1. ¹Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, Bristol, UK
2. ²Department of Plastic Surgery, Frenchay Hospital, Bristol, UK
3. ³Department of Pathology, Frenchay Hospital, Bristol, UK

Correspondence: Dr DO Bates, Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK. E-mail: Dave.Bates@bris.ac.uk

⁴These authors contributed equally to this work.

Received 15 February 2007; Revised 30 April 2007; Accepted 14 May 2007; Published online 26 June 2007.

Abstract

Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis – the growth of new vessels from preexisting vasculature – is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF_xxxb, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF_xxxb expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF_xxxb staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) P<0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGF_xxxb expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.