The angiogenesis process is a key event for glioma survival, malignancy and growth. The start of angiogenesis is mediated by a cascade of intratumoural events: alteration of the microvasculature network; a hypoxic microenvironment; adaptation of neoplastic cells and synthesis of pro-angiogenic factors. Due to a chaotic blood flow, a consequence of an aberrant microvasculature, tissue hypoxia phenomena are induced. Hypoxia inducible factor 1 is a major regulator in glioma invasiveness and angiogenesis. Clones of neoplastic cells with stem cell characteristics are selected by HIF-1. These cells, called “glioma stem cells” induce the synthesis of vascular endothelial growth factor. This factor is a pivotal mediator of angiogenesis. To elucidate the role of these angiogenic mediators during glioma growth, we have used a rat endogenous glioma model. Gliomas induced by prenatal ENU administration allowed us to study angiogenic events from early to advanced tumour stages. Events such as microvascular aberrations, hypoxia, GSC selection and VEGF synthesis may be studied in depth. Our data showed that for the treatment of gliomas, developing anti-angiogenic therapies could be aimed at GSCs, HIF-1 or VEGF. The ENU-glioma model can be considered to be a useful option to check novel designs of these treatment strategies. 1. Introduction Gliomas are the most common type of primary tumour in the central nervous system. Glioblastomas (GBM) are the malignant form of gliomas (World Health Organization Grade IV), and progress from a lower-grade glioma (secondary GBM) or appear de novo without any preceding tumour (primary GBM). Glioblastomas are strongly angiogenic tumours displaying a high degree of vascular proliferation and endothelial hyperplasia. It is a neoplasia of glial lineage with high proliferative and invasive capacity and may spread to occupy an entire lobe or even a hemisphere of the brain [1]. The growth of the glioblastoma is related to vascular network adaptation due to the increase of the metabolic necessities of neoplastic cells. During the early stages of gliomas, the metabolic demand is supplied by the vast microvasculature of the CNS; however, when the metabolic supply capacity is exceeded during neoplastic progression, new formation of vessels becomes necessary [2–4]. The genesis of new vessels from preexisting ones is called angiogenesis, in opposition to vasculogenesis, which refers to the formation of vessels from hematopoietic niches [5, 6]. Angiogenesis is a complex phenomenon, necessary for the progression of malignant gliomas [7]. The start
References
[1]
P. Kleihues, P. C. Burger, K. D. Aldape et al., “Glioblastoma,” in WHO Classification of Tumours of the Central Nervous System, D. N. Louis, H. Ohgaki, O. D. Wiestler, and W. K. Cavenee, Eds., pp. 33–49, Agency for Research on Cancer (IARC), Lyon, France, 2007.
[2]
G. Bergers and L. E. Benjamin, “Tumorigenesis and the angiogenic switch,” Nature Reviews Cancer, vol. 3, no. 6, pp. 401–410, 2003.
[3]
P. Carmeliet and R. K. Jain, “Angiogenesis in cancer and other diseases,” Nature, vol. 407, no. 6801, pp. 249–257, 2000.
[4]
G. D. Yancopoulos, S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash, “Vascular-specific growth factors and blood vessel formation,” Nature, vol. 407, no. 6801, pp. 242–248, 2000.
[5]
P. Carmeliet, “Angiogenesis in health and disease,” Nature Medicine, vol. 9, no. 6, pp. 653–660, 2003.
[6]
W. Risau, “Mechanisms of angiogenesis,” Nature, vol. 386, no. 6626, pp. 671–674, 1997.
[7]
J. Folkman, “Angiogenesis,” Annual Review of Medicine, vol. 57, pp. 1–18, 2006.
[8]
M. L. H. Wong, A. Prawira, A. H. Kaye, and C. M. Hovens, “Tumour angiogenesis: its mechanism and therapeutic implications in malignant gliomas,” Journal of Clinical Neuroscience, vol. 16, no. 9, pp. 1119–1130, 2009.
[9]
R. L. Jensen, “Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures,” Neurosurgical Focus, vol. 20, no. 4, p. E24, 2006.
[10]
G. H. Fong, “Mechanisms of adaptive angiogenesis to tissue hypoxia,” Angiogenesis, vol. 11, no. 2, pp. 121–140, 2008.
[11]
K. Jin, Y. Zhu, Y. Sun, X. O. Mao, L. Xie, and D. A. Greenberg, “Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 18, pp. 11946–11950, 2002.
[12]
H. J. H. Marti, M. Bernaudin, A. Bellail et al., “Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia,” American Journal of Pathology, vol. 156, no. 3, pp. 965–976, 2000.
[13]
G. L. Semenza, “Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics,” Oncogene, vol. 29, no. 5, pp. 625–634, 2010.
[14]
H. Bengoetxea, E. G. Argando？a, and J. V. Lafuente, “Effects of visual experience on vascular endothelial growth factor expression during the postnatal development of the rat visual cortex,” Cerebral Cortex, vol. 18, no. 7, pp. 1630–1639, 2008.
[15]
N. Ferrara, H. P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003.
[16]
L. R. Ment, W. B. Stewart, R. Fronc et al., “Vascular endothelial growth factor mediates reactive angiogenesis in the postnatal developing brain,” Developmental Brain Research, vol. 100, no. 1, pp. 52–61, 1997.
[17]
S. Bulnes and J. V. Lafuente, “VEGF immunopositivity related to malignancy degree, proliferative activity and angiogenesis in ENU-induced gliomas,” Journal of Molecular Neuroscience, vol. 33, no. 2, pp. 163–172, 2007.
[18]
J. V. Lafuente, B. Adán, K. Alkiza, J. M. Garibi, M. Rossi, and F. F. Cruz-Sánchez, “Expression of vascular endothelial growth factor (VEGF) and platelet- derived growth factor receptor-β (PDGFR-β) in human gliomas,” Journal of Molecular Neuroscience, vol. 13, no. 1-2, pp. 177–185, 1999.
[19]
K. H. Plate, “Mechanisms of angiogenesis in the brain,” Journal of Neuropathology and Experimental Neurology, vol. 58, no. 4, pp. 313–320, 1999.
[20]
B. Millauer, S. Wizigmann-Voos, H. Schnurch et al., “High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis,” Cell, vol. 72, no. 6, pp. 835–846, 1993.
[21]
N. Ortuzar, E. G. Argando？a, H. Bengoetxea, and J. V. Lafuente, “Combination of intracortically administered VEGF and environmental enrichment enhances brain protection in developing rats,” Journal of Neural Transmission, vol. 118, no. 1, pp. 135–144, 2011.
[22]
J. M. Rosenstein and J. M. Krum, “New roles for VEGF in nervous tissue—beyond blood vessels,” Experimental Neurology, vol. 187, no. 2, pp. 246–253, 2004.
[23]
E. Storkebaum, D. Lambrechts, and P. Carmeliet, “VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection,” BioEssays, vol. 26, no. 9, pp. 943–954, 2004.
[24]
S. Bao, Q. Wu, R. E. McLendon et al., “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response,” Nature, vol. 444, no. 7120, pp. 756–760, 2006.
[25]
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, vol. 8, no. 20, pp. 3274–3284, 2009.
[26]
Z. Li. Z., H. Wang, C. E. Eyler, A. B. Hjelmeland, and J. N. Rich, “Turning cancer stem cells inside out: an exploration of glioma stem cells signalling pathways,” The Journal of Biological Chemistry, vol. 284, no. 25, pp. 16705–16709, 2009.
[27]
S. Bulnes-Sesma, N. Ullibarri-Ortiz De Zárate, and J. V. Lafuente-Sánchez, “Tumour induction by ethylnitrosourea in the central nervous system,” Revista de Neurologia, vol. 43, no. 12, pp. 733–738, 2006.
[28]
P. E. Kish, M. Blaivas, M. Strawderman et al., “Magnetic resonance imaging of ethyl-nitrosourea-induced rat gliomas: a model for experimental therapeutics of low-grade gliomas,” Journal of Neuro-Oncology, vol. 53, no. 3, pp. 243–257, 2001.
[29]
P. L. Lantos, “Development of nitrosourea-induced brain tumours—with a special note on changes occurring during latency,” Food and Chemical Toxicology, vol. 24, no. 2, pp. 121–127, 1986.
[30]
D. Schiffer, L. Annovazzi, V. Caldera, and M. Mellai, “On the origin and growth of gliomas,” Anticancer Research, vol. 30, no. 6, pp. 1977–1998, 2010.
[31]
D. M. Kokkinakis, E. J. Rushing, M. M. Shareef et al., “Physiology and gene expression characteristics of carcinogen-initiated and tumor-transformed glial progenitor cells derived from the CNS of methylnitrosourea (MNU)-treated Sprague-Dawley rats,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 11, pp. 1182–1199, 2004.
[32]
N. Ferrara, “Vascular endothelial growth factor: basic science and clinical progress,” Endocrine Reviews, vol. 25, no. 4, pp. 581–611, 2004.
[33]
F. S. Grünewald, A. E. Prota, A. Giese, and K. Ballmer-Hofer, “Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling,” Biochimica et Biophysica Acta, vol. 1804, no. 3, pp. 567–580, 2010.
[34]
H. F. Dvorak, “Discovery of vascular permeability factor (VPF),” Experimental Cell Research, vol. 312, pp. 522–526, 2006.
[35]
N. Ferrara, “The role of VEGF in the regulation of physiological and pathological angiogenesis,” EXS, no. 94, pp. 209–231, 2005.
[36]
J. V. Lafuente, S. Bulnes, B. Mitre, and H. H. Riese, “Role of VEGF in an experimental model of cortical micronecrosis,” Amino Acids, vol. 23, no. 1–3, pp. 241–245, 2002.
[37]
G. Helmlinger, M. Endo, N. Ferrara, L. Hlatky, and R. K. Jain, “Growth factors: formation of endothelial cell networks,” Nature, vol. 405, no. 6783, pp. 139–141, 2000.
[38]
T. Tonini, F. Rossi, and P. P. Claudio, “Molecular basis of angiogenesis and cancer,” Oncogene, vol. 22, no. 43, pp. 6549–6556, 2003.
[39]
D. Zagzag, D. R. Friedlander, B. Margolis et al., “Molecular events implicated in brain tumor angiogenesis and invasion,” Pediatric Neurosurgery, vol. 33, no. 1, pp. 49–55, 2000.
[40]
B. Kaur, F. W. Khwaja, E. A. Severson, S. L. Matheny, D. J. Brat, and E. G. Van Meir, “Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis,” Neuro-Oncology, vol. 7, no. 2, pp. 134–153, 2005.
[41]
L. D. Ke, Y. X. Shi, S. A. Im, X. Chen, and W. K. A. Yung, “The relevance of cell proliferation, vascular endothelial growth factor, and basic fibroblast growth factor production to angiogenesis and tumorigenicity in human glioma cell lines,” Clinical Cancer Research, vol. 6, no. 6, pp. 2562–2572, 2000.
[42]
P. Baluk, H. Hashizume, and D. M. M, “Cellular abnormalities of blood vessels as targets in cancer,” Current Opinion in Genetics and Development, vol. 15, no. 1, pp. 102–111, 2005.
[43]
H. Hashizume, P. Baluk, S. Morikawa et al., “Openings between defective endothelial cells explain tumor vessel leakiness,” American Journal of Pathology, vol. 156, no. 4, pp. 1363–1380, 2000.
[44]
J. Holash, P. C. Maisonpierre, D. Compton et al., “Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF,” Science, vol. 284, no. 5422, pp. 1994–1998, 1999.
[45]
D. Zagzag, H. Zhong, J. M. Scalzitti, E. Laughner, J. W. Simons, and G. L. Semenza, “Expression of hypoxia-inducible factor 1α in brain tumors: association with angiogenesis, invasion, and progression,” Cancer, vol. 88, no. 11, pp. 2606–2618, 2000.
[46]
B. Blouw, H. Song, T. Tihan et al., “The hypoxic response of tumors is dependent on their microenvironment,” Cancer Cell, vol. 4, no. 2, pp. 133–146, 2003.
[47]
O. Méndez, J. Zavadil, M. Esencay et al., “Knock down of HIF-1α in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres,” Molecular Cancer, vol. 9, article 133, 2010.
[48]
R. Sullivan and C. H. Graham, “Hypoxia-driven selection of the metastatic phenotype,” Cancer and Metastasis Reviews, vol. 26, no. 2, pp. 319–331, 2007.
[49]
K. L. Jin, X. O. Mao, T. Nagayama, P. C. Goldsmith, and D. A. Greenberg, “Induction of vascular endothelial growth factor and hypoxia-inducible factor-1α by global ischemia in rat brain,” Neuroscience, vol. 99, no. 3, pp. 577–585, 2000.
[50]
P. Vajkoczy, M. Farhadi, A. Gaumann et al., “Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2,” The Journal of Clinical Investigation, vol. 109, no. 6, pp. 777–785, 2002.
[51]
R. H. Wenger and M. Gassmann, “Oxygen(es) and the hypoxia-inducible factor-1,” Biological Chemistry, vol. 378, no. 7, pp. 609–616, 1997.
[52]
M. H. Yang and K. J. Wu, “TWIST activation by hypoxia inducible factor-1 (HIF-1): implications in metastasis and development,” Cell Cycle, vol. 7, no. 14, pp. 2090–2096, 2008.
[53]
M. S. Wiesener, J. S. Jürgensen, C. Rosenberger et al., “Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs,” The FASEB Journal, vol. 17, no. 2, pp. 271–273, 2003.
[54]
W. Chen, R. P. Ostrowski, A. Obenaus, and J. H. Zhang, “Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury,” Experimental Neurology, vol. 216, no. 1, pp. 7–15, 2009.
[55]
C. E. Griguer, C. R. Oliva, E. Gobin et al., “CD133 is a marker of bioenergetic stress in human glioma,” PLoS ONE, vol. 3, no. 11, Article ID e3655, 2008.
[56]
J. M. Heddleston, Z. Li, J. D. Lathia, S. Bao, A. B. Hjelmeland, and J. N. Rich, “Hypoxia inducible factors in cancer stem cells,” British Journal of Cancer, vol. 102, no. 5, pp. 789–795, 2010.
[57]
Z. Li, S. Bao, Q. Wu et al., “Hypoxia-inducible factors regulate tumourigenic capacity of glioma stem cells,” Cancer Cell, vol. 15, no. 6, pp. 501–513, 2009.
[58]
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,” American Journal of Pathology, vol. 177, no. 3, pp. 1491–1502, 2010.
[59]
F. Pistollato, S. Abbadi, E. Rampazzo et al., “Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma,” Stem Cells, vol. 28, no. 6, pp. 851–862, 2010.
[60]
C. Folkins, Y. Shaked, S. Man et al., “Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1,” Cancer Research, vol. 69, no. 18, pp. 7243–7251, 2009.
[61]
P. Dell'Albani, “Stem cell markers in gliomas,” Neurochemical Research, vol. 33, no. 12, pp. 2407–2415, 2008.
[62]
T. Jang, N. S. Litofsky, T. W. Smith, A. H. Ross, and L. D. Recht, “Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis,” Neurobiology of Disease, vol. 15, no. 3, pp. 544–552, 2004.
[63]
C. G. Hadjipanayis and E. G. Van Meir, “Brain cancer propagating cells: biology, genetics and targeted therapies,” Trends in Molecular Medicine, vol. 15, no. 11, pp. 519–530, 2009.
[64]
I. Germano, V. Swiss, and P. Casaccia, “Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link?” Neuropharmacology, vol. 58, no. 6, pp. 903–910, 2010.
[65]
T. N. Ignatova, V. G. Kukekov, E. D. Laywell, O. N. Suslov, F. D. Vrionis, and D. A. Steindler, “Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro,” Glia, vol. 39, no. 3, pp. 193–206, 2002.
[66]
H. D. Mennel, N. Kosse, J. T. Heverhagen, and H. Alfke, “Primary and transplanted ENU induced rat tumors in neurooncology,” Experimental and Toxicologic Pathology, vol. 56, no. 1-2, pp. 25–35, 2004.
[67]
B. C. Zook and S. J. Simmens, “Neurogenic tumors in rats induced by ethylnitrosourea,” Experimental and Toxicologic Pathology, vol. 57, no. 1, pp. 7–14, 2005.
[68]
W. Slikker, N. Mei, and T. Chen, “N-ethyl-N-nitrosourea (ENU) increased brain mutations in prenatal and neonatal mice but not in the adults,” Toxicological Sciences, vol. 81, no. 1, pp. 112–120, 2004.
[69]
D. S. Beniashvili and V. N. Anisimov, “Morphology of experimentally induced tumors of the sympathetic nervous system in rats,” Experimental and Toxicologic Pathology, vol. 56, no. 1-2, pp. 53–58, 2004.
[70]
S. Bulnes, J. Bilbao, and J. V. Lafuente, “Microvascular adaptive changes in experimental endogenous brain gliomas,” Histology and Histopathology, vol. 24, no. 6, pp. 693–706, 2009.
[71]
N. Almog, “Molecular mechanisms underlying tumor dormancy,” Cancer Letters, vol. 294, no. 2, pp. 139–146, 2010.
[72]
N. Almog, L. Ma, R. Raychowdhury et al., “Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype,” Cancer Research, vol. 69, no. 3, pp. 836–844, 2009.
[73]
P. Korkolopoulou, E. Patsouris, N. Kavantzas et al., “Prognostic implications of microvessel morphometry in diffuse astrocytic neoplasms,” Neuropathology and Applied Neurobiology, vol. 28, no. 1, pp. 57–66, 2002.
[74]
V. Baeriswyl and G. Christofori, “The angiogenic switch in carcinogenesis,” Seminars in Cancer Biology, vol. 19, no. 5, pp. 329–337, 2009.
[75]
S. Bulnes, E. G. Argando？a, H. Bengoetxea, O. Leis, N. Ortuzar, and J. V. Lafuente, “The role of eNOS in vascular permeability in ENU-induced gliomas,” Acta Neurochirurgica. Supplement, vol. 106, pp. 277–282, 2010.
[76]
N. M. Mazure, E. Y. Chen, K. R. Laderoute, and A. J. Giaccia, “Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element,” Blood, vol. 90, no. 9, pp. 3322–3331, 1997.
[77]
S. Bulnes, á. García-Blanco, H. Bengoetxea, N. Ortuzar, E. G. Argando？a, and J. V. Lafuente, “Glial stem cells and their relationship with tumour angiogenesis process,” Revista de Neurologia, vol. 52, no. 12, pp. 743–750, 2011.
[78]
S. Bulnes, H. Bengoetxea, N. Ortuzar, E. G. Argandon？a, and J. V. Lafuente, “Endogenous experimental glioma model, links between glioma stem cells and angiogenesis,” in Glioma—Exploring Its Biology and Practical Relevance, A. Ghosh, Ed., InTech, 2011.
[79]
F. Zeppernick, R. Ahmadi, B. Campos et al., “Stem cell marker CD133 affects clinical outcome in glioma patients,” Clinical Cancer Research, vol. 14, no. 1, pp. 123–129, 2008.
[80]
M. C. Tate and M. K. Aghi, “Biology of Angiogenesis and Invasion in Glioma,” Neurotherapeutics, vol. 6, no. 3, pp. 447–457, 2009.
[81]
C. Calabrese, H. Poppleton, M. Kocak et al., “A perivascular niche for brain tumour stem cells,” Cancer Cell, vol. 11, no. 1, pp. 69–82, 2007.
[82]
R. J. Gilbertson and J. N. Rich, “Making a tumour's bed: glioblastoma stem cells and the vascular niche,” Nature Reviews Cancer, vol. 7, no. 10, pp. 733–736, 2007.
[83]
T. Borovski, J. J. C. Verhoeff, R. Ten Cate et al., “Tumor microvasculature supports proliferation and expansion of glioma-propagating cells,” International Journal of Cancer, vol. 125, no. 5, pp. 1222–1230, 2009.
[84]
E. Ruoslahti, “Specialization of tumour vasculature,” Nature Reviews Cancer, vol. 2, no. 2, pp. 83–90, 2002.
[85]
R. D. Folkerth, “Histologic measures of angiogenesis in human primary brain tumors,” Cancer Treatment and Research, vol. 117, pp. 79–95, 2004.
[86]
N. Ferrara, “Binding to the extracellular matrix and proteolytic processing: two key mechanisms regulating vascular endothelial growth factor action,” Molecular Biology of the Cell, vol. 21, no. 5, pp. 687–690, 2010.
[87]
M. C. Tate and M. K. Aghi, “Biology of angiogenesis and invasion in glioma,” Neurotherapeutics, vol. 6, no. 3, pp. 447–457, 2009.
