9. Nakai E, Park K, Yawata T, Chihara T, Kumazawa A, et al. (2009) Enhanced MDR1 expression and chemoresistance of cancer stem cells derived from glioblastoma. Cancer Invest 27: 901–908. 10. Salmaggi A, Boiardi A, Gelati M, Russo A, Calatozzolo C, et al. (2006) Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype. Glia 54: 850–860. 11. Rempel SA, Dudas S, Ge S, Gutierrez JA (2000) Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6: 102–111. 12. Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, et al. (2006) Hypoxia- inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86: 1221–1232. 13. Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, et al. (2006) Expression of CXC chemokine receptors 1–5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 49: 423–432. 14. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, et al. (2003) A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A 100: 13513–13518. 15. Woerner BM, Warrington NM, Kung AL, Perry A, Rubin JB (2005) Widespread CXCR4 activation in astrocytomas revealed by phospho- CXCR4-specific antibodies. Cancer Res 65: 11392–11399. 16. Kenig S, Alonso MB, Mueller MM, Lah TT (2010) Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. Cancer Lett 289: 53–61. 17. Salmaggi A, Gelati M, Pollo B, Frigerio S, Eoli M, et al. (2004) CXCL12 in malignant glial tumors: a possible role in angiogenesis and cross-talk between endothelial and tumoral cells. J Neurooncol 67: 305–317. 18. Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA (2006) Tumor stromal- derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 66: 9054–9064. 19. Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, et al. (2004) Chemokine- mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med 10: 64–71. 20. Reiss K, Mentlein R, Sievers J, Hartmann D (2002) Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer. Neuroscience 115: 295–305. 21. Zhu Y, Yu T, Zhang XC, Nagasawa T, Wu JY, et al. (2002) Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci 5: 719–720. 22. Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, et al. (2001) SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 128: 1971–1981. 23. Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, et al. (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A 95: 9448–9453. 24. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595–599. 25. Mishima S, Nagai A, Abdullah S, Matsuda C, Taketani T, et al. Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent. Eur J Haematol 84: 538–546. 26. Wu Y, Peng H, Cui M, Whitney NP, Huang Y, et al. (2009) CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway. J Neurochem 109: 1157–1167. 27. Zheng H, Dai T, Zhou B, Zhu J, Huang H, et al. (2008) SDF-1alpha/CXCR4 decreases endothelial progenitor cells apoptosis under serum deprivation by PI3K/Akt/eNOS pathway. Atherosclerosis 201: 36–42. 28. Patel JR, McCandless EE, Dorsey D, Klein RS CXCR4 promotes differen- tiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci U S A 107: 11062–11067. 29. Karin N The multiple faces of CXCL12 (SDF-1alpha) in the regulation of immunity during health and disease. J Leukoc Biol 88: 463–473. 30. Bian XW, Yang SX, Chen JH, Ping YF, Zhou XD, et al. (2007) Preferential expression of chemokine receptor CXCR4 by highly malignant human gliomas and its association with poor patient survival. Neurosurgery 61: 570–578; discussion 578–579. 31. Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D, et al. (2007) Blocking CXCR4-Mediated Cyclic AMP Suppression Inhibits Brain Tumor Growth In vivo. Cancer Res 67: 651–658. 32. Smith MC, Luker KE, Garbow JR, Prior JL, Jackson E, et al. (2004) CXCR4 regulates growth of both primary and metastatic breast cancer. Cancer Res 64: 8604–8612. 33. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, et al. (2010) Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120: 694–705. CXCL12 Mediated GBM-Endothelial Cell Interactions 34. Hattermann K, Held-Feindt J, Lucius R, Muerkoster SS, Penfold ME, et al. (2010) The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res 70: 3299–3308. 35. Calatozzolo C, Canazza A, Pollo B, Di Pierro E, Ciusani E, et al. (2011) Expression of the new CXCL12 receptor, CXCR7, in gliomas. Cancer Biol Ther 11: 242–253. 36. Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, et al. (2010) Cyclic AMP supppression is sufficient to induce gliomagenesis in a mouse model of Neurofibromatosis-1. Cancer Research 70: 5717–5727. 37. Goldhoff P, Warrington NM, Limbrick DD, Jr., Hope A, Woerner BM, et al. (2008) Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression. Clin Cancer Res 14: 7717–7725. 38. Sun T, Gianino SM, Jackson E, Piwnica-Worms D, Gutmann DH, et al. (2010) CXCL12 alone is insufficient for gliomagenesis in Nf1 mutant mice. J NeuroimmunolIn press. 39. Zagzag D, Esencay M, Mendez O, Yee H, Smirnova I, et al. (2008) Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor- 1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer’s structures. Am J Pathol 173: 545–560. 40. Kokovay E, Goderie S, Wang Y, Lotz S, Lin G, et al. (2011) Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/ CXCR4 signaling. Cell Stem Cell 7: 163–173. 41. Kleinman HK, McGarvey ML, Liotta LA, Robey PG, Tryggvason K, et al. (1982) Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma. Biochemistry 21: 6188–6193. 42. Kerever A, Schnack J, Vellinga D, Ichikawa N, Moon C, et al. (2007) Novel extracellular matrix structures in the neural stem cell niche capture the neurogenic factor fibroblast growth factor 2 from the extracellular milieu. Stem Cells 25: 2146–2157. 43. Hack I, Bancila M, Loulier K, Carroll P, Cremer H (2002) Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nat Neurosci 5: 939–945. 44. Aarum J, Sandberg K, Haeberlein SL, Persson MA (2003) Migration and differentiation of neural precursor cells can be directed by microglia. Proc Natl Acad Sci U S A 100: 15983–15988. 45. Uemura M, Refaat MM, Shinoyama M, Hayashi H, Hashimoto N, et al. Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell-derived neural precursor cells. J Neurosci Res 88: 542–551. 46. Cavenee WK, Furnari FB, Nagane M, Huang H-JS, Newcomb EW, Bigner DD, Weller M, Berens ME, Plate KH, Israel MA, Noble MD, Kleihues P (2000) Astrocytic Tumours. In: Cavevee PKWK, ed. World Health Organization Classification of Tumours: Tumours of the Central Nervous System. Lyon: IARC Press. pp 9–54. 47. Huang J, Chen K, Gong W, Dunlop NM, Wang JM (2008) G-protein coupled chemoattractant receptors and cancer. Front Biosci 13: 3352–3363. 48. Wurth R, Barbieri F, Bajetto A, Pattarozzi A, Gatti M, et al. Expression of CXCR7 chemokine receptor in human meningioma cells and in intratumoral microvasculature. J Neuroimmunol 234: 115–123. 49. Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, et al. (2006) A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med 203: 2201–2213. 50. Ma Q, Jones D, Springer TA (1999) The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10: 463–471. 51. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC (1997) The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 185: 111–120. 52. Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25: 977–988. 53. Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, et al. (2010) Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6: 141–152. 54. Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, et al. (2010) A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell 17: 362–375. 55. Sauvageot CM, Kesari S, Stiles CD (2007) Molecular pathogenesis of adult brain tumors and the role of stem cells. Neurol Clin 25: 891–924, vii. 56. Cheng L, Bao S, Rich JN (2010) Potential therapeutic implications of cancer stem cells in glioblastoma. Biochem Pharmacol 80: 654–665. 57. Liu G, Yuan X, Zeng Z, Tunici P, Ng H, et al. (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5: 67. 58. Redjal N, Chan JA, Segal RA, Kung AL (2006) CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res 12: 6765–6771. 59. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, et al. (2009) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 113: 6215–6224. PLoS ONE | www.plosone.org 11 March 2012 | Volume 7 | Issue 3 | e33005