Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies

Malignant gliomas are the most common primary brain tumors. Their deadliest manifestation, glioblastoma multiforme (GBM), accounts for 15% of all primary brain tumors and is associated with a median survival of only 15 months even after multimodal therapy. There is substantial presence of microglia and macrophages within and surrounding brain tumors. These immune cells acquire an alternatively activated phenotype with potent tumor-tropic functions that contribute to glioma growth and invasion. In this review, we briefly summarize recent data that has been reported on the interaction of microglia/macrophages with brain tumors and discuss potential application of these findings to the development of future antiglioma therapies.

[1]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[2]  A. Wesołowska,et al.  Microglia-derived TGF-β as an important regulator of glioblastoma invasion—an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor , 2008, Oncogene.

[3]  Hyun B Choi,et al.  ATP stimulates chemokine production via a store-operated calcium entry pathway in C6 glioma cells , 2009, BMC Cancer.

[4]  H. Mehdorn,et al.  CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). , 2010, Experimental cell research.

[5]  C. Chiang,et al.  Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model , 2012, Laboratory Investigation.

[6]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[7]  Wei Liu,et al.  Carbon Nanotubes Enhance CpG Uptake and Potentiate Antiglioma Immunity , 2010, Clinical Cancer Research.

[8]  B. Kamińska,et al.  Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental Gliomas , 2011, PloS one.

[9]  Baohui Xu,et al.  Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β , 2009, Cancer Immunology, Immunotherapy.

[10]  B. Badie,et al.  Selective uptake of multi-walled carbon nanotubes by tumor macrophages in a murine glioma model , 2009, Journal of Neuroimmunology.

[11]  K. Stocka,et al.  Gliomas induce and exploit microglial MT 1-MMP expression for tumor expansion , 2009 .

[12]  W. Marsden.  I and J , 2012 .

[13]  Yukio Fujiwara,et al.  Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3. , 2011, Oncology reports.

[14]  S. Kahn,et al.  Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells , 2012, Neuroscience.

[15]  F. Heppner,et al.  Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion , 2009, Proceedings of the National Academy of Sciences.

[16]  Mei-Jan Wang,et al.  Enhanced anti-glioblastoma activity of microglia by AAV2-mediated IL-12 through TRAIL and phagocytosis in vitro. , 2011, Oncology reports.

[17]  R. P. Landry,et al.  Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. , 2012, Neuro-oncology.

[18]  Michael Lim,et al.  Mechanisms of local immunoresistance in glioma. , 2010, Neurosurgery clinics of North America.

[19]  Hua Yu,et al.  Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice , 2009, Glia.

[20]  B. Badie,et al.  In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor. , 1999, Neurosurgery.

[21]  Peng Zhang,et al.  Tumor-Associated Microglia/Macrophages Enhance the Invasion of Glioma Stem-like Cells via TGF-β1 Signaling Pathway , 2012, The Journal of Immunology.

[22]  Allen Waziri,et al.  Dynamics of central and peripheral immunomodulation in a murine glioma model , 2009, BMC Immunology.

[23]  V. Jacobs,et al.  Propentofylline Targets TROY, a Novel Microglial Signaling Pathway , 2012, PloS one.

[24]  Wei Liu,et al.  S100B attenuates microglia activation in gliomas: Possible role of STAT3 pathway , 2011, Glia.

[25]  M. Preul,et al.  Monocyte-derived cells of the brain and malignant gliomas: the double face of Janus. , 2014, World neurosurgery.

[26]  K. Toyka,et al.  In situ detection of transforming growth factor-β mRNA in experimental rat glioma and reactive glial cells , 1994, Neuroscience Letters.

[27]  B. Badie,et al.  Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[28]  Erwin G. Van Meir,et al.  Human astrocytomas and glioblastomas express monocyte chemoattractant protein‐1 (MCP‐1) in vivo and in vitro , 1994, International journal of cancer.

[29]  C. Kruchko,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. , 2012, Neuro-oncology.

[30]  T. Song,et al.  S-Adenosylhomocysteine promotes the invasion of C6 glioma cells via increased secretion of matrix metalloproteinase-2 in murine microglial BV2 cells. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[32]  L. Bodea,et al.  Siglec‐h on activated microglia for recognition and engulfment of glioma cells , 2013, Glia.

[33]  B. Badie,et al.  S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages , 2013, Clinical Cancer Research.

[34]  Hua Yu,et al.  STATs in cancer inflammation and immunity: a leading role for STAT3 , 2009, Nature Reviews Cancer.

[35]  Yukio Fujiwara,et al.  Corosolic acid inhibits glioblastoma cell proliferation by suppressing the activation of signal transducer and activator of transcription‐3 and nuclear factor‐kappa B in tumor cells and tumor‐associated macrophages , 2011, Cancer science.

[36]  K. Hynynen,et al.  Chemotherapy delivery issues in central nervous system malignancy: a reality check. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  Fei Li,et al.  Glioma-initiating cells: A predominant role in microglia/macrophages tropism to glioma , 2011, Journal of Neuroimmunology.

[38]  Luciana Romão,et al.  Glioblastoma: therapeutic challenges, what lies ahead. , 2012, Biochimica et biophysica acta.

[39]  岡田 誠.  Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1 , 2009 .

[40]  H. Vogel,et al.  Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. , 2010, The Journal of clinical investigation.

[41]  Fabian Kiessling,et al.  Flt-1 signaling in macrophages promotes glioma growth in vivo. , 2008, Cancer research.

[42]  H. Kettenmann,et al.  Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression , 2011, Brain, Behavior, and Immunity.

[43]  M. Delville,et al.  In vivo MR tracking of therapeutic microglia to a human glioma model , 2011, NMR in biomedicine.

[44]  Nicole S. Bryce,et al.  p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells , 2012, Journal of Neuro-Oncology.

[45]  Yao Lu,et al.  In silico Experimentation of Glioma Microenvironment Development and Anti-tumor Therapy , 2012, PLoS Comput. Biol..

[46]  Steen J. Madsen,et al.  Photothermal treatment of glioma; an in vitro study of macrophage-mediated delivery of gold nanoshells , 2011, Journal of Neuro-Oncology.

[47]  A. Heimberger,et al.  Glioma cancer stem cells induce immunosuppressive macrophages/microglia. , 2010, Neuro-oncology.

[48]  Jin He,et al.  Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma , 2009, Clinical Cancer Research.

[49]  J. Segall,et al.  Microglial Stimulation of Glioblastoma Invasion Involves Epidermal Growth Factor Receptor (EGFR) and Colony Stimulating Factor 1 Receptor (CSF-1R) Signaling , 2012, Molecular medicine.

[50]  Aaas News,et al.  Book Reviews , 1893, Buffalo Medical and Surgical Journal.

[51]  H. Okada,et al.  Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy , 2011, Journal of Neuro-Oncology.

[52]  H. Kettenmann,et al.  An α5β1 integrin inhibitor attenuates glioma growth , 2008, Molecular and Cellular Neuroscience.

[53]  A. Gregory Sorensen,et al.  Angiogenesis in brain tumours , 2007, Nature Reviews Neuroscience.

[54]  Yan Zhou,et al.  A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. , 2012, Carcinogenesis.

[55]  A. Wesołowska,et al.  Microglia-derived TGF-beta as an important regulator of glioblastoma invasion--an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. , 2008, Oncogene.

[56]  B. Badie,et al.  Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. , 2000, Neurosurgery.

[57]  J. Kuratsu,et al.  Possible involvement of the M2 anti‐inflammatory macrophage phenotype in growth of human gliomas , 2008, The Journal of pathology.

[58]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. , 2013, Neuro-oncology.

[59]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[60]  A. Ernst,et al.  Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation. , 2012, Neuro-oncology.

[61]  Isaac Yang,et al.  The role of microglia in central nervous system immunity and glioma immunology , 2010, Journal of Clinical Neuroscience.

[62]  Helmut Kettenmann,et al.  The brain tumor microenvironment , 2011, Glia.