Targeting VEGF with bevacizumab inhibits malignant effusion formation of primary human herpesvirus 8‐unrelated effusion large B‐cell lymphoma in vivo

Primary human herpesvirus 8 (HHV8)‐unrelated effusion large B‐cell lymphoma (ELBCL) is recognized as a new clinical entity, but its pathogenesis and therapeutic strategies remain largely unknown. We have generated two mouse models with profuse lymphomatous effusions that resemble HHV8‐unrelated ELBCL occurring in humans, by grafting the cell lines designated as Pell‐1 and Pell‐2. Using these in vivo models, we evaluated the potential role of vascular endothelial growth factor (VEGF) in the pathogenesis of HHV8‐unrelated ELBCL. Both Pell‐1 and Pell‐2 cells consistently produced very high levels of VEGF in mice, in contrast to in vitro findings of relatively low VEGF production in culture medium by HHV8‐unrelated ELBCL cells, especially Pell‐1 cells. Conversely, returning Pell‐1 cells grown in mice to culture medium markedly suppressed VEGF production to the original in vitro level. These findings suggest that the tumour microenvironment plays a role in the steady production of VEGF. We also found that the interaction between HHV8‐unrelated ELBCL cells and peritoneal mesothelial cells increased the production of VEGF in vitro. Finally, we found that bevacizumab significantly suppressed effusion formation and lymphoma cell growth in both mouse models. These results suggest that bevacizumab is a rational approach to the treatment of HHV8‐unrelated ELBCL.