TY - JOUR
T1 - Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes
AU - Gabrusiewicz, Konrad
AU - Liu, Dan
AU - Cortes-Santiago, Nahir
AU - Hossain, Mohammad B.
AU - Conrad, Charles A.
AU - Aldape, Kenneth D.
AU - Fuller, Gregory N.
AU - Marini, Frank C.
AU - Alonso, Marta M.
AU - Idoate, Miguel Angel
AU - Gilbert, Mark R.
AU - Fueyo, Juan
AU - Gomez-Manzano, Candelaria
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Antiangiogenesis
KW - Brain tumors
KW - Monocyte
KW - Tie2
KW - Tumor microenvironment
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UR - http://www.scopus.com/inward/citedby.url?scp=84899554487&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.1893
DO - 10.18632/oncotarget.1893
M3 - Article
C2 - 24809734
AN - SCOPUS:84899554487
SN - 1949-2553
VL - 5
SP - 2208
EP - 2220
JO - Oncotarget
JF - Oncotarget
IS - 8
ER -