Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors (original) (raw)

Microglia-glioma cross-talk: a two way approach to new strategies against glioma

Frontiers in bioscience (Landmark edition), 2017

Glioblastoma (GBM) is the most malignant and aggressive among primary brain tumors, characterized by very low life expectancy. In vivo, glioma and glioblastoma in particular contain large numbers of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages (or glioma associated macrophages). These glioma-infiltrating myeloid cells comprise up to 30% of total tumor mass and have been suggested to play several roles in glioma progression including proliferation, survival, motility and immunosuppression. Although tumor microglia and macrophages can acquire proinflammatory (M1) phenotype being capable of releasing proinflammatory cytokines, phagocytosing and presenting antigens, their effector immune function in gliomas appears to be suppressed by the acquisition of an anti-inflammatory (M2) phenotype. In the present work we review the microglia-glioma interactions to highlight the close relationship between the two cell types and the factors that can influence ...

Microglial action in glioma: A boon turns bane

Immunology letters, 2010

Microglia has the potential to shape the neuroimmune defense with vast array of functional attributes. The cells prime infiltrated lymphocytes to retain their effector functions, play crucial role in controlling microenvironmental milieu and significantly participate in glioma. Reports demonstrate microglial accumulation in glioma and predict their assistance in glioma growth and spreading. Clarification of the 'double-edged' appearance of microglia is necessary to unfold its role in glioma biology. In this article the interpretation of microglial activities has been attempted to reveal their actual function in glioma. Contrary to the trendy acceptance of its glioma promoting infamy accumulated evidences make an effort to view the state of affairs in favor of the cell. Critical scrutiny indicates that microglial immune assaults are intended to demolish the neoplastic cells in brain. But the weaponry of microglia has been tactically utilized by glioma in their favor as the survival strategy. Hence the defender appears as enemy in advanced glioma.

Astrocytes, the rising stars of the glioblastoma microenvironment

Glia, 2018

Glioblastoma (GBM) is an aggressive primary tumor, causing thousands of deaths worldwide every year. The mean survival of patients with GBM remains below 15 months despite current available therapies. GBM cells' interactions with their stromal counterparts are crucial for tumor development. Astrocytes are glial cells that comprise approximately 50% of all brain cells and are therefore likely to establish direct contact with GBM cells. As other tumor cell types can hijack fibroblasts or immune cells to facilitate tumor growth, GBM cells can actually activate astrocytes, namely the tumor associated astrocytes (TAAs), to promote GBM invasion in the healthy tissue. TAAs have thus been shown to be involved in GBM cells growth and limited response to radiation or chemotherapy (i.e. Temozolomide). Nevertheless, even though the interest in the cancer research community is increasing, the role of TAAs during GBM development is still overlooked. Yet, obtaining an in-depth understanding of the mechanisms by which TAAs influence GBM progression might lead to the development of new therapeutic strategies. The current review therefore reports the different levels of GBM progression at which TAAs have been recently described to be involved in, including tumor cells' proliferation/invasion and resistance to therapies, especially through the activity of extracellular vesicles.

Review: Molecular mechanism of microglia stimulated glioblastoma invasion

Matrix Biology, 2013

Glioblastoma multiforme is one of the deadliest human cancers and is characterized by a high degree of microglia and macrophage infiltration. The role of these glioma infiltrating macrophages (GIMs) in disease progression has been the subject of recent investigation. While initially thought to reflect an immune response to the tumor, the balance of evidence clearly suggests GIMs can have potent tumor-tropic functions and assist in glioma cell growth and infiltration into normal brain. In this review, we focus on the evidence for GIMs aiding mediating glioblastoma motility and invasion. We survey the literature for molecular pathways that are involved in paracrine interaction between glioma cells and GIMs and assess which of these might serve as attractive targets for therapeutic intervention.

Microglia and astrocyte involvement in neurodegeneration and brain cancer

Journal of Neuroinflammation, 2021

The brain is unique and the most complex organ of the body, containing neurons and several types of glial cells of different origins and properties that protect and ensure normal brain structure and function. Neurological disorders are the result of a failure of the nervous system multifaceted cellular networks. Although great progress has been made in the understanding of glia involvement in neuropathology, therapeutic outcomes are still not satisfactory. Here, we discuss recent perspectives on the role of microglia and astrocytes in neurological disorders, including the two most common neurodegenerative conditions, Alzheimer disease and progranulin-related frontotemporal lobar dementia, as well as astrocytoma brain tumors. We emphasize key factors of microglia and astrocytic biology such as the highly heterogeneic glial nature strongly dependent on the environment, genetic factors that predispose to certain pathologies and glia senescence that inevitably changes the CNS landscape....

Molecular definition of the pro-tumorigenic phenotype of glioma-activated microglia

Glia, 2013

Microglia are myeloid cells residing in the central nervous system that participate in inflammatory responses and could promote injury and repair. Gliomas attract microglia and polarize them into tumor-supporting cells that participate in matrix remodeling, invasion, angiogenesis, and suppression of adaptive immunity. Although signaling pathways and critical regulators underlying classical inflammation are well established, signal transduction and transcriptional circuits underlying the alternative activation of microglia are poorly known. Using primary rat microglial cultures exposed to glioma conditioned medium or lipopolysaccharide (LPS), we demonstrate that microglia adapt different fates and polarize into pro-inflammatory or alternatively activated cells. Glioma-derived factors increased cell motility, phagocytosis, and sustained proliferation of microglial cells that was mediated by enhanced focal adhesion kinase and PI-3K/Akt signaling. The signals from glioma cells induced ERK and p38 MAPK but not JNK signaling and failed to activate pro-inflammatory Stat1 and NFjB signaling in microglial cells. Transcriptome analysis of microglial cultures at 6 h after exposure to glioma-conditioned medium or LPS revealed different patterns of gene expression. Glioma-induced activation was associated with induction of genes coding for ID (inhibitor of DNA binding) 1/3 and c-Myc, markers of the alternative phenotype Arg1, MT1-MMP, CXCL14, and numerous cytokines/chemokines implicated in immune cell trafficking. Many classical inflammation-related genes and signaling pathways failed to be induced. Our study indicates for the first time molecular pathways that direct microglia toward the pro-invasive, immunosuppressive phenotype.

The role of microglia and macrophages in glioma maintenance and progression

Nature neuroscience, 2015

There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.

GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis

Acta neuropathologica, 2013

High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. To identify factors that mediate the attraction of microglia/macrophages to malignant brain tumors, we established a glioma cell encapsulation model that was applied in vivo. Mouse GL261 glioma cell line and human high-grade glioma cells were seeded into hollow fibers (HF) that allow the passage of soluble molecules but not cells. The glioma cell containing HF were implanted into one brain hemisphere and simultaneously HF with non-transformed fibroblasts (controls) were introduced into the contralateral hemisphere. Implanted mouse and human glioma- but not fibroblast-containing HF attracted microglia and up-regulated immunoreactivity for GFAP, which is a marker of astrogliosis. In this study, we identified GDNF as an important factor for microglial attraction: (1) GL261 and human glioma cells secret GDNF, (2) reduced GDNF production by siRNA in GL261 in mouse glioma cells diminished attraction of microglia, (3) over-expression of GDNF in fibroblasts promoted microglia attraction in our HF assay. In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells.

The neuropathological basis to the functional role of microglia/macrophages in gliomas

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2017

The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas th...