Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes

// Konrad Gabrusiewicz 1,* , Dan Liu 1,* , Nahir Cortes-Santiago 1,* , Mohammad B. Hossain 1 , Charles A. Conrad 1 , Kenneth D. Aldape 2 , Gregory N. Fuller 2 , Frank C. Marini 3 , Marta M. Alonso 4 , Miguel Angel Idoate 5 , Mark R. Gilbert 1 , Juan Fueyo 1 , and Candelaria Gomez-Manzano 1,6 1 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Institute of Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina, USA 4 Department of Medical Oncology, University Hospital of Navarra, Pamplona, Spain 5 Department of Pathology, University Hospital of Navarra, Pamplona, Spain 6 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * contributed equally to the work Correspondence: Candelaria Gomez-Manzano, email: // Keywords : Brain tumors, antiangiogenesis, Tie2, tumor microenvironment, monocyte Received : January 6, 2014 Accepted : April 11, 2014 Published : April 11, 2014 Abstract The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2 + MMP9 + monocytic cells were consistently detected in the invasive tumor edge upon anti-VEGF therapies. Our results suggest the presence of a specific myeloid/monocytic subpopulation that plays a pivotal role in the mechanism of escape of malignant gliomas from anti-VEGF therapies and therefore constitutes a new cellular target for combination therapies in patients selected for anti-angiogenesis treatment.