Abstract
Malignant gliomas are primary brain tumors with poor prognoses. These tumors are infiltrated by brain intrinsic microglia and peripheral monocytes which promote glioma cell invasion. In our previous studies, we discovered that the activation of Toll-like receptor 2 (TLR2) on microglia/brain macrophages converts them into a protumorigenic phenotype through the induction of matrix metalloproteinases (MMP) 9 and 14. In the present study, we used in vitro and in situ microglia-glioma interaction experimental models to test the impact of a novel inhibitor of TLR 2, ortho vanillin (O-Vanillin) to block TLR2 mediated microglia protumorigenic phenotype. We demonstrate that O-Vanillin inhibits the TLR2 mediated upregulation of MMP 9, MMP 14, IL 6 and iNOS expression. Similarly, the glioma supernatant induced MMP 9 and MMP 14 expression in murine and human microglia is abrogated by O-Vanillin treatment. O-Vanillin is not toxic for microglia, astrocytes or oligodendrocytes. Glioma growth in murine brain slice cultures is significantly reduced after treatment with O-Vanillin, and this reduced glioma growth depends on the presence of microglia. In addition, we also found that O-Vanillin inhibited the glioma induced proliferation of murine primary microglia. In summary, O-Vanillin attenuates the pro-tumorigenic phenotype of microglia/brain macrophages and thus qualifies as a candidate for glioma therapy.
Highlights
Primary malignant brain tumors remain a devastating tumor entity characterized by poor prognoses despite extensive research and gains in knowledge concerning its genesis and progression [1]
We discovered that the activation of Toll-like receptor 2 (TLR2) on microglia/brain macrophages converts them into a protumorigenic phenotype through the induction of matrix metalloproteinases (MMP) 9 and 14
We demonstrate that O-Vanillin inhibits the TLR2 mediated upregulation of MMP 9, MMP 14, IL 6 and iNOS expression
Summary
Primary malignant brain tumors remain a devastating tumor entity characterized by poor prognoses despite extensive research and gains in knowledge concerning its genesis and progression [1]. Glioma induces the polarization of glioma associated microglia/macrophages (GAMs) into a glioma-supporting phenotype through complex interactions involving several signaling mechanisms [3]. While microglia in the healthy brain do not express MMP14, it is upregulated in glioma associated GAMs. While microglia in the healthy brain do not express MMP14, it is upregulated in glioma associated GAMs This upregulation is induced by versican released from glioma cells which signals via toll like receptor 2 (TLR2). This interaction between glioma and GAMs is an important contributor to microglia/macrophage-induced glioma invasiveness und progression [5,6]. We tested whether O-Vanillin can be used to inhibit glioma-induced TLR2 signaling in murine microglia. O-Vanillin attenuated the growth of gliomas injected into murine brain slice cultures and this effect was dependent on the presence of microglia
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