The Impact of Hypoxia and Mesenchymal Transition on Glioblastoma Pathogenesis and Cancer Stem Cells Regulation

World Neurosurgery

Volumn 88, Issue , 2016, Pages 222-236

  Karsy, Michael ^a   Guan, Jian ^a   Jensen, Randy ^a,b   Huang, L Eric ^a,c   Colman, Howard ^a,b  

^a Clinical Neurosciences Center   (United States)

^b UNIVERSITY OF UTAH   (United States)

^c UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

Cancer stem cell; Epithelial mesenchymal transition; Glioblastoma; Hypoxia; Hypoxia inducible factor

Indexed keywords

CCAAT ENHANCER BINDING PROTEIN BETA; CHEMOKINE RECEPTOR CXCR; HYPOXIA INDUCIBLE FACTOR; HYPOXIA INDUCIBLE FACTOR 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MONOCARBOXYLATE TRANSPORTER 4; MYC PROTEIN; NITRIC OXIDE; NOTCH RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PHOSPHOPROTEIN PHOSPHATASE 2A; PROTEIN; PROTEIN BCL W; PROTEIN KINASE B; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; STAT3 PROTEIN; SUCCINATE DEHYDROGENASE; TRANSCRIPTION FACTOR SNAIL; TRANSCRIPTION FACTOR TWIST; VASCULOTROPIN; OXYGEN;

CANCER STEM CELL; CELL POPULATION; EPITHELIAL MESENCHYMAL TRANSITION; GLIOBLASTOMA; HUMAN; HYPOXIA; PROTEIN EXPRESSION; REVIEW; TUMOR MICROENVIRONMENT; ANIMAL; CARCINOGENESIS; CELL HYPOXIA; METABOLISM; PATHOLOGY;

ANIMALS; CARCINOGENESIS; CELL HYPOXIA; EPITHELIAL-MESENCHYMAL TRANSITION; GLIOBLASTOMA; HUMANS; NEOPLASTIC STEM CELLS; OXYGEN;

EID: 84959387698     PISSN: 18788750     EISSN: 18788769     Source Type: Journal    
DOI: 10.1016/j.wneu.2015.12.032     Document Type: Review

References (126)

1. M.R. Gilbert, M. Wang, K.D. Aldape, R. Stupp, M.E. Hegi, K.A. Jaeckle, and et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial J Clin Oncol 31 2013 4085 4091
2. R. Stupp, M.E. Hegi, W.P. Mason, M.J. van den Bent, M.J. Taphoorn, R.C. Janzer, and 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 10 2009 459 466
3. M. Wang, J.J. Dignam, M. Won, W. Curran, M. Mehta, and M.R. Gilbert Variation over time and interdependence between disease progression and death among patients with glioblastoma on RTOG 0525 Neuro Oncol 17 2015 999 1006
4. Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 455 2008 1061 1068
5. R.G. Verhaak, K.A. Hoadley, E. Purdom, V. Wang, Y. Qi, M.D. Wilkerson, and et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 Cancer Cell 17 2010 98 110
6. C.W. Brennan, R.G. Verhaak, A. McKenna, B. Campos, H. Noushmehr, S.R. Salama, and et al. The somatic genomic landscape of glioblastoma Cell 155 2013 462 477
7. H. Noushmehr, D.J. Weisenberger, K. Diefes, H.S. Phillips, K. Pujara, B.P. Berman, and et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma Cancer Cell 17 2010 510 522
8. M. Jhanwar-Uniyal, L. Albert, E. McKenna, M. Karsy, P. Rajdev, A. Braun, and et al. Deciphering the signaling pathways of cancer stem cells of glioblastoma multiforme: role of Akt/mTOR and MAPK pathways Adv Enzyme Regul 51 2011 164 170
9. M. Womeldorff, D. Gillespie, and R.L. Jensen Hypoxia-inducible factor-1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma Neurosurg Focus 37 6 2014 E8
10. K.P. Bhat, V. Balasubramaniyan, B. Vaillant, R. Ezhilarasan, K. Hummelink, F. Hollingsworth, and et al. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma Cancer Cell 24 2013 331 346
11. C. Calabrese, H. Poppleton, M. Kocak, T.L. Hogg, C. Fuller, B. Hamner, and et al. A perivascular niche for brain tumor stem cells Cancer Cell 11 2007 69 82
12. N. Charles, T. Ozawa, M. Squatrito, A.M. Bleau, C.W. Brennan, D. Hambardzumyan, and et al. Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells Cell Stem Cell 6 2010 141 152
13. H. Colman, L. Zhang, E.P. Sulman, J.M. McDonald, N.L. Shooshtari, A. Rivera, and et al. A multigene predictor of outcome in glioblastoma Neuro Oncol 12 2010 49 57
14. A. Mohyeldin, T. Garzon-Muvdi, and A. Quinones-Hinojosa Oxygen in stem cell biology: a critical component of the stem cell niche Cell Stem Cell 7 2010 150 161
15. E.E. Bar, A. Lin, V. Mahairaki, W. Matsui, and C.G. Eberhart Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres Am J Pathol 177 2010 1491 1502
16. S. Bao, Q. Wu, R.E. McLendon, Y. Hao, Q. Shi, A.B. Hjelmeland, and et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response Nature 444 2006 756 760
17. J.M. Heddleston, Z. Li, R.E. McLendon, A.B. Hjelmeland, and J.N. Rich The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype Cell Cycle 8 2009 3274 3284
18. Z. Li, S. Bao, Q. Wu, H. Wang, C. Eyler, S. Sathornsumetee, and et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells Cancer Cell 15 2009 501 513
19. A. Soeda, M. Park, D. Lee, A. Mintz, A. Androutsellis-Theotokis, R.D. McKay, and et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha Oncogene 28 2009 3949 3959
20. R.L. Jensen, M.L. Mumert, D.L. Gillespie, A.Y. Kinney, M.C. Schabel, and K.L. Salzman Preoperative dynamic contrast-enhanced MRI correlates with molecular markers of hypoxia and vascularity in specific areas of intratumoral microenvironment and is predictive of patient outcome Neuro Oncol 16 2014 280 291
21. Y. Rong, D.L. Durden, E.G. Van Meir, and D.J. Brat 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis J Neuropathol Exp Neurol 65 2006 529 539
22. M.A. Goldberg, S.P. Dunning, and H.F. Bunn Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein Science 242 1988 1412 1415
23. G.L. Semenza, M.K. Nejfelt, S.M. Chi, and S.E. Antonarakis Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene Proc Natl Acad Sci U S A 88 1991 5680 5684
24. L.E. Huang, Z. Arany, D.M. Livingston, and H.F. Bunn Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit J Biol Chem 271 1996 32253 32259
25. L.E. Huang, and H.F. Bunn Hypoxia-inducible factor and its biomedical relevance J Biol Chem 278 2003 19575 19578
26. C.J. Schofield, and P.J. Ratcliffe Oxygen sensing by HIF hydroxylases Nat Rev Mol Cell Biol 5 2004 343 354
27. G.L. Semenza Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1 Annu Rev Cell Dev Biol 15 1999 551 578
28. L.E. Huang, J. Gu, M. Schau, and H.F. Bunn Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway Proc Natl Acad Sci U S A 95 1998 7987 7992
29. N.M. Haddad, J.D. Cavallerano, and P.S. Silva Von Hippel-Lindau disease: a genetic and clinical review Semin Ophthalmol 28 2013 377 386
30. P.J. Kallio, I. Pongratz, K. Gradin, J. McGuire, and L. Poellinger Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor Proc Natl Acad Sci U S A 94 1997 5667 5672
31. N.J. Mabjeesh, and S. Amir Hypoxia-inducible factor (HIF) in human tumorigenesis Histol Histopathol 22 2007 559 572
32. W.G. Kaelin Jr., and P.J. Ratcliffe Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway Mol Cell 30 2008 393 402
33. P.C. Mahon, K. Hirota, and G.L. Semenza FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity Genes Dev 15 2001 2675 2686
34. A.J. Majmundar, W.J. Wong, and M.C. Simon Hypoxia-inducible factors and the response to hypoxic stress Mol Cell 40 2010 294 309
35. E. Wang, C. Zhang, N. Polavaram, F. Liu, G. Wu, M.A. Schroeder, and et al. The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme PLoS One 9 2014 e86102
36. K.S. Lim, K.J. Lim, A.C. Price, B.A. Orr, C.G. Eberhart, and E.E. Bar Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner Oncogene 33 2014 4433 4441
37. X.Y. Hong, J. Wang, and Z. Li AGR2 expression is regulated by HIF-1 and contributes to growth and angiogenesis of glioblastoma Cell Biochem Biophys 67 2013 1487 1495
38. C.P. Hofstetter, J.K. Burkhardt, B.J. Shin, D.B. Gursel, L. Mubita, R. Gorrepati, and et al. Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia PLoS One 7 2012 e30059
39. C.H. Hsieh, W.C. Shyu, C.Y. Chiang, J.W. Kuo, W.C. Shen, and R.S. Liu NADPH oxidase subunit 4-mediated reactive oxygen species contribute to cycling hypoxia-promoted tumor progression in glioblastoma multiforme PLoS One 6 2011 e23945
40. G. Laurenti, E. Benedetti, B. D'Angelo, L. Cristiano, B. Cinque, S. Raysi, and et al. Hypoxia induces peroxisome proliferator-activated receptor alpha (PPARalpha) and lipid metabolism peroxisomal enzymes in human glioblastoma cells J Cell Biochem 112 2011 3891 3901
41. J.M. Heddleston, Q. Wu, M. Rivera, S. Minhas, J.D. Lathia, A.E. Sloan, and et al. Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential Cell Death Differ 19 2012 428 439
42. D. Zagzag, Y. Lukyanov, L. Lan, M.A. Ali, M. Esencay, O. Mendez, and et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion Lab Invest 86 2006 1221 1232
43. L. Qiang, T. Wu, H.W. Zhang, N. Lu, R. Hu, Y.J. Wang, and et al. HIF-1alpha is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway Cell Death Differ 19 2012 284 294
44. S. Chigurupati, R. Venkataraman, D. Barrera, A. Naganathan, M. Madan, L. Paul, and et al. Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness Cancer Res 70 2010 418 427
45. K.V. Lu, J.P. Chang, C.A. Parachoniak, M.M. Pandika, M.K. Aghi, D. Meyronet, and et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex Cancer Cell 22 2012 21 35
46. C.A. Clara, S.K. Marie, J.R. de Almeida, A. Wakamatsu, S.M. Oba-Shinjo, M. Uno, and et al. Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1alpha in human glioblastoma Neuropathology 34 2014 343 352
47. L.M. Ellis, and D.J. Hicklin VEGF-targeted therapy: mechanisms of anti-tumour activity Nat Rev Cancer 8 2008 579 591
48. M. Paez-Ribes, E. Allen, J. Hudock, T. Takeda, H. Okuyama, F. Vinals, and et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis Cancer Cell 15 2009 220 231
49. R. Agrawal, P. Pandey, P. Jha, V. Dwivedi, C. Sarkar, and R. Kulshreshtha Hypoxic signature of microRNAs in glioblastoma: insights from small RNA deep sequencing BMC Genomics 15 2014 686
50. C.W. Chou, C.C. Wang, C.P. Wu, Y.J. Lin, Y.C. Lee, Y.W. Cheng, and et al. Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1 Neuro Oncol 14 2012 1227 1238
51. J.D. Gordan, J.A. Bertout, C.J. Hu, J.A. Diehl, and M.C. Simon HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity Cancer Cell 11 2007 335 347
52. X.G. Mao, M. Yan, X.Y. Xue, X. Zhang, H.G. Ren, G. Guo, and et al. Overexpression of ZNF217 in glioblastoma contributes to the maintenance of glioma stem cells regulated by hypoxia-inducible factors Lab Invest 91 2011 1068 1078
53. F. Pistollato, S. Abbadi, E. Rampazzo, G. Viola, A. Della Puppa, L. Cavallini, and et al. Hypoxia and succinate antagonize 2-deoxyglucose effects on glioblastoma Biochem Pharmacol 80 2010 1517 1527
54. F. Pistollato, E. Rampazzo, S. Abbadi, A. Della Puppa, R. Scienza, D. D'Avella, and et al. Molecular mechanisms of HIF-1alpha modulation induced by oxygen tension and BMP2 in glioblastoma derived cells PLoS One 4 2009 e6206
55. U. Gopal, J.E. Bohonowych, C. Lema-Tome, A. Liu, E. Garrett-Mayer, B. Wang, and et al. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion PLoS One 6 2011 e17649
56. G. Wang, K. Sai, F. Gong, Q. Yang, F. Chen, and J. Lin Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via nuclear factor-kappaB activation in a hypoxia-inducible factor 1-alpha dependent manner Mol Med Rep 9 2014 1799 1805
57. J.T. Chi, Z. Wang, D.S. Nuyten, E.H. Rodriguez, M.E. Schaner, A. Salim, and et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers PLoS Med 3 2006 e47
58. Q. Ke, and M. Costa Hypoxia-inducible factor-1 (HIF-1) Mol Pharmacol 70 2006 1469 1480
59. G.L. Semenza Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy Trends Pharmacol Sci 33 2012 207 214
60. G.L. Semenza HIF-1: upstream and downstream of cancer metabolism Curr Opin Genet Dev 20 2010 51 56
61. R. Ravi, B. Mookerjee, Z.M. Bhujwalla, C.H. Sutter, D. Artemov, Q. Zeng, and et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha Genes Dev 14 2000 34 44
62. J. Jiang, Y.L. Tang, and X.H. Liang EMT: a new vision of hypoxia promoting cancer progression Cancer Biol Ther 11 2011 714 723
63. J. Anido, A. Saez-Borderias, A. Gonzalez-Junca, L. Rodon, G. Folch, M.A. Carmona, and et al. TGF-beta receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma Cancer Cell 18 2010 655 668
64. P.J. Eichhorn, L. Rodon, A. Gonzalez-Junca, A. Dirac, M. Gili, E. Martinez-Saez, and et al. USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma Nat Med 18 2012 429 435
65. S. Penuelas, J. Anido, R.M. Prieto-Sanchez, G. Folch, I. Barba, I. Cuartas, and et al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma Cancer Cell 15 2009 315 327
66. J. Seoane, H.V. Le, L. Shen, S.A. Anderson, and J. Massague Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation Cell 117 2004 211 223
67. H. Choi, D.L. Gillespie, S. Berg, C. Rice, S. Couldwell, J. Gu, and et al. Intermittent induction of HIF-1alpha produces lasting effects on malignant progression independent of its continued expression PLoS One 10 2015 e0125125
68. N. Raimundo, B.E. Baysal, and G.S. Shadel Revisiting the TCA cycle: signaling to tumor formation Trends Mol Med 17 2011 641 649
69. R. Chen, V.M. Ravindra, A.L. Cohen, R.L. Jensen, K.L. Salzman, A.P. Prescot, and et al. Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas Neurosurg Focus 38 3 2015 E2
70. M. Karsy, J.A. Neil, J. Guan, M.A. Mark, H. Colman, and R.L. Jensen A practical review of prognostic correlations of molecular biomarkers in glioblastoma Neurosurg Focus 38 3 2015 E4
71. D.W. Parsons, S. Jones, X. Zhang, J.C. Lin, R.J. Leary, P. Angenendt, and et al. An integrated genomic analysis of human glioblastoma multiforme Science 321 2008 1807 1812
72. J.A. Menendez, T. Alarcon, and J. Joven Gerometabolites: the pseudohypoxic aging side of cancer oncometabolites Cell Cycle 13 2014 699 709
73. P. Koivunen, S. Lee, C.G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, and et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation Nature 483 2012 484 488
74. G. Christofori New signals from the invasive front Nature 441 2006 444 450
75. S.A. Mikheeva, A.M. Mikheev, A. Petit, R. Beyer, R.G. Oxford, L. Khorasani, and et al. TWIST1 promotes invasion through mesenchymal change in human glioblastoma Mol Cancer 9 2010 194
76. W.S. Lee, E.Y. Woo, J. Kwon, M.J. Park, J.S. Lee, Y.H. Han, and et al. Bcl-w enhances mesenchymal changes and invasiveness of glioblastoma cells by inducing nuclear accumulation of beta-catenin PLoS One 8 2013 e68030
77. K.P. Bhat, K.L. Salazar, V. Balasubramaniyan, K. Wani, L. Heathcock, F. Hollingsworth, and et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma Genes Dev 25 2011 2594 2609
78. M.S. Carro, W.K. Lim, M.J. Alvarez, R.J. Bollo, X. Zhao, E.Y. Snyder, and et al. The transcriptional network for mesenchymal transformation of brain tumours Nature 463 2010 318 325
79. J.K. Myung, S.A. Choi, S.K. Kim, K.C. Wang, and S.H. Park Snail plays an oncogenic role in glioblastoma by promoting epithelial mesenchymal transition Int J Clin Exp Pathol 7 2014 1977 1987
80. W.Y. Cheng, J.J. Kandel, D.J. Yamashiro, P. Canoll, and D. Anastassiou A multi-cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma PLoS One 7 2012 e34705
81. H.W. Yang, L.G. Menon, P.M. Black, R.S. Carroll, and M.D. Johnson SNAI2/Slug promotes growth and invasion in human gliomas BMC Cancer 10 2010 301
82. H. Zarkoob, J.H. Taube, S.K. Singh, S.A. Mani, and M. Kohandel Investigating the link between molecular subtypes of glioblastoma, epithelial-mesenchymal transition, and CD133 cell surface protein PLoS One 8 2013 e64169
83. C.L. Tso, W.A. Freije, A. Day, Z. Chen, B. Merriman, A. Perlina, and et al. Distinct transcription profiles of primary and secondary glioblastoma subgroups Cancer Res 66 2006 159 167
84. F.A. Siebzehnrubl, D.J. Silver, B. Tugertimur, L.P. Deleyrolle, D. Siebzehnrubl, M.R. Sarkisian, and et al. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance EMBO Mol Med 5 2013 1196 1212
85. D.W. Lee, D. Ramakrishnan, J. Valenta, I.F. Parney, K.J. Bayless, and R. Sitcheran The NF-kappaB RelB protein is an oncogenic driver of mesenchymal glioma PLoS One 8 2013 e57489
86. Y.P. Tsai, and K.J. Wu Hypoxia-regulated target genes implicated in tumor metastasis J Biomed Sci 19 2012 102
87. D.T. Marie-Egyptienne, I. Lohse, and R.P. Hill Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia Cancer Lett 341 2013 63 72
88. J.A. Forsythe, B.H. Jiang, N.V. Iyer, F. Agani, S.W. Leung, R.D. Koos, and et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 Mol Cell Biol 16 1996 4604 4613
89. Y. Piao, J. Liang, L. Holmes, A.J. Zurita, V. Henry, J.V. Heymach, and et al. Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype Neuro Oncol 14 2012 1379 1392
90. C. Murdoch, M. Muthana, S.B. Coffelt, and C.E. Lewis The role of myeloid cells in the promotion of tumour angiogenesis Nat Rev Cancer 8 2008 618 631
91. U.D. Kahlert, D. Maciaczyk, S. Doostkam, B.A. Orr, B. Simons, T. Bogiel, and et al. Activation of canonical WNT/beta-catenin signaling enhances in vitro motility of glioblastoma cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition Cancer Lett 325 2012 42 53
92. T.C. Wang, S.J. Luo, C.L. Lin, P.J. Chang, and M.F. Chen Modulation of p75 neurotrophin receptor under hypoxic conditions induces migration and invasion of C6 glioma cells Clin Exp Metastasis 32 2015 73 81
93. L.K. Mathew, N. Skuli, V. Mucaj, S.S. Lee, P.O. Zinn, P. Sathyan, and et al. miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma Proc Natl Acad Sci U S A 111 2014 291 296
94. H.G. Moller, A.P. Rasmussen, H.H. Andersen, K.B. Johnsen, M. Henriksen, and M. Duroux A systematic review of microRNA in glioblastoma multiforme: micro-modulators in the mesenchymal mode of migration and invasion Mol Neurobiol 47 2013 131 144
95. J. Chen, Y. Li, T.S. Yu, R.M. McKay, D.K. Burns, S.G. Kernie, and et al. A restricted cell population propagates glioblastoma growth after chemotherapy Nature 488 2012 522 526
96. M. Karsy, L. Albert, R. Murali, and M. Jhanwar-Uniyal The impact of arsenic trioxide and all-trans retinoic acid on p53 R273H-codon mutant glioblastoma Tumour Biol 35 2014 4567 4580
97. K. Yan, K. Yang, and J.N. Rich The evolving landscape of glioblastoma stem cells Curr Opin Neurol 26 2013 701 707
98. H. Zheng, H. Ying, H. Yan, A.C. Kimmelman, D.J. Hiller, A.J. Chen, and et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation Nature 455 2008 1129 1133
99. M.J. Son, K. Woolard, D.H. Nam, J. Lee, and H.A. Fine SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma Cell Stem Cell 4 2009 440 452
100. D. Sturm, H. Witt, V. Hovestadt, D.A. Khuong-Quang, D.T. Jones, C. Konermann, and et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma Cancer Cell 22 2012 425 437
101. K. Akimoto, K. Kimura, M. Nagano, S. Takano, G. To'a Salazar, T. Yamashita, and et al. Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation Stem Cells Dev 22 2013 1370 1386
102. L. Ricci-Vitiani, R. Pallini, M. Biffoni, M. Todaro, G. Invernici, T. Cenci, and et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells Nature 468 2010 824 828
103. R. Wang, K. Chadalavada, J. Wilshire, U. Kowalik, K.E. Hovinga, A. Geber, and et al. Glioblastoma stem-like cells give rise to tumour endothelium Nature 468 2010 829 833
104. L. Cheng, Z. Huang, W. Zhou, Q. Wu, S. Donnola, J.K. Liu, and et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth Cell 153 2013 139 152
105. R. Du, K.V. Lu, C. Petritsch, P. Liu, R. Ganss, E. Passegue, and et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion Cancer Cell 13 2008 206 220
106. Y. Soda, T. Marumoto, D. Friedmann-Morvinski, M. Soda, F. Liu, H. Michiue, and et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells Proc Natl Acad Sci U S A 108 2011 4274 4280
107. S. El Hallani, C. Colin, Y. El Houfi, A. Idbaih, B. Boisselier, Y. Marie, and et al. Tumor and endothelial cell hybrids participate in glioblastoma vasculature Biomed Res Int 2014 2014 827327
108. K.S. Lehnus, L.K. Donovan, X. Huang, N. Zhao, T.J. Warr, G.J. Pilkington, and et al. CD133 glycosylation is enhanced by hypoxia in cultured glioma stem cells Int J Oncol 42 2013 1011 1017
109. A.M. McCord, M. Jamal, U.T. Shankavaram, F.F. Lang, K. Camphausen, and P.J. Tofilon Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro Mol Cancer Res 7 2009 489 497
110. O. Mendez, J. Zavadil, M. Esencay, Y. Lukyanov, D. Santovasi, S.C. Wang, and et al. Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres Mol Cancer 9 2010 133
111. S. Merighi, A. Benini, P. Mirandola, S. Gessi, K. Varani, E. Leung, and et al. Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells Biochem Pharmacol 72 2006 19 31
112. C. Xu, X. Wu, and J. Zhu VEGF promotes proliferation of human glioblastoma multiforme stem-like cells through VEGF receptor 2 Sci World J 2013 2013 417413
113. F. Pistollato, S. Abbadi, E. Rampazzo, L. Persano, A. Della Puppa, C. Frasson, and et al. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma Stem Cells 28 2010 851 862
114. S. Seidel, B.K. Garvalov, V. Wirta, L. von Stechow, A. Schanzer, K. Meletis, and et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha Brain 133 2010 983 995
115. S.K. Burroughs, S. Kaluz, D. Wang, K. Wang, E.G. Van Meir, and B. Wang Hypoxia inducible factor pathway inhibitors as anticancer therapeutics Future Med Chem 5 2013 553 572
116. F.M. Davis, T.A. Stewart, E.W. Thompson, and G.R. Monteith Targeting EMT in cancer: opportunities for pharmacological intervention Trends Pharmacol Sci 35 2014 479 488
117. O.L. Chinot, W. Wick, W. Mason, R. Henriksson, F. Saran, R. Nishikawa, and et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma N Engl J Med 370 2014 709 722
118. M. Khasraw, M.S. Ameratunga, R. Grant, H. Wheeler, and N. Pavlakis Antiangiogenic therapy for high-grade glioma Cochrane Database Syst Rev 9 2014 CD008218
119. T.T. Batchelor, P. Mulholland, B. Neyns, L.B. Nabors, M. Campone, A. Wick, and et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma J Clin Oncol 31 2013 3212 3218
120. S. Sathornsumetee, Y. Cao, J.E. Marcello, J.E. Herndon 2nd, R.E. McLendon, A. Desjardins, and et al. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan J Clin Oncol 26 2008 271 278
121. O. Keunen, M. Johansson, A. Oudin, M. Sanzey, S.A. Rahim, F. Fack, and et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma Proc Natl Acad Sci U S A 108 2011 3749 3754
122. D.L. Gillespie, K. Whang, B.T. Ragel, J.R. Flynn, D.A. Kelly, and R.L. Jensen Silencing of hypoxia inducible factor-1alpha by RNA interference attenuates human glioma cell growth in vivo Clin Cancer Res 13 2007 2441 2448
123. A.N. Kothari, Z. Mi, M. Zapf, and P.C. Kuo Novel clinical therapeutics targeting the epithelial to mesenchymal transition Clin Transl Med 3 2014 35
124. L. Ma, F. Reinhardt, E. Pan, J. Soutschek, B. Bhat, E.G. Marcusson, and et al. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model Nat Biotechnol 28 2010 341 347
125. A. Vazquez-Martin, C. Oliveras-Ferraros, S. Cufi, S. Del Barco, B. Martin-Castillo, and J.A. Menendez Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status Cell Cycle 9 2010 3807 3814
126. S. Lamouille, J. Xu, and R. Derynck Molecular mechanisms of epithelial-mesenchymal transition Nat Rev Mol Cell Biol 15 2014 178 196