Expression of VEGFxxxb, the inhibitory isoforms of VEGF, in malignant melanoma

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, VEGFxxxb, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGFxxxb 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, VEGFxxxb 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 VEGFxxxb 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

VEGF-A splicing: the key to anti-angiogenic therapeutics?

The physiology of microvessels limits the growth and development of tumours. Tumours gain nutrients and excrete waste through growth-associated microvessels. New anticancer therapies target this microvasculature by inhibiting vascular endothelial growth factor A (VEGF-A) splice isoforms that promote microvessel growth. However, certain VEGF-A splice isoforms in normal tissues inhibit growth of microvessels. Thus, it is the VEGF-A isoform balance, which is controlled by mRNA splicing, that orchestrates angiogenesis. Here, we highlight the functional differences between the pro-angiogenic and the anti-angiogenic VEGF-A isoform families and the potential to harness the synthetic capacity of cancer cells to produce factors that inhibit, rather than aid, cancer growth

Finding New Partnerships: The Function of Individual Extracellular Receptor Domains in Angiogenic Signalling by VEGF Receptors

Vascular endothelial growth factors (VEGFs) constitute a family of polypeptides regulating blood and lymphatic vessel development. VEGFs bind to type V receptor tyrosine kinases (RTKs), VEGFR-1, VEGFR-2, and VEGFR-3, but also bind directly to neuropilins and heparan sulphate glycosaminoglycans (HSPG), or indirectly to co-receptors such integrins and semaphorins. VEGFR activation results from ligand-induced dimerisation, which is mediated by the extracellular receptor domain (ECD). Recent studies established that dimerisation is necessary, but not sufficient, for receptor activation, since it was shown that only distinct orientations of receptor monomers give rise to active receptor dimers that are capable to instigate transmembrane signalling. Additional complexity in VEGFR signalling arises from association with specific co-receptors, which is determined by ligand- and ECD-specific interaction domains. In the following, the role of the different extracellular subdomains in VEGFR activation and signalling is discussed. We give an overview of the mechanistic concepts arising from recent structural studies that led to the development of novel allosteric receptor inhibitors and discuss their possible application in therapies aimed at pathological angiogenesis