Increased Glioma Growth in Mice Depleted of Macrophages

Galarneau, Hugo; Villeneuve, Jérôme; Gowing, Genevíève; Julien, Jean‐Pierre; Vallières, Luc

doi:10.1158/0008-5472.can-07-0177

Cited by 105 publications

(93 citation statements)

References 27 publications

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“…In a glioma model similar to our CD11b-HSVTK model (also using GL261 cells), it previously was suggested that microglia are anti-tumorigenic and that microglia depletion can promote tumor growth (28). However, these findings are based on systemic ganciclovir administration upon bone marrow transplantation including irradiation.…”

Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Simentioning

confidence: 86%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).Microglia are the intrinsic immune cells of the brain; they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Simentioning

confidence: 86%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

341

328

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“…The ganciclovir treatment led to a considerable depletion of microglia and to an 80% reduction in glioma volume (Markovic et al, 2009). Using the similar mouse model, Galarneau et al (2007) injected ganciclovir i.p. twice daily for 6 days starting 7 days after tumor implantation.…”

Section: Microglia Promote Glioma Migration and Tumor Growthmentioning

confidence: 99%

The brain tumor microenvironment

Charles

Holland

Gilbertson

et al. 2011

Glia

687

327

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High-grade brain tumors are heterogeneous with respect to the composition of bona fide tumor cells and with respect to a range of intermingling parenchymal cells. Glioblastomas harbor multiple cell types, some with increased tumorigenicity and stem cell-like capacity. The stem-like cells may be the cells of origin for tumor relapse. However, the tumor-associated parenchymal cells such as vascular cells, microglia, peripheral immune cells, and neural precursor cells also play a vital role in controlling the course of pathology. In this review, we describe the multiple interactions of bulk glioma cells and glioma stem cells with parenchymal cell populations and highlight the pathological impact as well as signaling pathways known for these types of cell-cell communication. The tumor-vasculature not only nourishes glioblastomas, but also provides a specialized niche for these stem-like cells. In addition, microglial cells, which can contribute up to 30% of a brain tumor mass, play a role in glioblastoma cell invasion. Moreover, non-neoplastic astrocytes can be converted into a reactive phenotype by the glioma microenvironment and can then secrete a number of factors which influences tumor biology. The young brain may have the capacity to inhibit gliomagenesis by the endogenous neural precursor cells, which secrete tumor suppressive factors. The factors, pathways, and interactions described in this review provide a new prospective on the cell biology of primary brain tumors, which may ultimately generate new treatment modalities. However, our picture of the multiple interactions between parenchymal and tumor cells is still incomplete. V

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“…The CD11b-TK mut-30 model has previously been used to determine the role of proliferating microglia in several mouse models of CNS disease, including cerebral ischemia, gliomas, Alzheimer's disease, CNS viral infection, and axonal regeneration (Carmen et al, 2006;Simard et al, 2006;Galarneau et al, 2007;Lalancette-Hébert et al, 2007;Barette et al, 2008). In all of these paradigms, the selective ablation of proliferating microglia was deleterious.…”

Section: Introductionmentioning

confidence: 99%