Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF ? expression

Abstract

Vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF‐1 and ‐2), and transforming growth factor β (TGFβ) are potent angiogenic cytokines. Malignant mesothelioma of the pleura presents with a high intra‐tumoural microvascular density (IMD) which also has prognostic relevance. This study was designed to verify the immunohistochemical expression of the angiogenic cytokines in mesothelioma as well as in non‐neoplastic human mesothelial cells and to study the individual as well as the combined expression of these cytokines in mesothelioma in relation to both IMD and prognosis. In addition, four mesothelioma cell lines were studied by ELISA for the secretion of VEGF and FGF‐2 in their supernatants and were shown to contain high levels of both of these cytokines. Immunohistochemically, VEGF, FGF‐1 and ‐2, and TGFβ immunoreactivity was present in 81, 67, 92 and 96 per cent of mesotheliomas, and in 20, 50, 40, and 10 per cent of samples of the non‐neoplastic mesothelium, respectively. Co‐ordinate expression of the cytokines was observed whereby mesotheliomas expressed more than one cytokine. The combined immunohistochemical expression levels for all four cytokines correlated significantly with both IMD ( p=0·01) and prognosis ( p=0·0013). When studied individually, high FGF‐2 expression correlated best with more tumour aggressiveness and worse prognosis for mesothelioma ( p=0·0011). There was no significant correlation between prognosis and immunoexpression of VEGF ( p=0·07), FGF‐1 ( p=0·3), or TGFβ ( p=0·1), or between IMD and any of the cytokines studied individually. These data support the assertion that selective angiogenic cytokines might contribute to the progressive changes of mesothelioma by tumour angiogenesis. Copyright © 1999 John Wiley & Sons, Ltd.

Angiogenesis is an independent prognostic factor in malignant mesothelioma

“…These include HGF/SF (Tolnay et al, 1998), IL-8 (Antony et al, 1996) and urokinase plasminogen activator (Shetty et al, 1995). VEGF expression was correlated to MVD in MM by Ohta (Ohta et al, 1999) but not in the KumarSingh study (Kumar-Singh et al, 1999). However VEGF expression was not found to be a significant poor prognostic factor in either study.…”

“…Other biological prognostic markers in MM include the cytokeratin marker Cyfra 21-1 (Schouwink et al, 1999), syndecan-1 (Kumar-Singh et al, 1998), bFGF (Kumar-Singh et al, 1999) and Simian virus-40 sequences (Procopio et al, 2000). We have recently presented data in operable non-small-cell lung cancer indicating that MVD contributes to a biological prognostic model which is independent of TNM stage (Cox et al, 2001).…”

Oral Cyclophosphamide and Etoposide in Treatment of Malignant Pleural Mesothelioma

“…Tumor growth is strongly dependent on angiogenesis (Folkman, 1971). Mesothelioma cells often express VEGF and fibroblast growth factor (bFGF) (Kumar-Singh et al, 1999). Some trials showed patients with malignant pleural mesothelioma expressing serum VEGF concentrations that are higher than with other solid tumors or healthy individuals.…”

Imaging in pleural mesothelioma: A review of the 11th International Conference of the International Mesothelioma Interest Group

“…These challenges are reflected in routine diagnostic CT scans, with two recent studies reporting CT sensitivities for pleural malignancy of 68% and 57% [29][30]. In a pilot study, Tsim and colleagues sought to develop a novel perfusionbased MRI biomarker for pleural malignancy that utilises the high spatial resolution provided by MRI; this technique was intended to target typical early features of the pleural tumour micro-environment, including neovascularisation and increases in constituent blood vessel density [31][32].…”