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      Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

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          Abstract

          Characterized by a dismal survival rate and limited response to therapy, glioblastoma (GBM) remains one of the most aggressive human malignancies. Recent studies of the role of tumor-associated macrophages (TAMs) in the progression of GBMs have demonstrated that TAMs are significant contributors to tumor growth, invasion, and therapeutic resistance. TAMs, which include brain-resident microglia and circulating bone marrow derived-monocytes (BMDMs), are typically grouped together in histopathological and molecular analyses due to the lack of reliable markers of distinction. To develop more effective therapies aimed at specific TAM populations, we must first understand how these cells differ both morphologically and behaviorally. Furthermore, we must develop a deeper understanding of the mechanisms encouraging their infiltration and how these mechanisms can be therapeutically exploited. In this study, we combined immunocompetent lineage tracing mouse models of GBM with high-resolution open-skull 2-photon microscopy to investigate the phenotypical and functional characteristics of TAMs. We demonstrate that TAMs are composed of 2 morphologically distinct cell types that have differential migratory propensities. We show that BMDMs are smaller, minimally branched cells that are highly migratory compared with microglia, which are larger, highly branched stationary cells. In addition, 2 populations of monocytic macrophages were observed that differed in terms of CX3CR1 expression and migratory capacity. Finally, we demonstrate the efficacy of anti-vascular endothelial growth factor A blockade for prohibiting TAM infiltration, especially against BMDMs. Taken together, our data clearly define characteristics of individual TAM populations and suggest that combination therapy with antivascular and antichemotaxis therapy may be an attractive option for treating these tumors.

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          Most cited references35

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          Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

          Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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            Control of microglial neurotoxicity by the fractalkine receptor.

            Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
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              Brain tumour cells interconnect to a functional and resistant network.

              Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proc Natl Acad Sci USA
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                June 24 2019
                : 201902366
                Article
                10.1073/pnas.1902366116
                6628659
                31235603
                8da2c8ad-12b3-49d7-bd05-d165effe9714
                © 2019

                Free to read

                https://www.pnas.org/site/aboutpnas/licenses.xhtml

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