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Cancers  2012 

Tumor Microenvironment in the Brain

DOI: 10.3390/cancers4010218

Keywords: tumor microenvironment, brain metastases, brain tumors, microglia, macrophages, astrocytes, pericytes, angiogenesis

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In addition to malignant cancer cells, tumors contain a variety of different stromal cells that constitute the tumor microenvironment. Some of these cell types provide crucial support for tumor growth, while others have been suggested to actually inhibit tumor progression. The composition of tumor microenvironment varies depending on the tumor site. The brain in particular consists of numerous specialized cell types such as microglia, astrocytes, and brain endothelial cells. In addition to these brain-resident cells, primary and metastatic brain tumors have also been shown to be infiltrated by different populations of bone marrow-derived cells. The role of different cell types that constitute tumor microenvironment in the progression of brain malignancies is only poorly understood. Tumor microenvironment has been shown to be a promising therapeutic target and diagnostic marker in extracranial malignancies. A better understanding of tumor microenvironment in the brain would therefore be expected to contribute to the development of improved therapies for brain tumors that are urgently required due to a poor availability of treatments for these malignancies. This review summarizes some of the known interactions between brain tumors and different stromal cells, and also discusses potential therapeutic approaches within this context.


[1]  Al-Shamy, G.; Sawaya, R. Management of brain metastases: The indispensable role of surgery. J. Neurooncol. 2009, 92, 275–282, doi:10.1007/s11060-009-9839-y.
[2]  DeAngelis, L.M. Treatment of brain metastasis. J. Support. Oncol. 2008, 6, 87–88.
[3]  Gavrilovic, I.T.; Posner, J.B. Brain metastases: Epidemiology and pathophysiology. J. Neurooncol. 2005, 75, 5–14, doi:10.1007/s11060-004-8093-6.
[4]  Gerrard, G.E.; Franks, K.N. Overview of the diagnosis and management of brain, spine, and meningeal metastases. J. Neurol. Neurosurg. Psychiatr. 2004, 75, ii37–ii42, doi:10.1136/jnnp.2004.040493.
[5]  Nikiforova, M.N.; Hamilton, R.L. Molecular diagnostics of gliomas. Arch. Pathol. Lab. Med. 2011, 135, 558–568. 21526954
[6]  Davis, F.G.; Freels, S.; Grutsch, J.; Barlas, S.; Brem, S. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: An analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991. J. Neurosurg. 1998, 88, 1–10, doi:10.3171/jns.1998.88.1.0001.
[7]  Davis, F.G.; McCarthy, B.J.; Berger, M.S. Centralized databases available for describing primary brain tumor incidence, survival, and treatment: Central Brain Tumor Registry of the United States; Surveillance, Epidemiology, and End Results; and National Cancer Data Base. Neuro-Oncology 1999, 1, 205–211. 11554389
[8]  Ballman, K.V.; Buckner, J.C.; Brown, P.D.; Giannini, C.; Flynn, P.J.; LaPlant, B.R.; Jaeckle, K.A. 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-Oncology 2007, 9, 29–38. 17108063
[9]  Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-Year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009, 10, 459–466, doi:10.1016/S1470-2045(09)70025-7.
[10]  Wong, E.T.; Hess, K.R.; Gleason, M.J.; Jaeckle, K.A.; Kyritsis, A.P.; Prados, M.D.; Levin, V.A.; Yung, W.K. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J. Clin. Oncol. 1999, 17, 2572–2578. 10561324
[11]  Albini, A.; Sporn, M.B. The tumour microenvironment as a target for chemoprevention. Nat. Rev. Cancer 2007, 7, 139–147. 17218951
[12]  Joyce, J.A.; Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 2009, 9, 239–252, doi:10.1038/nrc2618.
[13]  Witkiewicz, A.K.; Casimiro, M.C.; Dasgupta, A.; Mercier, I.; Wang, C.; Bonuccelli, G.; Jasmin, J.F.; Frank, P.G.; Pestell, R.G.; Kleer, C.G.; et al. Towards a new “stromal-based” classification system for human breast cancer prognosis and therapy. Cell Cycle 2009, 8, 1654–1658, doi:10.4161/cc.8.11.8544. 19448435
[14]  Nicolson, G.L.; Menter, D.G.; Herrmann, J.L.; Yun, Z.; Cavanaugh, P.; Marchetti, D. Brain metastasis: Role of trophic, autocrine, and paracrine factors in tumor invasion and colonization of the central nervous system. Curr. Top. Microbiol. Immunol. 1996, 213, 89–115. 9053298
[15]  Zhang, C.; Zhang, F.; Tsan, R.; Fidler, I.J. Transforming growth factor-beta2 is a molecular determinant for site-specific melanoma metastasis in the brain. Cancer Res. 2009, 69, 828–835, doi:10.1158/0008-5472.CAN-08-2588. 19141644
[16]  Blouw, B.; Song, H.; Tihan, T.; Bosze, J.; Ferrara, N.; Gerber, H.P.; Johnson, R.S.; Bergers, G. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 2003, 4, 133–146, doi:10.1016/S1535-6108(03)00194-6.
[17]  Lorger, M.; Krueger, J.S.; O'Neal, M.; Staflin, K.; Felding-Habermann, B. Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc. Natl. Acad. Sci. USA 2009, 106, 10666–10671, doi:10.1073/pnas.0903035106. 19541645
[18]  Guo, P.; Xu, L.; Pan, S.; Brekken, R.A.; Yang, S.T.; Whitaker, G.B.; Nagane, M.; Thorpe, P.E.; Rosenbaum, J.S.; Su Huang, H.J.; et al. Vascular endothelial growth factor isoforms display distinct activities in promoting tumor angiogenesis at different anatomic sites. Cancer Res. 2001, 61, 8569–8577. 11731444
[19]  Deli, M.A.; Abraham, C.S.; Kataoka, Y.; Niwa, M. Permeability studies on in vitro blood-brain barrier models: Physiology, pathology, and pharmacology. Cell. Mol. Neurobiol. 2005, 25, 59–127, doi:10.1007/s10571-004-1377-8.
[20]  Lee, S.W.; Kim, W.J.; Park, J.A.; Choi, Y.K.; Kwon, Y.W.; Kim, K.W. Blood-brain barrier interfaces and brain tumors. Arch. Pharm. Res. 2006, 29, 265–275, doi:10.1007/BF02968569.
[21]  Nag, S. Morphology and molecular properties of cellular components of normal cerebral vessels. Methods Mol. Med. 2003, 89, 3–36. 12958410
[22]  Carbonell, W.S.; Ansorge, O.; Sibson, N.; Muschel, R. The vascular basement membrane as “soil” in brain metastasis. PLoS One 2009, 4, e5857, doi:10.1371/journal.pone.0005857. 19516901
[23]  Lorger, M.; Felding-Habermann, B. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am. J. Pathol. 2010, 176, 2958–2971, doi:10.2353/ajpath.2010.090838.
[24]  Kienast, Y.; von Baumgarten, L.; Fuhrmann, M.; Klinkert, W.E.; Goldbrunner, R.; Herms, J.; Winkler, F. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 2010, 16, 116–122, doi:10.1038/nm.2072. 20023634
[25]  Fidler, I.J.; Yano, S.; Zhang, R.D.; Fujimaki, T.; Bucana, C.D. The seed and soil hypothesis: Vascularisation and brain metastases. Lancet Oncol. 2002, 3, 53–57, doi:10.1016/S1470-2045(01)00622-2.
[26]  Nir, I.; Levanon, D.; Iosilevsky, G. Permeability of blood vessels in experimental gliomas: Uptake of 99mTc-glucoheptonate and alteration in blood-brain barrier as determined by cytochemistry and electron microscopy. Neurosurgery 1989, 25, 523–532, doi:10.1227/00006123-198910000-00004.
[27]  Zhang, R.D.; Price, J.E.; Fujimaki, T.; Bucana, C.D.; Fidler, I.J. Differential permeability of the blood-brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am. J. Pathol. 1992, 141, 1115–1124. 1443046
[28]  Lockman, P.R.; Mittapalli, R.K.; Taskar, K.S.; Rudraraju, V.; Gril, B.; Bohn, K.A.; Adkins, C.E.; Roberts, A.; Thorsheim, H.R.; Gaasch, J.A.; et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin. Cancer Res. 2010, 16, 5664–5678, doi:10.1158/1078-0432.CCR-10-1564. 20829328
[29]  Wen, P.Y.; Kesari, S. Malignant gliomas in adults. N. Engl. J. Med. 2008, 359, 492–507, doi:10.1056/NEJMra0708126.
[30]  Chao, H.; Hirschi, K.K. Hemato-vascular origins of endothelial progenitor cells? Microvasc. Res. 2010, 79, 169–173, doi:10.1016/j.mvr.2010.02.003.
[31]  Dome, B.; Dobos, J.; Tovari, J.; Paku, S.; Kovacs, G.; Ostoros, G.; Timar, J. Circulating bone marrow-derived endothelial progenitor cells: Characterization, mobilization, and therapeutic considerations in malignant disease. Cytometry A 2008, 73, 186–193. 18000872
[32]  Ricci-Vitiani, L.; Pallini, R.; Biffoni, M.; Todaro, M.; Invernici, G.; Cenci, T.; Maira, G.; Parati, E.A.; Stassi, G.; Larocca, L.M.; et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 2010, 468, 824–828, doi:10.1038/nature09557. 21102434
[33]  Bernstein, J.J.; Woodard, C.A. Glioblastoma cells do not intravasate into blood vessels. Neurosurgery 1995, 36, 124–132, doi:10.1227/00006123-199501000-00016.
[34]  Holash, J.; Maisonpierre, P.C.; Compton, D.; Boland, P.; Alexander, C.R.; Zagzag, D.; Yancopoulos, G.D.; Wiegand, S.J. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999, 284, 1994–1998, doi:10.1126/science.284.5422.1994. 10373119
[35]  Baeriswyl, V.; Christofori, G. The angiogenic switch in carcinogenesis. Semin. Cancer Biol. 2009, 19, 329–337, doi:10.1016/j.semcancer.2009.05.003.
[36]  Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86, 353–364, doi:10.1016/S0092-8674(00)80108-7.
[37]  Harper, J.; Moses, M.A. Molecular regulation of tumor angiogenesis: Mechanisms and therapeutic implications. EXS 2006, 96, 223–268. 16383021
[38]  Iruela-Arispe, M.L.; Dvorak, H.F. Angiogenesis: A dynamic balance of stimulators and inhibitors. Thromb. Haemost. 1997, 78, 672–677. 9198237
[39]  Shweiki, D.; Neeman, M.; Itin, A.; Keshet, E. Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: Implications for tumor angiogenesis. Proc. Natl. Acad. Sci. USA 1995, 92, 768–772, doi:10.1073/pnas.92.3.768. 7531342
[40]  Du, R.; Petritsch, C.; Lu, K.; Liu, P.; Haller, A.; Ganss, R.; Song, H.; Vandenberg, S.; Bergers, G. Matrix metalloproteinase-2 regulates vascular patterning and growth affecting tumor cell survival and invasion in GBM. Neuro-Oncology 2008, 10, 254–264, doi:10.1215/15228517-2008-001.
[41]  Leenders, W.P.; Kusters, B.; Verrijp, K.; Maass, C.; Wesseling, P.; Heerschap, A.; Ruiter, D.; Ryan, A.; de Waal, R. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin. Cancer Res. 2004, 10, 6222–6230, doi:10.1158/1078-0432.CCR-04-0823. 15448011
[42]  Paez-Ribes, M.; Allen, E.; Hudock, J.; Takeda, T.; Okuyama, H.; Vinals, F.; Inoue, M.; Bergers, G.; Hanahan, D.; Casanovas, O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009, 15, 220–231, doi:10.1016/j.ccr.2009.01.027.
[43]  Aicher, A.; Zeiher, A.M.; Dimmeler, S. Mobilizing endothelial progenitor cells. Hypertension 2005, 45, 321–325, doi:10.1161/01.HYP.0000154789.28695.ea.
[44]  Bertolini, F.; Shaked, Y.; Mancuso, P.; Kerbel, R.S. The multifaceted circulating endothelial cell in cancer: Towards marker and target identification. Nat. Rev. Cancer 2006, 6, 835–845, doi:10.1038/nrc1971.
[45]  Rafat, N.; Beck, G.; Schulte, J.; Tuettenberg, J.; Vajkoczy, P. Circulating endothelial progenitor cells in malignant gliomas. J. Neurosurg. 2009, 112, 43–49.
[46]  Zheng, P.P.; Hop, W.C.; Luider, T.M.; Sillevis Smitt, P.A.; Kros, J.M. Increased levels of circulating endothelial progenitor cells and circulating endothelial nitric oxide synthase in patients with gliomas. Ann. Neurol. 2007, 62, 40–48, doi:10.1002/ana.21151.
[47]  Aghi, M.; Cohen, K.S.; Klein, R.J.; Scadden, D.T.; Chiocca, E.A. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res. 2006, 66, 9054–9064, doi:10.1158/0008-5472.CAN-05-3759. 16982747
[48]  de Palma, M.; Venneri, M.A.; Galli, R.; Sergi Sergi, L.; Politi, L.S.; Sampaolesi, M.; Naldini, L. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 2005, 8, 211–226, doi:10.1016/j.ccr.2005.08.002.
[49]  Duda, D.G.; Cohen, K.S.; Kozin, S.V.; Perentes, J.Y.; Fukumura, D.; Scadden, D.T.; Jain, R.K. Evidence for incorporation of bone marrow-derived endothelial cells into perfused blood vessels in tumors. Blood 2006, 107, 2774–2776, doi:10.1182/blood-2005-08-3210.
[50]  Machein, M.R.; Renninger, S.; de Lima-Hahn, E.; Plate, K.H. Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol. 2003, 13, 582–597. 14655762
[51]  Moore, X.L.; Lu, J.; Sun, L.; Zhu, C.J.; Tan, P.; Wong, M.C. Endothelial progenitor cells’ “homing” specificity to brain tumors. Gene Ther. 2004, 11, 811–818, doi:10.1038/sj.gt.3302151.
[52]  Santarelli, J.G.; Udani, V.; Yung, Y.C.; Cheshier, S.; Wagers, A.; Brekken, R.A.; Weissman, I.; Tse, V. Incorporation of bone marrow-derived Flk-1-expressing CD34+ cells in the endothelium of tumor vessels in the mouse brain. Neurosurgery 2006, 59, 374–382, doi:10.1227/01.NEU.0000222658.66878.CC.
[53]  Udani, V.; Santarelli, J.; Yung, Y.; Cheshier, S.; Andrews, A.; Kasad, Z.; Tse, V. Differential expression of angiopoietin-1 and angiopoietin-2 may enhance recruitment of bone-marrow-derived endothelial precursor cells into brain tumors. Neurol. Res. 2005, 27, 801–806, doi:10.1179/016164105X49319.
[54]  Bertolini, F.; Paul, S.; Mancuso, P.; Monestiroli, S.; Gobbi, A.; Shaked, Y.; Kerbel, R.S. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 2003, 63, 4342–4346. 12907602
[55]  Shaked, Y.; Ciarrocchi, A.; Franco, M.; Lee, C.R.; Man, S.; Cheung, A.M.; Hicklin, D.J.; Chaplin, D.; Foster, F.S.; Benezra, R.; et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 2006, 313, 1785–1787, doi:10.1126/science.1127592. 16990548
[56]  Dome, B.; Timar, J.; Paku, S. A novel concept of glomeruloid body formation in experimental cerebral metastases. J. Neuropathol. Exp. Neurol. 2003, 62, 655–661. 12834110
[57]  Winkler, F.; Kienast, Y.; Fuhrmann, M.; von Baumgarten, L.; Burgold, S.; Mitteregger, G.; Kretzschmar, H.; Herms, J. Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia 2009, 57, 1306–1315, doi:10.1002/glia.20850.
[58]  Zadeh, G.; Reti, R.; Koushan, K.; Baoping, Q.; Shannon, P.; Guha, A. Regulation of the pathological vasculature of malignant astrocytomas by angiopoietin-1. Neoplasia 2005, 7, 1081–1090, doi:10.1593/neo.05424.
[59]  Farin, A.; Suzuki, S.O.; Weiker, M.; Goldman, J.E.; Bruce, J.N.; Canoll, P. Transplanted glioma cells migrate and proliferate on host brain vasculature: A dynamic analysis. Glia 2006, 53, 799–808, doi:10.1002/glia.20334.
[60]  Calabrese, C.; Poppleton, H.; Kocak, M.; Hogg, T.L.; Fuller, C.; Hamner, B.; Oh, E.Y.; Gaber, M.W.; Finklestein, D.; Allen, M.; et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007, 11, 69–82, doi:10.1016/j.ccr.2006.11.020.
[61]  Veeravagu, A.; Bababeygy, S.R.; Kalani, M.Y.; Hou, L.C.; Tse, V. The cancer stem cell-vascular niche complex in brain tumor formation. Stem Cells Dev. 2008, 17, 859–867, doi:10.1089/scd.2008.0047.
[62]  Charles, N.; Ozawa, T.; Squatrito, M.; Bleau, A.M.; Brennan, C.W.; Hambardzumyan, D.; Holland, E.C. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 2010, 6, 141–152, doi:10.1016/j.stem.2010.01.001.
[63]  Bao, S.; Wu, Q.; Sathornsumetee, S.; Hao, Y.; Li, Z.; Hjelmeland, A.B.; Shi, Q.; McLendon, R.E.; Bigner, D.D.; Rich, J.N. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 2006, 66, 7843–7848, doi:10.1158/0008-5472.CAN-06-1010. 16912155
[64]  Bergers, G.; Song, S. The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology 2005, 7, 452–464, doi:10.1215/S1152851705000232.
[65]  Hellstrom, M.; Kalen, M.; Lindahl, P.; Abramsson, A.; Betsholtz, C. 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, 3047–3055. 10375497
[66]  Leveen, P.; Pekny, M.; Gebre-Medhin, S.; Swolin, B.; Larsson, E.; Betsholtz, C. Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev. 1994, 8, 1875–1887, doi:10.1101/gad.8.16.1875.
[67]  Soriano, P. Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev. 1994, 8, 1888–1896, doi:10.1101/gad.8.16.1888.
[68]  Song, S.; Ewald, A.J.; Stallcup, W.; Werb, Z.; Bergers, G. PDGFRbeta+ perivascular progenitor cellsin tumours regulate pericyte differentiation and vascular survival. Nat. Cell Biol. 2005, 7, 870–879, doi:10.1038/ncb1288.
[69]  Huang, F.J.; You, W.K.; Bonaldo, P.; Seyfried, T.N.; Pasquale, E.B.; Stallcup, W.B. Pericyte deficiencies lead to aberrant tumor vascularizaton in the brain of the NG2 null mouse. Dev. Biol. 2010, 344, 1035–1046, doi:10.1016/j.ydbio.2010.06.023. 20599895
[70]  Ozerdem, U.; Stallcup, W.B. Pathological angiogenesis is reduced by targeting pericytes via the NG2 proteoglycan. Angiogenesis 2004, 7, 269–276, doi:10.1007/s10456-004-4182-6.
[71]  Fukushi, J.; Makagiansar, I.T.; Stallcup, W.B. NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol. Biol. Cell 2004, 15, 3580–3590, doi:10.1091/mbc.E04-03-0236.
[72]  Lamagna, C.; Bergers, G. The bone marrow constitutes a reservoir of pericyte progenitors. J. Leukoc. Biol. 2006, 80, 677–681, doi:10.1189/jlb.0506309.
[73]  Bababeygy, S.R.; Cheshier, S.H.; Hou, L.C.; Higgins, D.M.; Weissman, I.L.; Tse, V.C. Hematopoietic stem cell-derived pericytic cells in brain tumor angio-architecture. Stem Cells Dev. 2008, 17, 11–18, doi:10.1089/scd.2007.0117.
[74]  Bexell, D.; Gunnarsson, S.; Tormin, A.; Darabi, A.; Gisselsson, D.; Roybon, L.; Scheding, S.; Bengzon, J. Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Mol. Ther. 2009, 17, 183–190, doi:10.1038/mt.2008.229.
[75]  Winkler, E.A.; Bell, R.D.; Zlokovic, B.V. Central nervous system pericytes in health and disease. Nat. Neurosci. 2011, 14, 1398–1405, doi:10.1038/nn.2946. 22030551
[76]  Armulik, A.; Genove, G.; Mae, M.; Nisancioglu, M.H.; Wallgard, E.; Niaudet, C.; He, L.; Norlin, J.; Lindblom, P.; Strittmatter, K.; et al. Pericytes regulate the blood-brain barrier. Nature 2010, 468, 557–561, doi:10.1038/nature09522. 20944627
[77]  Daneman, R.; Zhou, L.; Kebede, A.A.; Barres, B.A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 2010, 468, 562–566, doi:10.1038/nature09513. 20944625
[78]  Birnbaum, T.; Hildebrandt, J.; Nuebling, G.; Sostak, P.; Straube, A. Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro. Neuro-Oncology 2011, 105, 57–65, doi:10.1007/s11060-011-0561-1.
[79]  Nakamura, K.; Ito, Y.; Kawano, Y.; Kurozumi, K.; Kobune, M.; Tsuda, H.; Bizen, A.; Honmou, O.; Niitsu, Y.; Hamada, H. Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther. 2004, 11, 1155–1164, doi:10.1038/sj.gt.3302276.
[80]  Nakamizo, A.; Marini, F.; Amano, T.; Khan, A.; Studeny, M.; Gumin, J.; Chen, J.; Hentschel, S.; Vecil, G.; Dembinski, J.; et al. Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res. 2005, 65, 3307–3318. 15833864
[81]  Du, R.; Lu, K.V.; Petritsch, C.; Liu, P.; Ganss, R.; Passegue, E.; Song, H.; Vandenberg, S.; Johnson, R.S.; Werb, Z.; et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008, 13, 206–220, doi:10.1016/j.ccr.2008.01.034.
[82]  You, W.K.; Bonaldo, P.; Stallcup, W.B. Collagen VI ablation retards brain tumor progression due to deficits in assembly of the vascular basal lamina. Am. J. Pathol. 2012, 180, 1145–1158, doi:10.1016/j.ajpath.2011.11.006.
[83]  Geissmann, F.; Jung, S.; Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003, 19, 71–82, doi:10.1016/S1074-7613(03)00174-2.
[84]  Gordon, S.; Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 2005, 5, 953–964, doi:10.1038/nri1733.
[85]  Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 2003, 3, 23–35, doi:10.1038/nri978.
[86]  Pollard, J.W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 2004, 4, 71–78, doi:10.1038/nrc1256.
[87]  Mantovani, A.; Sica, A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr. Opin. Immunol. 2010, 22, 231–237, doi:10.1016/j.coi.2010.01.009. 20144856
[88]  Mills, C.D.; Kincaid, K.; Alt, J.M.; Heilman, M.J.; Hill, A.M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 2000, 164, 6166–6173. 10843666
[89]  Davis, E.J.; Foster, T.D.; Thomas, W.E. Cellular forms and functions of brain microglia. Brain Res. Bull. 1994, 34, 73–78, doi:10.1016/0361-9230(94)90189-9.
[90]  Guillemin, G.J.; Brew, B.J. Microglia, macrophages, perivascular macrophages, and pericytes: A review of function and identification. J. Leukoc. Biol. 2004, 75, 388–397, doi:10.1189/jlb.0303114.
[91]  Hickey, W.F.; Kimura, H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 1988, 239, 290–292, doi:10.1126/science.3276004. 3276004
[92]  Streit, W.J.; Conde, J.R.; Fendrick, S.E.; Flanary, B.E.; Mariani, C.L. Role of microglia in the central nervous system's immune response. Neurol. Res. 2005, 27, 685–691. 16197805
[93]  Cartier, N.; Hacein-Bey-Abina, S.; Bartholomae, C.C.; Veres, G.; Schmidt, M.; Kutschera, I.; Vidaud, M.; Abel, U.; Dal-Cortivo, L.; Caccavelli, L.; et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 2009, 326, 818–823, doi:10.1126/science.1171242. 19892975
[94]  Hess, D.C.; Abe, T.; Hill, W.D.; Studdard, A.M.; Carothers, J.; Masuya, M.; Fleming, P.A.; Drake, C.J.; Ogawa, M. Hematopoietic origin of microglial and perivascular cells in brain. Exp. Neurol. 2004, 186, 134–144, doi:10.1016/j.expneurol.2003.11.005.
[95]  Lesniak, M.S.; Kelleher, E.; Pardoll, D.; Cui, Y. Targeted gene therapy to antigen-presenting cells in the central nervous system using hematopoietic stem cells. Neurol. Res. 2005, 27, 820–826, doi:10.1179/016164105X49454.
[96]  Priller, J.; Flugel, A.; Wehner, T.; Boentert, M.; Haas, C.A.; Prinz, M.; Fernandez-Klett, F.; Prass, K.; Bechmann, I.; de Boer, B.A.; et al. Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 2001, 7, 1356–1361, doi:10.1038/nm1201-1356. 11726978
[97]  Soulas, C.; Donahue, R.E.; Dunbar, C.E.; Persons, D.A.; Alvarez, X.; Williams, K.C. Genetically modified CD34+ hematopoietic stem cells contribute to turnover of brain perivascular macrophages in long-term repopulated primates. Am. J. Pathol. 2009, 174, 1808–1817, doi:10.2353/ajpath.2009.081010.
[98]  Vallieres, L.; Sawchenko, P.E. Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J. Neurosci. 2003, 23, 5197–5207. 12832544
[99]  Biffi, A.; de Palma, M.; Quattrini, A.; Del Carro, U.; Amadio, S.; Visigalli, I.; Sessa, M.; Fasano, S.; Brambilla, R.; Marchesini, S.; et al. Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J. Clin. Invest. 2004, 113, 1118–1129. 15085191
[100]  Getts, D.R.; Terry, R.L.; Getts, M.T.; Muller, M.; Rana, S.; Shrestha, B.; Radford, J.; van Rooijen, N.; Campbell, I.L.; King, N.J. Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J. Exp. Med. 2008, 205, 2319–2337, doi:10.1084/jem.20080421.
[101]  Yang, I.; Han, S.J.; Kaur, G.; Crane, C.; Parsa, A.T. The role of microglia in central nervous system immunity and glioma immunology. J. Clin. Neurosci. 2009, 17, 6–10. 19926287
[102]  Kettenmann, H.; Hanisch, U.K.; Noda, M.; Verkhratsky, A. Physiology of microglia. Physiol. Rev. 2011, 91, 461–553, doi:10.1152/physrev.00011.2010.
[103]  Davoust, N.; Vuaillat, C.; Androdias, G.; Nataf, S. From bone marrow to microglia: Barriers and avenues. Trends Immunol. 2008, 29, 227–234, doi:10.1016/j.it.2008.01.010.
[104]  Sedgwick, J.D.; Schwender, S.; Imrich, H.; Dorries, R.; Butcher, G.W.; ter Meulen, V. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc. Natl. Acad. Sci. USA 1991, 88, 7438–7442, doi:10.1073/pnas.88.16.7438. 1651506
[105]  Bertolotto, A.; Agresti, C.; Castello, A.; Manzardo, E.; Riccio, A. 5D4 keratan sulfate epitope identifies a subset of ramified microglia in normal central nervous system parenchyma. J. Neuroimmunol. 1998, 85, 69–77, doi:10.1016/S0165-5728(97)00251-8.
[106]  Wilms, H.; Wollmer, M.A.; Sievers, J. In vitro-staining specificity of the antibody 5-D-4 for microglia but not for monocytes and macrophages indicates that microglia are a unique subgroup of the myelomonocytic lineage. J. Neuroimmunol. 1999, 98, 89–95, doi:10.1016/S0165-5728(99)00066-1.
[107]  Daginakatte, G.C.; Gutmann, D.H. Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum. Mol. Genet. 2007, 16, 1098–1112, doi:10.1093/hmg/ddm059.
[108]  Fitzgerald, D.P.; Palmieri, D.; Hua, E.; Hargrave, E.; Herring, J.M.; Qian, Y.; Vega-Valle, E.; Weil, R.J.; Stark, A.M.; Vortmeyer, A.O.; 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, doi:10.1007/s10585-008-9193-z.
[109]  He, B.P.; Wang, J.J.; Zhang, X.; Wu, Y.; Wang, M.; Bay, B.H.; Chang, A.Y. Differential reactions of microglia to brain metastasis of lung cancer. Mol. Med. 2006, 12, 161–170, doi:10.1007/s00894-005-0012-z.
[110]  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, 1583–1593, doi:10.1093/jnci/djm187.
[111]  Roggendorf, W.; Strupp, S.; Paulus, W. Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol. 1996, 92, 288–293, doi:10.1007/s004010050520.
[112]  Zhang, M.; Olsson, Y. Reactions of astrocytes and microglial cells around hematogenous metastases of the human brain. Expression of endothelin-like immunoreactivity in reactive astrocytes and activation of microglial cells. J. Neurol. Sci. 1995, 134, 26–32, doi:10.1016/0022-510X(95)00227-9.
[113]  Morantz, R.A.; Wood, G.W.; Foster, M.; Clark, M.; Gollahon, K. Macrophages in experimental and human brain tumors. Part 2: Studies of the macrophage content of human brain tumors. J. Neurosurg. 1979, 50, 305–311, doi:10.3171/jns.1979.50.3.0305.
[114]  Morantz, R.A.; Wood, G.W.; Foster, M.; Clark, M.; Gollahon, K. Macrophages in experimental and human brain tumors. Part 1: Studies of the macrophage content of experimental rat brain tumors of varying immunogenicity. J. Neurosurg. 1979, 50, 298–304, doi:10.3171/jns.1979.50.3.0298.
[115]  Badie, B.; Schartner, J.; Prabakaran, S.; Paul, J.; Vorpahl, J. Expression of Fas ligand by microglia: Possible role in glioma immune evasion. J. Neuroimmunol. 2001, 120, 19–24, doi:10.1016/S0165-5728(01)00361-7.
[116]  Klein, R.; Roggendorf, W. Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: A double labeling study. Acta Neuropathol. 2001, 101, 245–248. 11307624
[117]  Badie, B.; Schartner, J. Role of microglia in glioma biology. Microsc. Res. Tech. 2001, 54, 106–113, doi:10.1002/jemt.1125.
[118]  Kielian, T.; van Rooijen, N.; Hickey, W.F. MCP-1 expression in CNS-1 astrocytoma cells: Implications for macrophage infiltration into tumors in vivo. J. Neurooncol. 2002, 56, 1–12, doi:10.1023/A:1014495613455.
[119]  Leung, S.Y.; Wong, M.P.; Chung, L.P.; Chan, A.S.; Yuen, S.T. Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas. Acta Neuropathol. 1997, 93, 518–527, doi:10.1007/s004010050647.
[120]  Mantovani, A.; Bottazzi, B.; Colotta, F.; Sozzani, S.; Ruco, L. The origin and function of tumor-associated macrophages. Immunol. Today 1992, 13, 265–270, doi:10.1016/0167-5699(92)90008-U.
[121]  Okada, M.; Saio, M.; Kito, Y.; Ohe, N.; Yano, H.; Yoshimura, S.; Iwama, T.; Takami, T. Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int. J. Oncol. 2009, 34, 1621–1627. 19424580
[122]  Badie, B.; Schartner, J.; Klaver, J.; Vorpahl, J. In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor. Neurosurgery 1999, 44, 1077–1082, doi:10.1097/00006123-199905000-00075.
[123]  Nishie, A.; Ono, M.; Shono, T.; Fukushi, J.; Otsubo, M.; Onoue, H.; Ito, Y.; Inamura, T.; Ikezaki, K.; Fukui, M.; et al. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin. Cancer Res. 1999, 5, 1107–1113. 10353745
[124]  Komohara, Y.; Ohnishi, K.; Kuratsu, J.; Takeya, M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J. Pathol. 2008, 216, 15–24, doi:10.1002/path.2370.
[125]  Markovic, D.S.; Glass, R.; Synowitz, M.; Rooijen, N.; Kettenmann, H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J. Neuropathol. Exp. Neurol. 2005, 64, 754–762, doi:10.1097/01.jnen.0000178445.33972.a9.
[126]  Markovic, D.S.; Vinnakota, K.; Chirasani, S.; Synowitz, M.; Raguet, H.; Stock, K.; Sliwa, M.; Lehmann, S.; Kalin, R.; van Rooijen, N.; et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc. Natl. Acad. Sci. USA 2009, 106, 12530–12535, doi:10.1073/pnas.0804273106. 19617536
[127]  Kioi, M.; Vogel, H.; Schultz, G.; Hoffman, R.M.; Harsh, G.R.; Brown, J.M. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 2010, 120, 694–705, doi:10.1172/JCI40283.
[128]  Pucci, F.; Venneri, M.A.; Biziato, D.; Nonis, A.; Moi, D.; Sica, A.; di Serio, C.; Naldini, L.; de Palma, M. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood “resident” monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood 2009, 114, 901–914, doi:10.1182/blood-2009-01-200931. 19383967
[129]  Galarneau, H.; Villeneuve, J.; Gowing, G.; Julien, J.P.; Vallieres, L. Increased glioma growth in mice depleted of macrophages. Cancer Res. 2007, 67, 8874–8881, doi:10.1158/0008-5472.CAN-07-0177.
[130]  Kanamori, M.; Kawaguchi, T.; Berger, M.S.; Pieper, R.O. Intracranial microenvironment reveals independent opposing functions of host alphaVbeta3 expression on glioma growth and angiogenesis. J. Biol. Chem. 2006, 281, 37256–37264, doi:10.1074/jbc.M605344200. 17028191
[131]  Murata, J.; Ricciardi-Castagnoli, P.; Dessous L'Eglise Mange, P.; Martin, F.; Juillerat-Jeanneret, L. Microglial cells induce cytotoxic effects toward colon carcinoma cells: Measurement of tumor cytotoxicity with a gamma-glutamyl transpeptidase assay. Int. J. Cancer 1997, 70, 169–174, doi:10.1002/(SICI)1097-0215(19970117)70:2<169::AID-IJC6>3.0.CO;2-V.
[132]  Carson, M.J.; Doose, J.M.; Melchior, B.; Schmid, C.D.; Ploix, C.C. CNS immune privilege: Hiding in plain sight. Immunol. Rev. 2006, 213, 48–65, doi:10.1111/j.1600-065X.2006.00441.x.
[133]  Flugel, A.; Labeur, M.S.; Grasbon-Frodl, E.M.; Kreutzberg, G.W.; Graeber, M.B. Microglia only weakly present glioma antigen to cytotoxic T cells. Int. J. Dev. Neurosci. 1999, 17, 547–556, doi:10.1016/S0736-5748(99)00020-9.
[134]  Huettner, C.; Czub, S.; Kerkau, S.; Roggendorf, W.; Tonn, J.C. Interleukin 10 is expressed in human gliomas in vivo and increases glioma cell proliferation and motility in vitro. Anticancer Res. 1997, 17, 3217–3224. 9413151
[135]  Kiefer, R.; Supler, M.L.; Toyka, K.V.; Streit, W.J. In situ detection of transforming growth factor-beta mRNA in experimental rat glioma and reactive glial cells. Neurosci. Lett. 1994, 166, 161–164, doi:10.1016/0304-3940(94)90475-8.
[136]  Kostianovsky, A.M.; Maier, L.M.; Anderson, R.C.; Bruce, J.N.; Anderson, D.E. Astrocytic regulation of human monocytic/microglial activation. J. Immunol. 2008, 181, 5425–5432. 18832699
[137]  Kuppner, M.C.; Sawamura, Y.; Hamou, M.F.; de Tribolet, N. Influence of PGE2- and cAMP-modulating agents on human glioblastoma cell killing by interleukin-2-activated lymphocytes. J. Neurosurg. 1990, 72, 619–625, doi:10.3171/jns.1990.72.4.0619.
[138]  O'Keefe, 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. 1999, 29, 1275–1285, doi:10.1002/(SICI)1521-4141(199904)29:04<1275::AID-IMMU1275>3.0.CO;2-T.
[139]  Wagner, S.; Czub, S.; Greif, M.; Vince, G.H.; Suss, N.; Kerkau, S.; Rieckmann, P.; Roggendorf, W.; Roosen, K.; Tonn, J.C. Microglial/macrophage expression of interleukin 10 in human glioblastomas. Int. J. Cancer 1999, 82, 12–16, doi:10.1002/(SICI)1097-0215(19990702)82:1<12::AID-IJC3>3.0.CO;2-O.
[140]  Schartner, J.M.; Hagar, A.R.; van Handel, M.; Zhang, L.; Nadkarni, N.; Badie, B. Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia 2005, 51, 279–285, doi:10.1002/glia.20201.
[141]  Taniguchi, Y.; Ono, K.; Yoshida, S.; Tanaka, R. Antigen-presenting capability of glial cells under glioma-harboring conditions and the effect of glioma-derived factors on antigen presentation. J. Neuroimmunol. 2000, 111, 177–185, doi:10.1016/S0165-5728(00)00361-1.
[142]  Ogden, A.T.; Horgan, D.; Waziri, A.; Anderson, D.; Louca, J.; McKhann, G.M.; Sisti, M.B.; Parsa, A.T.; Bruce, J.N. Defective receptor expression and dendritic cell differentiation of monocytes in glioblastomas. Neurosurgery 2006, 59, 902–910, doi:10.1227/01.NEU.0000233907.03070.7B.
[143]  Gabrilovich, D.I.; Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009, 9, 162–174, doi:10.1038/nri2506.
[144]  Greten, T.F.; Manns, M.P.; Korangy, F. Myeloid derived suppressor cells in human diseases. Int. Immunopharmacol. 2011, 11, 802–807, doi:10.1016/j.intimp.2011.01.003.
[145]  Talmadge, J.E. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin. Cancer Res. 2007, 13, 5243–5248, doi:10.1158/1078-0432.CCR-07-0182.
[146]  Melani, C.; Chiodoni, C.; Forni, G.; Colombo, M.P. Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 2003, 102, 2138–2145, doi:10.1182/blood-2003-01-0190.
[147]  Umemura, N.; Saio, M.; Suwa, T.; Kitoh, Y.; Bai, J.; Nonaka, K.; Ouyang, G.F.; Okada, M.; Balazs, M.; Adany, R.; et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J. Leukoc. Biol. 2008, 83, 1136–1144, doi:10.1189/jlb.0907611.
[148]  Gallina, G.; Dolcetti, L.; Serafini, P.; de Santo, C.; Marigo, I.; Colombo, M.P.; Basso, G.; Brombacher, F.; Borrello, I.; Zanovello, P.; et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 2006, 116, 2777–2790, doi:10.1172/JCI28828. 17016559
[149]  Sofroniew, M.V. Reactive astrocytes in neural repair and protection. Neuroscientist 2005, 11, 400–407, doi:10.1177/1073858405278321.
[150]  Sofroniew, M.V.; Vinters, H.V. Astrocytes: Biology and pathology. Acta Neuropathol. 2010, 119, 7–35, doi:10.1007/s00401-009-0619-8.
[151]  Fontana, A.; Fierz, W.; Wekerle, H. Astrocytes present myelin basic protein to encephalitogenic T-cell lines. Nature 1984, 307, 273–276, doi:10.1038/307273a0. 6198590
[152]  Yong, V.W.; Yong, F.P.; Ruijs, T.C.; Antel, J.P.; Kim, S.U. Expression and modulation of HLA-DR on cultured human adult astrocytes. J. Neuropathol. Exp. Neurol. 1991, 50, 16–28, doi:10.1097/00005072-199101000-00002.
[153]  Zhang, M.; Olsson, Y. Hematogenous metastases of the human brain—Characteristics of peritumoral brain changes: A review. J. Neurooncol. 1997, 35, 81–89, doi:10.1023/A:1005799805335.
[154]  Sierra, A.; Price, J. E.; Garcia-Ramirez, M.; Mendez, O.; Lopez, L.; Fabra, A. Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab. Invest. 1997, 77, 357–368. 9354770
[155]  Seike, T.; Fujita, K.; Yamakawa, Y.; Kido, M.A.; Takiguchi, S.; Teramoto, N.; Iguchi, H.; Noda, M. Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis. Clin. Exp. Metastasis 2010, 28, 13–25. 20953899
[156]  Langley, R.R.; Fan, D.; Guo, L.; Zhang, C.; Lin, Q.; Brantley, E.C.; McCarty, J.H.; Fidler, I.J. Generation of an immortalized astrocyte cell line from H-2Kb-tsA58 mice to study the role of astrocytes in brain metastasis. Int. J. Oncol. 2009, 35, 665–672. 19724901
[157]  Marchetti, D.; Li, J.; Shen, R. Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Res. 2000, 60, 4767–4770. 10987284
[158]  Yoshida, K.; Gage, F.H. Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res. 1991, 538, 118–126, doi:10.1016/0006-8993(91)90385-9.
[159]  Le, D.M.; Besson, A.; Fogg, D.K.; Choi, K.S.; Waisman, D.M.; Goodyer, C.G.; Rewcastle, B.; Yong, V.W. 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, 4034–4043. 12764090
[160]  Lin, Q.; Balasubramanian, K.; Fan, D.; Kim, S.J.; Guo, L.; Wang, H.; Bar-Eli, M.; Aldape, K.D.; Fidler, I.J. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia 2010, 12, 748–754. 20824051
[161]  Bechmann, I.; Steiner, B.; Gimsa, U.; Mor, G.; Wolf, S.; Beyer, M.; Nitsch, R.; Zipp, F. Astrocyte-induced T cell elimination is CD95 ligand dependent. J. Neuroimmunol. 2002, 132, 60–65, doi:10.1016/S0165-5728(02)00311-9. 12417434
[162]  Jain, R.K.; di Tomaso, E.; Duda, D.G.; Loeffler, J.S.; Sorensen, A.G.; Batchelor, T.T. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 2007, 8, 610–622. 17643088
[163]  Batchelor, T.T.; Sorensen, A.G.; di Tomaso, E.; Zhang, W.T.; Duda, D.G.; Cohen, K.S.; Kozak, K.R.; Cahill, D.P.; Chen, P.J.; Zhu, M.; et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007, 11, 83–95, doi:10.1016/j.ccr.2006.11.021.
[164]  JuanYin, J.; Tracy, K.; Zhang, L.; Munasinghe, J.; Shapiro, E.; Koretsky, A.; Kelly, K. Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model. Clin. Exp. Metastasis 2009, 26, 403–414, doi:10.1007/s10585-009-9238-y.
[165]  Kim, L.S.; Huang, S.; Lu, W.; Lev, D.C.; Price, J.E. Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin. Exp. Metastasis 2004, 21, 107–118, doi:10.1023/B:CLIN.0000024761.00373.55.
[166]  Narayana, A.; Kelly, P.; Golfinos, J.; Parker, E.; Johnson, G.; Knopp, E.; Zagzag, D.; Fischer, I.; Raza, S.; Medabalmi, P.; et al. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: Impact on local control and patient survival. J. Neurosurg. 2009, 110, 173–180, doi:10.3171/2008.4.17492. 18834263
[167]  Norden, A.D.; Young, G.S.; Setayesh, K.; Muzikansky, A.; Klufas, R.; Ross, G.L.; Ciampa, A.S.; Ebbeling, L.G.; Levy, B.; Drappatz, J.; et al. Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence. Neurology 2008, 70, 779–787, doi:10.1212/01.wnl.0000304121.57857.38. 18316689
[168]  Folkins, C.; Man, S.; Xu, P.; Shaked, Y.; Hicklin, D.J.; Kerbel, R.S. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007, 67, 3560–3564, doi:10.1158/0008-5472.CAN-06-4238. 17440065
[169]  de Palma, M.; Mazzieri, R.; Politi, L.S.; Pucci, F.; Zonari, E.; Sitia, G.; Mazzoleni, S.; Moi, D.; Venneri, M.A.; Indraccolo, S.; et al. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell 2008, 14, 299–311, doi:10.1016/j.ccr.2008.09.004.
[170]  Aboody, K.S.; Brown, A.; Rainov, N.G.; Bower, K.A.; Liu, S.; Yang, W.; Small, J.E.; Herrlinger, U.; Ourednik, V.; Black, P.M.; et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc. Natl. Acad. Sci. USA 2000, 97, 12846–12851, doi:10.1073/pnas.97.23.12846. 11070094
[171]  Kim, S.K.; Kim, S.U.; Park, I.H.; Bang, J.H.; Aboody, K.S.; Wang, K.C.; Cho, B.K.; Kim, M.; Menon, L.G.; Black, P.M.; et al. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin. Cancer Res. 2006, 12, 5550–5556, doi:10.1158/1078-0432.CCR-05-2508. 17000692
[172]  Bexell, D.; Gunnarsson, S.; Svensson, A.; Tormin, A.; Henriques-Oliveira, C.; Siesjo, P.; Paul, G.; Salford, L.G.; Scheding, S.; Bengzon, J. Rat multipotent mesenchymal stromal cells lack long-distance tropism to three different rat glioma models. Neurosurgery 2011.
[173]  Balyasnikova, I.V.; Ferguson, S.D.; Sengupta, S.; Han, Y.; Lesniak, M.S. Mesenchymal stem cells modified with a single-chain antibody against EGFRvIII successfully inhibit the growth of human xenograft malignant glioma. PloS One 2010, 5, e9750, doi:10.1371/journal.pone.0009750. 20305783


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