Alan Lyell Center for Dermatology

Glasgow, United Kingdom

Alan Lyell Center for Dermatology

Glasgow, United Kingdom
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Muinonen-Martin A.J.,CRUK Beatson Institute | Muinonen-Martin A.J.,York Teaching Hospital NHS Foundation Trust | Muinonen-Martin A.J.,The Leeds Teaching Hospitals NHS Trust | Susanto O.,CRUK Beatson Institute | And 16 more authors.
PLoS Biology | Year: 2014

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient. © 2014 Muinonen-Martin et al.


PubMed | Alan Lyell Center for Dermatology, York Teaching Hospital NHS Foundation Trust, University of Connecticut, St George's, University of London and 2 more.
Type: Journal Article | Journal: PLoS biology | Year: 2014

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient.


Kerr A.C.,Ninewells Hospital | Ferguson J.,Ninewells Hospital | Attili S.K.,Ninewells Hospital | Beattie P.E.,Alan Lyell Center for Dermatology | And 12 more authors.
Clinical and Experimental Dermatology | Year: 2012

Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK. Click for the corresponding questions to this CME article. © 2012 British Association of Dermatologists.


Mackintosh L.J.,Alan Lyell Center for Dermatology | Geddes C.C.,Glasgow Renal and Transplant Unit | Herd R.M.,Alan Lyell Center for Dermatology
British Journal of Dermatology | Year: 2013

Background Organ transplant recipients have an increased risk of skin cancers. A specialist dermatology clinic for renal transplant recipients (RTRs) was established in 2005. Objectives To analyse the type and incidence of skin cancers in prevalent patients in the West of Scotland after renal transplant, and to analyse the impact of the time since transplant and the immunosuppression regimen. Methods Skin cancer data for RTRs attending the transplant dermatology clinic over a 38-month period were collected and recorded in the West of Scotland electronic renal patient record. Skin cancer data were intrinsically linked to each individual's transplant and immunosuppression data. Results Overall, 610 patients attended. The median follow-up time from the date of first transplant was 10 years. Ninety-three patients (15·2%) had experienced a total of 368 skin cancers since transplant, and the prevalence increased with time since transplant. Basal cell carcinomas (BCCs) occurred in 74 patients (12·1%) and squamous cell carcinomas (SCCs) in 42 patients (6·9%). Three patients (0·5%) had experienced a melanoma. The SCC:BCC ratio was 0·7. Survival analysis showed significant reduction in the time to develop skin cancer in patients transplanted from 1995 onwards (P < 0·0001) and in patients who had been on triple immunosuppressant therapy at 1 year after transplant, compared with dual therapy (P < 0·0001). Conclusions This is the first study of skin cancer in prevalent Scottish RTRs. The incidence of skin cancer is high and appears to have a direct relationship to the overall burden of immunosuppression. The SCC:BCC ratio, which is lower than reports from other centres, deserves further scrutiny. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

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