Abstract
Brain tumors are complex cellular ecosystems, composed of populations of both neoplastic and non-neoplastic cell types. While the contributions of the cancer cells in low-grade and high-grade gliomas have been extensively studied, there is comparatively less known about the contributions of the non-neoplastic cells in these tumors. As such, a large proportion of the non-neoplastic cells in gliomas are resident brain microglia, infiltrating circulating macrophages, and T lymphocytes. These immune system-like stromal cells are recruited into the evolving tumor through the elaboration of chemokines, and are reprogrammed to adopt new cellular identities critical for glioma formation, maintenance, and progression. In this manner, these populations of tumor-associated microglia and macrophages produce growth factors that support gliomagenesis and continued tumor growth. As we begin to characterize these immune cell contributions, future therapies might emerge as adjuvant approaches to glioma treatment.
Biological diversity is the key to the maintenance of the world as we know it. Life in a local site struck down by a passing storm springs back quickly: opportunistic species rush in to fill the spaces. They entrain the succession that circles back to something resembling the original state of the environment.
Edward O. Wilson
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References
Masui K, Cavenee WK, Mischel PS (2016) Cancer metabolism as a central driving force of glioma pathogenesis. Brain Tumor Pathol 33(3):161–168
Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5):510–522
Ozawa T, Riester M, Cheng YK, Huse JT, Squatrito M, Helmy K et al (2014) Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell 26(2):288–300
Buhl JL, Selt F, Hielscher T, Guiho R, Ecker J, Sahm F et al (2019) The senescence-associated secretory phenotype mediates oncogene-induced senescence in pediatric pilocytic astrocytoma. Clin Cancer Res 25(6):1851–1866
Han Y, Mu Y, Li X, Xu P, Tong J, Liu Z et al (2011) Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28. Hum Mol Genet 20(16):3213–3226
Larribere L, Wu H, Novak D, Galach M, Bernhardt M, Orouji E et al (2015) NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model. Pigment Cell Melanoma Res 28(4):407–416
Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, Nikkhah G et al (2011) BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res 17(11):3590–3599
Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR, Gutmann DH (2003) Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 63(24):8573–8577
Bajenaru ML, Zhu Y, Hedrick NM, Donahoe J, Parada LF, Gutmann DH (2002) Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol 22(14):5100–5113
Chen R, Keoni C, Waker CA, Lober RM, Chen YH, Gutmann DH (2019) KIAA1549-BRAF expression establishes a permissive tumor microenvironment through NFkappaB-mediated CCL2 production. Neoplasia 21(1):52–60
Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH (2012) Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 26(23):2561–2566
Kaul A, Chen YH, Emnett RJ, Gianino SM, Gutmann DH (2013) Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects. Genesis 51(10):708–716
Lee DY, Gianino SM, Gutmann DH (2012) Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 22(1):131–138
Lee DY, Yeh TH, Emnett RJ, White CR, Gutmann DH (2010) Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev 24(20):2317–2329
Ozawa PM, Ariza CB, Ishibashi CM, Fujita TC, Banin-Hirata BK, Oda JM, Watanabe MA (2016) Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma. Int J Cancer 138(1):10–13
Wick W, Platten M, Wick A, Hertenstein A, Radbruch A, Bendszus M, Winkler F (2016) Current status and future directions of anti-angiogenic therapy for gliomas. Neuro-Oncology 18(3):315–328
Simmons GW, Pong WW, Emnett RJ, White CR, Gianino SM, Rodriguez FJ, Gutmann DH (2011) Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol 70(1):51–62
Hammond TR, Robinton D, Stevens B (2018) Microglia and the brain: complementary partners in development and disease. Annu Rev Cell Dev Biol 34:523–544
Li Q, Barres BA (2018) Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18(4):225–242
Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19(1):20–27
Salter MW, Stevens B (2017) Microglia emerge as central players in brain disease. Nat Med 23(9):1018–1027
Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D et al (2016) CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 76(19):5671–5682
Chen Z, Feng X, Herting CJ, Garcia VA, Nie K, Pong WW et al (2017) Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res 77(9):2266–2278
Pong WW, Higer SB, Gianino SM, Emnett RJ, Gutmann DH (2013) Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol 73(2):303–308
Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19(10):1264–1272
Guo X, Pan Y, Gutmann DH (2019) Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia. Neuro-Oncology 21(10):1250–1262
Pan Y, Xiong M, Chen R, Ma Y, Corman C, Maricos M et al (2018) Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. Genes Dev 32(7–8):491–496
Feng X, Szulzewsky F, Yerevanian A, Chen Z, Heinzmann D, Rasmussen RD et al (2015) Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis. Oncotarget 6(17):15077–15094
Platten M, Kretz A, Naumann U, Aulwurm S, Egashira K, Isenmann S, Weller M (2003) Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 54(3):388–392
Amankulor NM, Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M et al (2017) Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes Dev 31(8):774–786
Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L et al (2017) Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 32(1):42–56.e46
Wood MD, Mukherjee J, Pieper RO (2018) Neurofibromin knockdown in glioma cell lines is associated with changes in cytokine and chemokine secretion in vitro. Sci Rep 8(1):5805
Bowman RL, Klemm F, Akkari L, Pyonteck SM, Sevenich L, Quail DF et al (2016) Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep 17(9):2445–2459
Hu F, Dzaye O, Hahn A, Yu Y, Scavetta RJ, Dittmar G et al (2015) Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling. Neuro-Oncology 17(2):200–210
Miyauchi JT, Caponegro MD, Chen D, Choi MK, Li M, Tsirka SE (2018) Deletion of Neuropilin 1 from microglia or bone marrow-derived macrophages slows glioma progression. Cancer Res 78(3):685–694
Szulzewsky F, Schwendinger N, Guneykaya D, Cimino PJ, Hambardzumyan D, Synowitz M et al (2018) Loss of host-derived osteopontin creates a glioblastoma-promoting microenvironment. Neuro-Oncology 20(3):355–366
Muller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A et al (2017) Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol 18(1):234
Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S et al (2016) Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget 7(9):9801–9814
Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT et al (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352(6288):aad3018
Daginakatte GC, Gianino SM, Zhao NW, Parsadanian AS, Gutmann DH (2008) Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation. Cancer Res 68(24):10358–10366
Daginakatte GC, Gutmann DH (2007) Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet 16(9):1098–1112
Solga AC, Pong WW, Kim KY, Cimino PJ, Toonen JA, Walker J et al (2015) RNA sequencing of tumor-associated microglia reveals Ccl5 as a stromal chemokine critical for neurofibromatosis-1 glioma growth. Neoplasia 17(10):776–788
Louveau A, Harris TH, Kipnis J (2015) Revisiting the mechanisms of CNS immune privilege. Trends Immunol 36(10):569–577
Ellwardt E, Walsh JT, Kipnis J, Zipp F (2016) Understanding the role of T cells in CNS homeostasis. Trends Immunol 37(2):154–165
Filiano AJ, Gadani SP, Kipnis J (2017) How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci 18(6):375–384
Louveau A, Herz J, Alme MN, Salvador AF, Dong MQ, Viar KE et al (2018) CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci 21(10):1380–1391
D’Angelo F, Ceccarelli M, Tala, Garofano L, Zhang J, Frattini V et al (2019) The molecular landscape of glioma in patients with Neurofibromatosis 1. Nat Med 25(1):176–187
Pan Y, Smithson LJ, Ma Y, Hambardzumyan D, Gutmann DH (2017) Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival. Oncotarget 8(20):32977–32989
Han W, Umekawa T, Zhou K, Zhang XM, Ohshima M, Dominguez CA et al (2016) Cranial irradiation induces transient microglia accumulation, followed by long-lasting inflammation and loss of microglia. Oncotarget 7(50):82305–82323
Kalm M, Lannering B, Bjork-Eriksson T, Blomgren K (2009) Irradiation-induced loss of microglia in the young brain. J Neuroimmunol 206(1–2):70–75
Li MD, Burns TC, Kumar S, Morgan AA, Sloan SA, Palmer TD (2015) Aging-like changes in the transcriptome of irradiated microglia. Glia 63(5):754–767
Gibson EM, Nagaraja S, Ocampo A, Tam LT, Wood LS, Pallegar PN et al (2019) Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell 176(1–2):43–55.e13
Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, Parada LF (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488(7412):522–526
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The author was funded by a Research Program Award grant from the National Institutes of Health (1-R35-NS07211-01).
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Gutmann, D.H. (2020). The Sociobiology of Brain Tumors. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1225. Springer, Cham. https://doi.org/10.1007/978-3-030-35727-6_8
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DOI: https://doi.org/10.1007/978-3-030-35727-6_8
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