Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma

Abstract

Vascular endothelial growth factor (VEGF), a potent mitogen for vascular endothelium, is expressed in malignant pleural mesothelioma (MM). The present report examines the effect of VEGF on MM growth. Four MM cell lines produced significantly higher VEGF levels than normal mesothelial cells (1946+/-14 pg/ml vs. 180+/-17 pg/ml; p<0.001). In addition, MM cells expressed the tyrosine kinase-related VEGF receptors Flt-1 and KDR. Recombinant human VEGF phosphorylated both Flt-1 and KDR and increased proliferation of all four MM cell lines in a dose-dependent fashion. Neutralizing antibodies against either VEGF, Flt-1 or KDR significantly reduced MM cellular proliferation. In addition, expression of VEGF, Flt-1, and KDR was observed in MM biopsies. Moreover, higher VEGF levels were found in the pleural effusions of MM patients than in the effusions of patients with non-malignant pleural disease (1885.7+/-894.9 pg/ml vs. 266.9+/-180.5 pg/ml; p<0.001). Linear regression analysis showed a significant inverse correlation between serum VEGF levels and MM patient survival (r=0.72; p<0.01). No correlation was found between tumour vessel density and either serum (r=0.26; p=0.42) or pleural effusion (r=0.35; p=0.26) VEGF levels. These results indicate that VEGF, via activation of its tyrosine kinase receptors, may be a key regulator of MM growth. In addition, VEGF production could have an impact on patient survival, not only by promoting tumour angiogenesis but also by directly stimulating tumour growth.

Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models

“…Vascular endothelial growth factor receptors are in most cases specifically expressed on vascular endothelial cells, but certain tumour cells also express VEGFR2 (Masood et al, 1997;Dias et al, 2000;Masood et al, 2001;Podar et al, 2001;Strizzi et al, 2001;Jackson et al, 2002;Nakopoulou et al, 2002). The expression of VEGFR2 by tumour cells may be a mechanism to become less dependent on VEGF signalling for tumour angiogenesis as well as to negatively regulate the VEGF expression (Hiratsuka et al, 1998;Kearney et al, 2002).…”

Role of genetic polymorphisms in tumour angiogenesis

“…VEGF stimulates proliferation, migration and tube formation of endothelial cells in vitro and regulates vascular permeability in vivo (Veikkola and Alitalo, 1999). VEGF expression correlates with angiogenesis and prognosis in several tumours including breast, lung and malignant mesothelioma (Toi et al, 2001;Strizzi et al, 2001). Several polymorphisms have been described within the promoter and 5'UTR of the VEGF gene, some of which (+405 C4G, 71154G4A and -2578C4A) correlate with VEGF production.…”

Downregulation of VEGF-C expression in lung and colon cancer cells decelerates tumor growth and inhibits metastasis via multiple mechanisms

“…It binds to Flt4/VEGF receptor 3 (VEGFR3), a receptor tyrosine kinase that is expressed in lymphatic endothelial cells (Joukov et al, 1996), certain non-endothelial cells such as osteoblasts (Orlandini et al, 2006) and many cancer cell types (Strizzi et al, 2001;Jackson et al, 2002;Su et al, 2006;Timoshenko et al, 2007). With significantly lower affinity VEGF-C interacts with VEGFR2, which is primarily involved in the induction of hemangiogenesis (Skobe et al, 1999;Shibuya and Claesson-Welsh, 2006) and coreceptors, including the neuropilin-2 expressed on veins and lymphatic vessels (Karkkainen et al, 2001;Karpanen et al, 2006;Xu et al, 2010).…”