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BACKGROUND: The addition of anti-angiogenic therapy to the few treatments that are available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on findings from initial preclinical and clinical studies which showed encouraging results. However, tumors that initially respond to this therapy invariably recur with the acquisition of highly aggressive and invasive phenotype. Although several myeloid populations have been associated to the recurrence of these tumors, a specific targetable population has not been yet identified as responsible for the heightened invasion observed upon antiangiogenesis therapies. METHODS: Immunocompromised mice and immunocompetent GFP macrophage Fas-induced apoptosis (MAFIA) transgenic mice were used to model the response of malignant gliomas to several antiangiogenesis therapies, such as bevacizumab, VEGF Trap, DC101, and to temozolomide. Analysis of tumors and monocytic populations were performed by immunohistochemistry and double immunofluorescence. In vitro studies encompass the use of isolated monocytes from donors and a novel experimental model based on a THP1 human monocytic cell line. Data was corroborated in surgical specimens from human malignant gliomas RESULTS: Here we present evidence for the accumulation of Tie2-expressing cells at the tumor/normal brain interface of immunocompromised mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. This cell population was further characterized as having markers of M2 polarized monocytes/macrophages compatible with Tie2-expressing monocytes (TEMs). We validated these results using the immunocompetent MAFIA transgenic mice treated with an anti-VEGFR compound. In contrast, TEMs were almost undetectable in the brains of glioma-bearing mice treated with temozolomide or anti-VEGF therapies that did not result in an invasive tumoral pattern. In vitro studies showed that TEMs enhanced the invasive properties of glioma cells compared with monocytes that did not express Tie2 (non-TEMs). Moreover, TEMs displayed a higher gelatinase enzymatic activity and, specifically, secreted higher levels of MMP2 and MMP9 than non-TEMs did. Consistently Tie2/MMP9 monocytic cells were detected in the invasive tumoral edge of mice treated with anti-VEGF therapies. Of clinical relevance, we detected the presence of TEMs in human surgical specimens after anti-VEGF therapy. CONCLUSIONS: Collectively, our results described the association of a specific myeloid/monocytic subpopulation characterized as Tie2-expressing monocytes with the heightened invasion observed after antiangiogenic therapy. Our results suggest that his distinctive population might explain the mechanism of escape of malignant gliomas to anti-angiogenesis therapies. Therefore, combination of antiangiogenesis therapies with approaches to decrease the tumor recruitment of TEMs might be required to obtain a therapeutic effect. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.

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