RESUMEN
BACKGROUND: Glioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, polarizes GAMs to an immunosuppressive phenotype, promoting tumor growth. Here, the role of MerTK inhibition in the glioblastoma microenvironment is investigated in vitro and in vivo. METHODS: Effects of MRX-2843 in glioblastoma microenvironment regulation were determined in vitro by cell viability, cytokine array, in vitro tube formation, Western blotting, and wound healing assays. A syngeneic GL261 orthotopic glioblastoma mouse model was used to evaluate the survival benefit of MRX-2843 treatment. Multiplex fluorescent immunohistochemistry was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs, and angiogenesis in murine brain tumor tissues. RESULTS: MRX-2843 inhibited cell growth and induced apoptosis in human glioblastoma cells and decreased protein expression of phosphorylated MerTK, AKT, and ERK, which are essential for cell survival signaling. Interleukin-8 and C-C motif chemokine ligand 2, the pro-glioma and pro-angiogenic cytokines, were decreased by MRX-2843. Decreased vascular formation and numbers of immunosuppressive (CD206+) GAMs were observed following MRX-2843 treatment in vivo, suggesting that in addition to alleviating immunosuppression, MRX-2843 also inhibits neoangiogenesis in the glioma microenvironment. These results were supported by a prolonged survival in the syngeneic mouse orthotopic GL261 glioblastoma model following MRX-2843 treatment. CONCLUSION: Our findings suggest that MRX-2843 has a therapeutic benefit via promoting GAM polarization away from immunosuppressive condition, inhibiting neoangiogenesis in the glioblastoma microenvironment and inducing tumor cell death.
RESUMEN
The World Health Organization recently updated its classification of central nervous system tumors, adding 8 entities, as well as defining new variants and morphologic patterns of existing entities. Despite the continued refinement of brain tumor histologic classification and grading, there remain some diagnostic "gray zones" that challenge general surgical pathologists and neuropathologists alike. These include the presence of oligodendroglial features in (mixed) oligoastrocytomas and glioblastomas (GBMs), GBM variants (such as small cell GBM), meningioma classification and grading, medulloblastoma variants, ependymoma grading, the presence of "neuronal features" in otherwise morphologically classic gliomas, and low-grade gliomas with high Ki-67 labeling indices. In the current review, we discuss these issues and offer some practical guidelines for dealing with problematic cases.