Fol. Biol. 2013, 59, 26-31

https://doi.org/10.14712/fb2013059010026

In Vivo Growth of Mantle Cell Lymphoma Xenografts in Immunodeficient Mice Is Positively Regulated by VEGF and Associated with Significant Up-regulation of CD31/PECAM1

Jan Molinský1,2, M. Klánová1,2, B. Maswabi2, T. Soukup3, M. Trněný1,4, E. Nečas2, J. Živný2, P. Klener1,2

11st Department of Medicine – Department of Haematology, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
2Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
3Department of Histology and Embryology, Medical Faculty in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic
4Institute of Haematology and Blood Transfusion, Prague, Czech Republic

Received October 2012
Accepted October 2012

Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with dismal prognosis. New treatments are needed to improve outcome of relapsed/refractory disease. Recently, several drugs targeting at least partially the process of angiogenesis have been successfully tested in the therapy of MCL. Molecular mechanisms that regulate MCL-induced angiogenesis and that might represent potential new druggable targets remain, however, incompletely understood. We established two mouse models of human MCL by subcutaneous xenotransplantation of JEKO-1 and HBL-2 cell lines into immunodeficient mice. Histological analyses of xenografts confirmed their neovascularization. The growth of xenografts was significantly suppressed by single-agent therapy with bevacizumab, monoclonal antibody targeting vascular endothelial growth factor (VEGF). Subsequently, we analysed expression of 94 angiogenesis-related genes in ex vivo isolated JEKO-1 and HBL-2 cells compared to in vitro growing cells using TaqMan low-density arrays. The most up-regulated genes in both JEKO-1 and HBL-2 xenografts were genes encoding platelet/endothelial cell-adhesion molecule (CD31/PECAM1), VEGF receptor 1 (FLT1), hepatocyte growth factor (HGF), angiogenin (ANG) and transcription factor PROX1. The most downregulated genes in both JEKO-1 and HBL-2 xenografts were midkine (MDK) and ephrine B2 (EPHB2). In summary, our results demonstrate an important role of angiogenesis in the biology of MCL and provide preclinical evidence of potent anti-MCL activity of bevacizumab. In addition, gene expression profiling of 94 angiogenesis-related targets revealed several in vivo up-regulated and down-regulated transcripts. The most differentially expressed target in both MCL tumours was CD31/PECAM1. Whether any of these molecules might represent a potential druggable target in MCL patients remains to be elucidated.

Funding

This work was supported by grants from the grant Agency of Charles University in Prague GAUK 259211/110709 and UNCE 204021, PRVOUK P24/LF1/3.

References

28 live references