Angiogenesis, cyclooxygenase-2 and matrix metalloproteinases in malignant mesothelioma

Malignant Mesothelioma (MM) is a fatal tumour, related to prior asbestos exposure, of increasing incidence. Current treatment modalities may provide symptom palliation but survival benefits remain unclear. Angiogenesis is essential for tumour growth of greater than 1-2mm in diameter and is stimulated by hypoxia, which is reflected by tumour necrosis (TN). Angiogenesis can be assessed by the intratumoural microvessel density (MVD). Cyclooxygenase(COX)-2 plays a central role in the upregulation of angiogeneic growth factors, such as vascular endothelial growth factor and matrix metalloproteinases (MMPs). Epidermal Growth Factor Receptor (EGFR) is overexpressed in many solid tumours and participates both in COX-2 and MMP upregulation. These factors may be prognostic in solid tumours. A database of MM cases in Leicester from 1987 to 2001 was created. Clinical and pathological prognostic factors were derived. Angiogenesis, TN and EGFR were assessed in 171 MM cases by immunohistochemistry and/or microscopy. COX-2 and MMP expression were analysed prospectively by semi-quantitative Western blotting and gelatin zymography, respectively, in up to 47 snap-frozen samples. TN, COX-2 and MMPs were identified for the first time in MM. MVD, COX-2, and EGFR correlated with TN but not with each other. The prognostic significance of MVD and EGFR were confirmed in the largest series of MM studied. TN, COX-2 and MMP-2 were novel prognostic factors. MVD, TN, EGFR, COX-2 and MMP-2 each contributed both the CALGB and EORTC prognostic scoring systems in multivariate analyses. In addition to establishing new laboratory methods and the prognostic importance of these factors, this work has identified novel targeted therapies for MM. These include anti-angiogenic therapies, such as thalidomide, and COX-2, EGFR and MMP inhibition, all of which are now either under current or future investigation in clinical trials in Leicester and other international centres.