Phosphorylated VEGFR2/KDR receptors are widely expressed in B-cell non-Hodgkin's lymphomas and correlate with hypoxia inducible factor activation

The expression of hypoxia inducible factors (HIF) 1 alpha and 2 alpha, of vascular endothelial growth factor (VEGF) and of the phosphorylated form of its receptor VEGFR2 (pVEGFR2/KDR) were investigated immunohistochemically in a series of 146 B-cell non-Hodgkin's lymphomas and 48 normal lymph nodes. These proteins were significantly up-regulated in neoplastic lymphocytes and a significantly higher expression of HIF1 alpha (p = 0.05), VEGF (p = 0.02) and pVEGFR2/KDR (p = 0.007) was recorded in diffuse large B-cell lymphomas (DLBCL) compared to follicular lymphomas (FL). A strong statistical association of pVEGFR2/KDR expression with high HIF1 alpha, HIF2 alpha and VEGF was noted in both DLBCL and FL. HIF1 alpha and HIF2 alpha were linked with VEGF expression but no association between HIF1 alpha and HIF2 alpha was noted. Vascular density was significantly higher in the lymphoma compared to normal tissue, but there was no association with any of the examined parameters. It is concluded that the VEGF/receptor pathway is active in more than half of NHLs and particularly in DLBCL. The intimate correlation of VEGF production with the presence of phosphorylated VEGF-receptors strongly supports the concept of an autocrine pathway. The strong association of HIF alpha s with the expression of VEGF and pVEGFR2/KDR found in the study provide strong evidence on the role of HIF alpha s in the activation of angiogenic and VEGF-autocrine pathways that may be critical therapeutic targets for HIF-inhibitors or other anti-angiogenic agents. Copyright (C) 2008 John Wiley & Sons, Ltd.