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.
Highlights
Despite therapeutic advances over the last decade, the diagnosis of glioblastoma, the most frequent and aggressive type of primary brain tumor, is associated with a median overall survival of 15-18 months and with a 5-year survival rate of less than 5% [1, 2]
Our findings suggested that the presence of Tie2-expressing monocytes/macrophages (TEMs) is associated with the development of an invasive glioma phenotype that is resistant to anti-vascular endothelial growth factor (VEGF) therapy
We reported that greater glioma invasion was associated with the 6-week schedule, as characterized by the presence of “satellitosis” or “secondary structures” involving tumor cell aggregations in perivascular regions and in Virchow-Robin spaces. These structures were identified because this animal glioma model does not display invasive features [25, 26]; the gliomas of human Fc region-treated animals were well delineated and exhibited no signs of invasion. We observed that this invasive glioma phenotype was present in animals that had been treated with the anti-VEGF antibody bevacizumab, as previously reported [12]
Summary
Despite therapeutic advances over the last decade, the diagnosis of glioblastoma, the most frequent and aggressive type of primary brain tumor, is associated with a median overall survival of 15-18 months and with a 5-year survival rate of less than 5% [1, 2]. On the basis of reports of response rates [4, 5], the U.S Food and Drug Administration approved in 2009 the use of bevacizumab, a human recombinant www.impactjournals.com/oncotarget monoclonal antibody against vascular endothelial growth factor (VEGF), for the treatment of recurrent glioblastoma. Additional anti-angiogenic monotherapies have been or are being tested in trials for patients with recurrent glioblastoma, such as the VEGF trap aflibercept, which is a recombinant fusion protein that inhibits both VEGF and placental growth factor, and the VEGF receptor (VEGFR) inhibitor cediranib. Current evidence from experimental and clinical studies suggests that glioblastomas can recur after these therapies [10, 11] as highly aggressive tumors characterized by enhanced invasiveness and resistance to all currently available therapies [9, 12,13,14,15,16]. The mechanisms underlying the development of this invasive phenotype are not fully understood
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