoyable collaborations - the meetings are the right size - they contain a number of disciplines all focussed on the melanocyte and you can be pretty sure of meeting up with your colleagues on an annual basis. If you have never attended one of these meetings before, don't be put off - we are a very easy society to join, very friendly, newcomers are made very welcome and guest lecturers are chosen with infinite care to provide topical overviews of particular areas of melanocyte biology. That was certainly the case at this meeting where the quality of the guest lectures was excellent throughout. So, enough advertising - here are some of the highlights from this meeting.
Particularly commended by many colleagues was the guest lecture by Jonathan Rees on genetic approaches to melanoma susceptibility in which he reviewed recent work from Newcastle and other Centres on mutations affecting the melanocortin-1 receptor gene. There are now known to be a considerable number of mutations of this receptor and Professor Rees group is leading the research into looking at the possible relationships between gene variants and inheritance of red hair and between gene variants and the likelihood of developing melanoma. This work is likely to open new vistas not only on the origin of skin tumours but especially on the complex mechanisms affecting skin type and hair colour - these studies favour a gradual shift of interest from the eumelanin to the phaeomelanin pathway as the key to the understanding of melanoma susceptibility - it will be interesting to see how these results will be integrated into the current knowledge of the biochemistry of phaeomelanin pigmentation - Marco d'Ischia.
Other excellent guest lectures were from Seth Orlow on the comparative genetics of oculo-cutaneous pigmentation (detailing the different stages at which differences in genetics could have an effect on pigmentation encompassing melanocyte migration, melanosome biogenesis and melanosome trafficking and transfer) and from Barbara Gilchrest who addressed the issue of how melanocytes in vivo are undoubtedly under the control of factors produced by adjacent cells which will themselves change in response to UV. Professor Gualde also reviewed the very wide array of approaches to inducing immunogenicity in melanoma that are currently under investigation in a very clear presentation.
Another excellent guest lecture was from Nicole Le Douarin on factors controlling the development of the melanocytic lineage from the neural crest. This was closely followed by a presentation from Laure Lecoins from Professor Le Douarin's laboratory on a novel sequence for an avian endothelin receptor which may help in understanding the evolution of function of these receptors (Dorothy Bennett).
AND NOW TO SOME OF OUR FAVOURITE THINGS ...
With respect to interactions between a-MSH and cytokines, things are looking interesting - on one hand, we learned that inhibition of melanogenesis by TNF-a is mediated through a downregulation of the tyrosinase promoter activity (Englaro et al.) - on the other hand, we learned that a-MSH itself can oppose the action of TNF-a in melanocytes (Hedley & Mac Neil) and melanoma cells (Morandini & Ghanem). The implications of a-MSH opposing the response of melanocytes and melanoma cells to cytokines are potentially quite exciting - time and further work will tell.
a-MSH was also found to increase production of nitric oxide in melanocytes and to potentiate UV-induced nitric oxide production (Alison Graham and Tony Thody) - whether this will relate to any melanogenic actions of a-MSH or other actions of this busy little hormone, time will tell.
How the agouti protein fits into things is slowly emerging. Vincent Hearing showed that agouti protein is capable of upregulating some and downregulating other genes. These genes are likely to be important in control of eumelanin and phaeomelanin synthesis and determining hair colour and may provide further key information on the biochemical pathways responsible - possibly some important missing pieces of our jigsaw - Dorothy Bennett. Dorothy also singled out a talk from Fritz Anders on a new class of oncodeterminants as the most important talk of the meeting - Dorothy explains - that the Xiphorus fish work produced the first oncogene and the first tumour suppressor gene and mammals followed fish on both these occasions. In his talk, Dr. Anders presented evidence of retrotransposons as heritable and amplifiable tumour-suppressor-suppressors. He also pointed out that all of these sequences are found in telomeres and one repeat sequence that he gave in detail was crammed full with methylation sites (of CG). Methylated DNA goes heterochromatic and can silence neighbouring genes by spread of this state - apparently a well known phenomenon. Once again, these little fish in Dr. Anders capable hands may be pointing the way ..........
I am indebted to Marco d'Ischia for highlights of the session on the biophysics and biochemistry of melanins. The effect of thiol compounds on melanogenesis was the central theme of two contributions by Smit, Pavel et al. and Potterf Benathan, Hearing and co-workers. While the first paper focussed on the effects of varying concentrations of tyrosine and cysteine on melanogenesis highlighting a role of melanin production on glutathione depletion in melanocytes cultured with high tyrosine and low cysteine concentrations, the second paper addressed the relationship between agouti signal protein, cysteine transport and uptake in melanosomes and cysteinyl dopa formation to reinforce the notion that it is cysteine and not glutathione that is the actual ultimate precursor of cysteinyldopas. In another partially related paper, Dr. Benathan went on to show that tyrosinase could play a protective role against UV irradiation by catalysing the formation of cysteinyldopa conjugates.
Dr. Mars and Professor Larsson used a microautoradiographic technique to conclude that persons with a high content of phaeomelanin in their skin have toxicological risks of melanin-related adverse effects compared to those of dark skinned people.
Similarities and differences in the process of pigment formation between cutaneous melanocytes and melanogenesis in the ink gland of Sepia Officinalis were presented by Dr. Palumbo. Analysis of the nature of melanins is improving - Wakamatsu Ito and co-workers have used an improved version of a spectrophotometric method for melanin analysis combined with gel filtration HPLC to evaluate the DHICA content of eumelanins and their molecular size.
Also, in what must be the biggest ever group of related posters - 4 related poster presentations by Riley, Land, Pavel, Smit and co-workers on the mechanism of tyrosinase activation and the synthesis and properties of novel indoliumolate derivatives - these workers concluded that the actual product of the action of tyrosinase on tyrosine is dopaquinone and not dopa which is formed only by a reduction of dopaquinone by leucodopachrome. Other significant contributions dealt with the structural modifications of synthetic eumelanins under aerobic conditions by Prota, d'Ischia and co-workers, the characterisation of melanins from tetrahydroisoquinolines by Rosei, Mosca and colleagues and a MALDI/MS study of oligomers of 5-hydroxytryptimine by Allegri, Traldi et al.
Putting the melanocyte back where it belongs ...
A number of groups are now looking at the behaviour of the melanocyte in in vitro models of reconstructed skin. Clearly leading this field is work from Professor Taieb's laboratory in which a number of basic and fundamental parameters about the behaviour of melanocytes from different skin types and from vitiligo skin have been established. These models are obviously going to prove very useful for studies of pigmentation research and may yield a few surprises - a poster by Hedley et al. showed that fibroblasts added to such an epidermal/dermal reconstituted skin tended to reduce spontaneous pigmentation of these composites. To date, the majority of composites have examined melanocyte/keratinocyte interaction in either an artificial collagen matrix or on acellular human dermis. Such composites are now also being used to investigate invasion of melanoma cells and should be a particularly useful tool for studying melanoma cells/ECM interactions (Bizik et al.).
Do melanocytes differ from melanoma cells in their ability to cope with oxidative stress?
Further evidence supporting this hypothesis was presented in a poster by Chau, Meyskens and Buckmeier showing essentially that melanoma cells cope less well than melanocytes with reactive oxygen species suggesting impairment of redox regulation in melanoma. Following on from this, this same group (Meyskens, Buckmeier and Tohidian) showed that the transcription factor NF'B which is activated by a variety of stimuli including inflammatory cytokines and reactive oxygen species appear to be differently regulated in melanoma cells compared to melanocytes. Differences in expression of rel family members between normal human melanocytes and metastatic melanoma were noted which may go some way to explain the differing abilities of the cells to cope with reactive oxygen species.