Abstract
Gliomas and brain-metastatic tumors contribute to hundreds of thousands of deaths every year. Typical survival times for brain cancer patients, even with surgical, chemotherapy, and radiation treatment, remain very low despite advances in treatment. In brain cancers, astrocytes, which comprise approximately 50 % of the cells in the brain, become activated, resulting in a layer of reactive astrocytes surrounding the tumor. This process of reactive gliosis, which involves the secretion of growth factors and cytokines, helps repair injury in the brain, but also plays a role in disease progression. In this review, we survey the mechanisms by which astrocytes modulate the local tumor microenvironment, enhancing proliferation, invasion, chemoprotection, and immunoprotection of tumor cells. Consideration of the effect of astrocytes and reactive gliosis in in vitro and in vivo assays may allow us to obtain a more complete picture of the interactions occurring at the tumor microenvironment, which will provide additional insight into potential pathways that can be targeted by brain cancer therapeutics.
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References
Median cancer survival times. Macmillan Cancer Support. 2011.
Glioblastoma and malignant astrocytoma. American Brain Tumor Association. 2014.
Eichler AF, Chung E, Kodack DP, Loeffler JS, Fukumura D, Jain RK. The biology of brain metastases—translation to new therapies. Nat Rev Clin Oncol. 2011;8:344–56.
Chaichana KL, Gadkaree S, Rao K, Link T, Rigamonti D, Purtell M, et al. Patients undergoing surgery of intracranial metastases have different outcomes based on their primary pathology. Neurol Res. 2013;35:1059–69.
Kaneko Y, Tajiri N, Staples M, Reyes S, Lozano D, Sanberg PR, et al. Bone marrow-derived stem cell therapy for metastatic brain cancers. Cell Transplant. 2015;24:625–30.
O’Brien ER, Howarth C, Sibson NR. The role of astrocytes in CNS tumors: pre-clinical models and novel imaging approaches. Front Cell Neurosci. 2013;7:40.
Coniglio SJ, Segall JE. Review: molecular mechanism of microglia stimulated glioblastoma invasion. Matrix Biol. 2013;32:372–80.
Li W, Graeber MB. The molecular profile of microglia under the influence of glioma. Neuro-oncology. 2012:nos116.
Wei J, Gabrusiewicz K, Heimberger A. The controversial role of microglia in malignant gliomas. Clin Dev Immunol 2013;2013.
Ridet J, Privat A, Malhotra S, Gage F. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20:570–7.
Zamanian JL, Xu L, Foo LC, Nouri N, Zhou L, Giffard RG, et al. Genomic analysis of reactive astrogliosis. J Neurosci. 2012;32:6391–410.
Li R, Li G, Deng L, Liu Q, Dai J, Shen J, et al. IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin-1. Oncol Rep. 2010;23:1553–9.
Rathke-Hartlieb S, Budde P, Ewert S, Schlomann U, Staege MS, Jockusch H, et al. Elevated expression of membrane type 1 metalloproteinase (MT1-MMP) in reactive astrocytes following neurodegeneration in mouse central nervous system. FEBS Lett. 2000;481:227–34.
Seike T, Fujita K, Yamakawa Y, Kido MA, Takiguchi S, Teramoto N, et al. Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin Exp Metastasis. 2011;28:13–25.
Roth P, Junker M, Tritschler I, Mittelbronn M, Dombrowski Y, Breit SN, et al. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin Cancer Res. 2010;16:3851–9.
Sierra A, Price JE, Garcia-Ramirez M, Méndez O, López L, Fabra A. Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Investig; J Tech Methods Pathol. 1997;77:357–68.
Rath BH, Fair JM, Jamal M, Camphausen K, Tofilon PJ. Astrocytes enhance the invasion potential of glioblastoma stem-like cells. PLoS One. 2013;8, e54752.
Heldin C-H. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11:97.
Chuang HN, van Rossum D, Sieger D, Siam L, Klemm F, Bleckmann A, et al. Carcinoma cells misuse the host tissue damage response to invade the brain. Glia. 2013;61:1331–46.
Hu F, a Dzaye OD, Hahn A, Yu Y, Scavetta RJ, Dittmar G, et al. Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages toll-like receptor 2 signaling. Neuro-Oncology. 2015;17:200–10.
Marchetti D, Li J, Shen R. Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Res. 2000;60:4767–70.
Huang J-Y, Cheng Y-J, Lin Y-P, Lin H-C, Su C-C, Juliano R, et al. Extracellular matrix of glioblastoma inhibits polarization and transmigration of T cells: the role of tenascin-C in immune suppression. J Immunol. 2010;185:1450–9.
Joseph B, Venero JL. A brief overview of multitalented microglia. Microglia, Springer, 2013, pp 3–8.
Gonzalez-Perez O, Lopez-Virgen V, Quiñones-Hinojosa A. Astrocytes: everything but the glue. Neuroimmunol Neuroinflammation. 2015;2:115.
Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci. 2005;6:626–40.
Placone AL, McGuiggan PM, Bergles DE, Guerrero-Cazares H, Quiñones-Hinojosa A, Searson PC. Human astrocytes develop physiological morphology and remain quiescent in a novel 3D matrix. Biomaterials. 2015;42:134–43.
Torres-Platas SG, Comeau S, Rachalski A, Bo GD, Cruceanu C, Turecki G, et al. Morphometric characterization of microglial phenotypes in human cerebral cortex. J Neuroinflammation. 2014;11:12.
Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53.
Quiñones-Hinojosa A, Chaichana K. The human subventricular zone: a source of new cells and a potential source of brain tumors. Exp Neurol. 2007;205:313–24.
Fitzgerald DP, Palmieri D, Hua E, Hargrave E, Herring JM, Qian Y, et al. Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization. Clin Exp Metastasis. 2008;25:799–810.
Pedersen PH, Ness GO, Engebraaten O, Bjerkvig R, Lillehaug JR, Laerum OD. Heterogeneous response to the growth factors [EGF, PDGF (bb), TGF‐α, BFGF, il‐2] on glioma spheroid growth, migration and invasion. Int J Cancer. 1994;56:255–61.
Wang L, Cossette SM, Rarick KR, Gershan J, Dwinell MB, Harder DR, et al. Astrocytes directly influence tumor cell invasion and metastasis in vivo. PLoS One. 2013;8, e80933.
Klein A, Schwartz H, Sagi‐Assif O, Meshel T, Izraely S, Menachem SB, et al. Astrocytes facilitate melanoma brain metastasis via secretion of IL‐23. J Pathol. 2015;236(1):116–27.
Le DM, Besson A, Fogg DK, Choi K-S, Waisman DM, Goodyer CG, et al. Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator–plasmin cascade. J Neurosci. 2003;23:4034–43.
Kim S-J, Kim J-S, Park ES, Lee J-S, Lin Q, Langley RR, et al. Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. Neoplasia. 2011;13:286–98.
Chen W, Wang D, Du X, He Y, Chen S, Shao Q, et al. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med Oncol. 2015;32:1–13.
Lin Q, Balasubramanian K, Fan D, Kim S-J, Guo L, Wang H, et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia. 2010;12:748–54.
Kim SW, Choi HJ, Lee H-J, He J, Wu Q, Langley RR, et al. Role of the endothelin axis in astrocyte-and endothelial cell-mediated chemoprotection of cancer cells. Neuro-Oncology. 2014;16:1585–98.
Lou W, Ni Z, Dyer K, Tweardy DJ, Gao AC. Interleukin‐6 induces prostate cancer cell growth accompanied by activation of stat3 signaling pathway. Prostate. 2000;42:239–42.
Knüpfer H, Preiß R. Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat. 2007;102:129–35.
Abrey LE, Christodoulou C. Temozolomide for treating brain metastases: seminars in oncology. Elsevier. 2001;28:34–42.
Agarwala SS, Kirkwood JM. Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist. 2000;5:144–51.
Gerstner ER, Fine RL. Increased permeability of the blood–brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25:2306–12.
Doolittle ND, Muldoon LL, Culp AY, Neuwelt EA. Chapter seven—delivery of chemotherapeutics across the blood–brain barrier: challenges and advances. In: Thomas PD, editors. Advances in pharmacology. Academic Press, 2014, Volume 71, pp 203–243.
Roderick HL, Cook SJ. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer. 2008;8:361–75.
Gomez GG, Kruse CA. Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol. 2006;10:133.
Grütz G. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol. 2005;77:3–15.
Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B. Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia. 2009;57:1458–67.
Hishii M, Nitta T, Ishida H, Ebato M, Kurosu A, Yagita H, et al. Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro. Neurosurgery. 1995;37:1160–7.
Fujita M, Zhu X, Sasaki K, Ueda R, Low KL, Pollack IF, et al. Inhibition of stat3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma. J Immunol. 2008;180:2089–98.
Lee J, Borboa AK, Baird A, Eliceiri BP. Non-invasive quantification of brain tumor-induced astrogliosis. BMC Neurosci. 2011;12:9.
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Placone, A.L., Quiñones-Hinojosa, A. & Searson, P.C. The role of astrocytes in the progression of brain cancer: complicating the picture of the tumor microenvironment. Tumor Biol. 37, 61–69 (2016). https://doi.org/10.1007/s13277-015-4242-0
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DOI: https://doi.org/10.1007/s13277-015-4242-0