Latest Research Findings on the Role of Non-Tumor Cells in Glioma Microenvironment
Abstract
As the tumor cell-centered treatment strategies cannot curb the malignant progression of glioblastoma effectively, the therapeutic effect of glioblastoma is still not satisfactory. In addition to glioma cells, glioma microenvironment (GME) comprises massive numbers of non-tumor cells and soluble cytokines. The non-tumor cells include endothelial cells, pericytes, microglia/macrophages, mesenchymal cells, astrocytes, neurons, etc. These non-tumor cell components, together with glioma cells, form one organism which regulates the progression of glioma. Considerable progress has been been in research on GME, which will be conducive to the development of non-tumor cell targeted therapies and and improvements in the prognosis of glioma patients. Herein, we summarized the interaction of glioma cells with endothelial cells, pericytes, microglia/macrophages, astrocytes, neurons and mesenchymal cells, a topic that has been extensively researched, as well as the corresponding translational studies. We also discussed the potential challenges and opportunities of developing glioma treatments based on tumor microenvironment.
Keywords: Glioma, Tumor microenvironment, Non-tumor cells
Full Text:
PDFReferences
OSTROM Q T, GITTLEMAN H, TRUITT G, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol,2018,20(Suppl_4): iv1–iv86.
BALLMAN K V, BUCKNER J C, BROWN P D, et al. The relationship between six-month progression-free survival and 12-month overall survival end points for phase Ⅱ trials in patients with glioblastoma multiforme. Neuro Oncol,2007,9(1): 29–38.
WONG E T, HESS K R, GLEASON M J, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase Ⅱ clinical trials. J Cli Oncol,1999,17(8): 2572–2578.
LOUIS D N, PERRY A, WESSELING P, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol,2021,23(8): 1231–1251.
QUAIL D F, JOYCE J A. Microenvironmental regulation of tumor progression and metastasis. Nat Med,2013,19(11): 1423–1437.
ALBINI A, SPORN M B. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer,2007,7(2): 139–147.
AHGI M, COHEN K S, KLEIN R J, et al. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res,2006,66(18): 9054–9064.
XIN M, CHEN Y S, CHEN F R, et al. Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging. Neuro Oncol,2017(8): iii55–iii55.
BERTOLINI F, SHAKED Y, MANCUSO P, et al. The multifaceted circulating endothelial cell in cancer: Towards marker and target identification. Nat Rev Cancer,2006,6(11): 835–845.
CARLSON J C, GUTIERREZ M C, LOZZI B, et al. Identification of diverse tumor endothelial cell populations in malignant glioma. Neuro Oncol,2020,23(6): 932–944.
FARIN A, SUZUKI S O, WEIKER M, et al. Transplanted glioma cells migrate and proliferate on host brain vasculature: A dynamic analysis. Glia,2006,53(8): 799–808.
CHARLES N, OZAWA T, SQUATRITO M, et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell,2010,6(2): 141–152.
BAO S, WU Q L, SATHORNSUMETEE S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res,2006,66(16): 7843–7848.
WANG Z M, YUAN Y F, XIONG J, et al. The Hippo-TAZ axis mediates vascular endothelial growth factor C in glioblastoma-derived exosomes to promote angiogenesis. Cancer Lett,2021,513: 1–13.
HUANG H, GEORGANAKI M, CONZE L L, et al. ELTD1-deletion reduces vascular abnormality and improves T-cell recruitment after PD-1 blockade in glioma. Neuro Oncol,2021,24(3): 398–411.
VEERAVAGU A, BABABEYGY S R, KALANI M Y, et al. The cancer stem cell-vascular niche complex in brain tumor formation. Stem Cells Dev,2008,17(5): 859–867.
LAMAGNA C, BERGERS G. The bone marrow constitutes a reservoir of pericyte progenitors. J Leukoc Biol,2006,80(4): 677–681.
HELLSTRM M, KALEN M, LINDAHL P, et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development, 1999,126(14): 3047–3055.
HUANG F J, YOU W K, BONALDO P, et al. Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the NG2 null mouse. Dev Biol,2010,344(2): 1035–1046.
BERTA S C, MARIA G A, BEATRIZ H, et al. Tumor-derived pericytes driven by eGFR mutations govern the vascular and immune microenvironment of gliomas. Cancer Res,2021,81(8): 2142–2156.
CHENG L, HUANG Z, ZHOU W C, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell,2013,153(1): 139–152.
VALDOR R, DAVID G B, DOLORES R, et al. Glioblastoma ablates pericytes antitumor immune function through aberrant up-regulation of chaperone-mediated autophagy. Proc Natl Acad Sci U S A,2019,116(41): 20655–20665.
OUDENAARDEN C, SJLUND J, PIETRAS K. Upregulated functional gene expression programmes in tumour pericytes mark progression in patients with low-grade glioma. Mol Oncol,2021,16(2): 405–421.
ZHANG X N, YANG K D, CHEN C, et al. Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling. Cell Res,2021,31(10): 1072–1087.
HICKEY W F, KIMURA H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science,1988, 239(4837): 290–292.
STREIT W J, CONDE J R, FENDRICK S E, et al. Role of microglia in the central nervous system's immune response. Neurol Res,2005,27(7): 685–691.
SOULAS C, DONAHUE R E, DUNBAR C E, et al. Genetically modified cd34+ hematopoietic stem cells contribute to turnover of brain perivascular macrophages in long-term repopulated primates. Am J Pathol,2009,174(5): 1808–1817.
MANTOVANI A, SICA A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr Opi Immunol,2010,22(2): 231–237.
NISHIE A, ONO M, SHONO T, et al. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res,1999,5(5): 1107–1113.
KOMOHARA Y, OHNISHI K, KURATSU J, et al. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol,2010,216(1): 15–24.
HOELZINGER D B, DEMUTH T, BERENS M E. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst,2007,99(21): 1583–1593.
MARKOVIC D S, VINNAKOTA K, CHIRASANI S, et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci U S A,2009,106(30): 12530–12535.
ENE C I, KREUSER S A, JUNG M, et al. Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma. Neuro Oncol,2020,22(5): 639–651.
OKEEFE G M, NGUYEN V T, BENVENISTE E N. Class Ⅱ transactivator and class Ⅱ MHC gene expression in microglia: Modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10. Eur J Immunol,2010,29(4): 1275–1285.
BADIE B, SCHARTNER J, PRABAKARAN S, et al. Expression of Fas ligand by microglia: Possible role in glioma immune evasion. J Neuroimmunol,2001,120(1): 19–24.
WANG Q W, SUN L H, ZHANG Y, et al. MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas. J Immunother Cancer,2021,9(10): e002451[2021-10-25] . https://doi.org/10.1136/jitc-2021-002451.
Refbacks
- There are currently no refbacks.



