Currently, antiangiogenic agents are routinely used for the treatment of patients with glioma. However, despite advances in pharmacological and surgical therapy, glioma remains an incurable disease. Indeed, the formation of an abnormal tumor vasculature and the invasion of glioma cells along neuronal tracts are proposed to comprise the major factors that are attributed to the therapeutic resistance of these tumors. The development of curative therapeutic modalities for the treatment of glioma requires further investigation of the molecular mechanisms regulating angiogenesis and invasion. In this review, we discuss the molecular characteristics of angiogenesis and invasion in human malignant glioma, we present several available drugs that are used or can potentially be utilized for the inhibition of angiogenesis in glioma, and we focus our attention on the key mediators of the molecular mechanisms underlying the resistance of glioma to antiangiogenic therapy. 1. Introduction Angiogenesis and tumor cell invasion play a critical role in glioma development and growth, even during the earliest phases [1]. Indeed, the formation of abnormal tumor vasculature and glioma cell invasion along white matter tracts are proposed to be the major causes of the therapeutic resistance of these tumors; thus, glioma remains a fatal disease despite advances in surgical and medical therapy. Glioma tumors are an example of highly vascularized tumors, which induce angiogenesis by upregulating vascular endothelial growth factor (VEGF) and its downstream pathways. Indeed, several molecular abnormalities have been described in glioma that promote angiogenesis, such as mutations and/or upregulation of PI3K/Akt and the VEGF receptor (VEGFR) in the glioma endothelium [2]. Interestingly, each of these signaling pathways involves alterations that can be therapeutically targeted [3]. Evaluation of drugs that target these pathways requires novel preclinical and clinical experimental trial design to define the optimal drug dose and delivery times to avoid toxicity during the first months of treatment [4, 5]. Furthermore, whether these agents can be used in combination with classical cytotoxic chemotherapy, what molecular markers can predict response, and whether they can be potentiated by such combinatorial treatments are important issues that remain to be explored. In this paper, we first discuss the molecular characteristics of angiogenesis and invasion in human malignant glioma. Secondly, we discuss the commercially available drugs that are currently used or might be potentially
References
[1]
L. Bello, C. Giussani, G. Carrabba, M. Pluderi, F. Costa, and A. Bikfalvi, “Angiogenesis and invasion in gliomas,” Cancer treatment and research, vol. 117, pp. 263–284, 2004.
[2]
K. H. Plate, G. Breier, H. A. Weich, H. D. Mennel, and W. Risau, “Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms,” International Journal of Cancer, vol. 59, no. 4, pp. 520–529, 1994.
[3]
D. G. Duda, T. T. Batchelor, C. G. Willett, and R. K. Jain, “VEGF-targeted Cancer therapy strategies: current progress, hurdles and future prospects,” Trends in Molecular Medicine, vol. 13, no. 6, pp. 223–230, 2007.
[4]
D. G. Duda, K. S. Cohen, D. T. Scadden, and R. K. Jain, “A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood,” Nature Protocols, vol. 2, no. 4, pp. 805–810, 2007.
[5]
F. Bertolini, Y. Shaked, P. Mancuso, and R. S. Kerbel, “The multifaceted circulating endothelial cell in Cancer: towards marker and target identification,” Nature Reviews Cancer, vol. 6, no. 11, pp. 835–845, 2006.
[6]
S. L. Holbeck, “Update on NCI in vitro drug screen utilities,” European Journal of Cancer, vol. 40, no. 6, pp. 785–793, 2004.
[7]
K. D. Paull, R. H. Shoemaker, L. Hodes et al., “Display and analysis of patterns of differential activity of drugs against human tumor cell lines: development of mean graph and COMPARE algorithm,” Journal of the National Cancer Institute, vol. 81, no. 14, pp. 1088–1092, 1989.
[8]
B. Lambert, L. De Ridder, F. De Vos et al., “Assessment of supra-additive effects of cytotoxic drugs and low dose rate irradiation in an in vitro model for hepatocellular carcinoma,” Canadian journal of physiology and pharmacology, vol. 84, no. 10, pp. 1021–1028, 2006.
[9]
H. Hirschberg, C. H. Sun, T. Krasieva, and S. J. Madsen, “Effects of ALA-mediated photodynamic therapy on the invasiveness of human glioma cells,” Lasers in Surgery and Medicine, vol. 38, no. 10, pp. 939–945, 2006.
[10]
J. Kern, M. Steurer, G. Gastl, E. Gunsilius, and G. Untergasser, “Vasohibin inhibits angiogenic sprouting in vitro and supports vascular maturation processes in vivo,” BMC Cancer, vol. 9, article 1471, p. 284, 2009.
[11]
L. A. Kunz-Schughart, J. A. Schroeder, M. Wondrak et al., “Potential of fibroblasts to regulate the formation of three-dimensional vessel-like structures from endothelial cells in vitro,” American Journal of Physiology, vol. 290, no. 5, pp. C1385–C1398, 2006.
[12]
S. Ghosh, M. B. Joshi, D. Ivanov et al., “Use of multicellular tumor spheroids to dissect endothelial cell-tumor cell interactions: a role for T-cadherin in tumor angiogenesis,” FEBS Letters, vol. 581, no. 23, pp. 4523–4528, 2007.
[13]
K. W. Kross, J. H. Heimdal, C. Olsnes, J. Olofsson, and H. J. Aarstad, “Co-culture of head and neck squamous cell carcinoma spheroids with autologous monocytes predicts prognosis,” Scandinavian Journal of Immunology, vol. 67, no. 4, pp. 392–399, 2008.
[14]
F. Durupt, D. Koppers-Lalic, B. Balme et al., “The chicken chorioallantoic membrane tumor assay as model for qualitative testing of oncolytic adenoviruses,” Cancer Gene Therapy, vol. 19, no. 1, pp. 58–68, 2012.
[15]
L. Ko, A. Koestner, and W. Wechsler, “Morphological characterization of nitrosourea-induced glioma cell lines and clones,” Acta Neuropathologica, vol. 51, no. 1, pp. 23–31, 1980.
[16]
E. A. Sausville and A. M. Burger, “Contributions of human tumor xenografts to antiCancer drug development,” Cancer Research, vol. 66, no. 7, pp. 3351–3354, 2006.
[17]
G. G. Steel, V. D. Courtenay, and M. J. Peckham, “The response to chemotherapy of a variety of human tumour xenografts,” British Journal of Cancer, vol. 47, no. 1, pp. 1–13, 1983.
[18]
T. H. Kuo, T. Kubota, M. Watanabe et al., “Site-specific chemosensitivity of human small-cell lung carcinoma growing orthotopically compared to subcutaneously in SCID mice: the importance of orthotopic models to obtain relevant drug evaluation data,” AntiCancer Research, vol. 13, no. 3, pp. 627–630, 1993.
[19]
R. M. Hoffman, “Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic,” Investigational New Drugs, vol. 17, no. 4, pp. 343–359, 1999.
[20]
M. Candolfi, J. F. Curtin, W. S. Nichols et al., “Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression,” Journal of Neuro-Oncology, vol. 85, no. 2, pp. 133–148, 2007.
[21]
S. Inoue, et al., “Novel animal glioma models that separately exhibit two different invasive and angiogenic phenotypes of human glioblastomas,” World Neurosurg. In press.
[22]
M. A. Elmeliegy, A. M. Carcaboso, L. M. L. Chow et al., “Magnetic resonance imaging-guided microdialysis cannula implantation in a spontaneous high-grade glioma murine model,” Journal of Pharmaceutical Sciences, vol. 100, no. 10, pp. 4210–4214, 2011.
[23]
L. Chow, R. Endersby, X. Zhu et al., “Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain,” Cancer Cell, vol. 19, no. 3, pp. 305–316, 2011.
[24]
L. M. Shelton, P. Mukherjee, L. C. Huysentruyt, I. Urits, J. A. Rosenberg, and T. N. Seyfried, “A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion,” Journal of Neuro-Oncology, vol. 99, no. 2, pp. 165–176, 2010.
[25]
P. J. Dickinson, R. A. LeCouteur, R. J. Higgins et al., “Canine spontaneous glioma: a translational model system for convection-enhanced delivery,” Neuro-Oncology, vol. 12, no. 9, pp. 928–940, 2010.
[26]
G. L. Heidner, J. N. Kornegay, R. L. Page, R. K. Dodge, and D. E. Thrall, “Analysis of survival in a retrospective study of 86 dogs with brain tumors,” Journal of Veterinary Internal Medicine, vol. 5, no. 4, pp. 219–226, 1991.
[27]
N. Kobayashi, N. Allen, and N. R. Clendenon, “An improved rat brain-tumor model,” Journal of Neurosurgery, vol. 53, no. 6, pp. 808–815, 1980.
[28]
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.
[29]
S. Brem, R. Cotran, and J. Folkman, “Tumor angiogenesis: a quantitative method for histologic grading,” Journal of the National Cancer Institute, vol. 48, no. 2, pp. 347–356, 1972.
[30]
B. Birlik, S. Canda, and E. Ozer, “Tumour vascularity is of prognostic significance in adult, but not paediatric astrocytomas,” Neuropathology and Applied Neurobiology, vol. 32, no. 5, pp. 532–538, 2006.
[31]
S. P. Leon, R. D. Folkerth, and P. McL. Black, “Microvessel density is a prognostic indicator for patients with astroglial brain tumors,” Cancer, vol. 77, no. 2, pp. 362–372, 1996.
[32]
A. Tandle, D. G. Blazer, and S. K. Libutti, “Antiangiogenic gene therapy of Cancer: recent developments,” Journal of Translational Medicine, vol. 2, article 22, 2004.
[33]
K. M. Dameron, O. V. Volpert, M. A. Tainsky, and N. Bouck, “Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1,” Science, vol. 265, no. 5178, pp. 1582–1584, 1994.
[34]
D. J. Good, P. J. Polverini, F. Rastinejad et al., “A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 17, pp. 6624–6628, 1990.
[35]
J. Fang, Y. Shing, D. Wiederschain et al., “Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 8, pp. 3884–3889, 2000.
[36]
S. A. Raithatha, H. Muzik, N. B. Rewcastle, R. N. Johnston, D. R. Edwards, and P. A. Forsyth, “Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas,” Neuro-Oncology, vol. 2, no. 3, pp. 145–150, 2000.
[37]
T. Martens, Y. Laabs, H. S. Günther et al., “Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2,” Clinical Cancer Research, vol. 14, no. 17, pp. 5447–5458, 2008.
[38]
D. Hanahan and J. Folkman, “Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis,” Cell, vol. 86, no. 3, pp. 353–364, 1996.
[39]
Y. Zhang, N. Zhang, B. Dai et al., “FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells,” Cancer Research, vol. 68, no. 21, pp. 8733–8742, 2008.
[40]
K. Ido, T. Nakagawa, T. Sakuma, H. Takeuchi, K. Sato, and T. Kubota, “Expression of vascular endothelial growth factor-A and mRNA stability factor HuR in human astrocytic tumors,” Neuropathology, vol. 28, no. 6, pp. 604–611, 2008.
[41]
K. Nakamura, K. C. Martin, J. K. Jackson, K. Beppu, C. W. Woo, and C. J. Thiele, “Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1α in neuroblastoma cells,” Cancer Research, vol. 66, no. 8, pp. 4249–4255, 2006.
[42]
C. Tan, S. Cruet-Hennequart, A. Troussard et al., “Regulation of tumor angiogenesis by integrin-linked kinase (ILK),” Cancer Cell, vol. 5, no. 1, pp. 79–90, 2004.
[43]
K. H. Plate, G. Breier, H. A. Weich, and W. Risau, “Vascular endothelial growth factor is a potential tumour angiogenssis factor in human gliomas in vivo,” Nature, vol. 359, no. 6398, pp. 845–848, 1992.
[44]
M. Kerber, Y. Reiss, A. Wickersheim et al., “Flt-1 signaling in macrophages promotes glioma growth in vivo,” Cancer Research, vol. 68, no. 18, pp. 7342–7351, 2008.
[45]
E. Y. Lin and J. W. Pollard, “Tumor-associated macrophages press the angiogenic switch in breast Cancer,” Cancer Research, vol. 67, no. 11, pp. 5064–5066, 2007.
[46]
M. K. Jones, R. M. Itani, H. Wang et al., “Activation of VEGF and Ras genes in gastric mucosa during angiogenic response to ethanol injury,” American Journal of Physiology, vol. 276, part 1, no. 6, pp. G1345–G1355, 1999.
[47]
T. Takahashi and M. Shibuya, “The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-γ pathway and partially induces mitotic signals in NIH3T3 fibroblasts,” Oncogene, vol. 14, no. 17, pp. 2079–2089, 1997.
[48]
B. K. Lal, S. Varma, P. J. Pappas, R. W. Hobson, and W. N. Durán, “VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways,” Microvascular Research, vol. 62, no. 3, pp. 252–262, 2001.
[49]
S. Esser, K. Wolburg, H. Wolburg, G. Breier, T. Kurzchalia, and W. Risau, “Vascular endothelial growth factor induces endothelial fenestrations in vitro,” Journal of Cell Biology, vol. 140, no. 4, pp. 947–959, 1998.
[50]
C. G. Kevil, N. Ohno, D. C. Gute et al., “Role of cadherin internalization in hydrogen peroxide-mediated endothelial permeability,” Free Radical Biology and Medicine, vol. 24, no. 6, pp. 1015–1022, 1998.
[51]
B. Li, C. M. Chang, M. Yuan, W. G. McKenna, and H. K. G. Shu, “Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas,” Cancer Research, vol. 63, no. 21, pp. 7443–7450, 2003.
[52]
M. Takahashi, A. Matsui, M. Inao, S. Mochida, and K. Fujiwara, “ERK/MAPK-dependent PI3K/Akt phosphorylation through VEGFR-1 after VEGF stimulation in activated hepatic stellate cells,” Hepatology Research, vol. 26, no. 3, pp. 232–236, 2003.
[53]
R. C. Castellino and D. L. Durden, “Mechanisms of disease: the PI3K-Akt-PTEN signaling node—an intercept point for the control of angiogenesis in brain tumors,” Nature Clinical Practice Neurology, vol. 3, no. 12, pp. 682–693, 2007.
[54]
S. K. Hobbs, W. L. Monsky, F. Yuan et al., “Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 8, pp. 4607–4612, 1998.
[55]
W. L. Monsky, D. Fukumura, T. Gohongi et al., “Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor,” Cancer Research, vol. 59, no. 16, pp. 4129–4135, 1999.
[56]
E. Bullitt, D. Zeng, G. Gerig et al., “Vessel tortuosity and brain tumor malignancy: a blinded study,” Academic Radiology, vol. 12, no. 10, pp. 1232–1240, 2005.
[57]
D. Zagzag, A. Hooper, D. R. Friedlander et al., “In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis,” Experimental Neurology, vol. 159, no. 2, pp. 391–400, 1999.
[58]
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.
[59]
K. J. Kim, B. Li, J. Winer et al., “Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo,” Nature, vol. 362, no. 6423, pp. 841–844, 1993.
[60]
H. Hurwitz, L. Fehrenbacher, W. Novotny et al., “Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal Cancer,” The New England Journal of Medicine, vol. 350, no. 23, pp. 2335–2342, 2004.
[61]
M. C. Chamberlain, “Bevacizumab for the treatment of recurrent glioblastoma,” Clinical Medicine Insights, vol. 5, pp. 117–129, 2011.
[62]
D. Shweiki, A. Itin, D. Soffer, and E. Keshet, “Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis,” Nature, vol. 359, no. 6398, pp. 843–845, 1992.
[63]
E. J. Bernhard, “Interventions that induce modifications in the tumor microenvironment,” Cancer/Radiotherapie, vol. 15, no. 5, pp. 376–382, 2011.
[64]
M. Relf, S. Lejeune, P. A. E. Scott et al., “Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor β-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast Cancer and its relation to angiogenesis,” Cancer Research, vol. 57, no. 5, pp. 963–969, 1997.
[65]
R. Kerbel and J. Folkman, “Clinical translation of angiogenesis inhibitors,” Nature Reviews Cancer, vol. 2, no. 10, pp. 727–739, 2002.
[66]
A. Abdollahi, K. E. Lipson, A. Sckell et al., “Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects,” Cancer Research, vol. 63, no. 24, pp. 8890–8898, 2003.
[67]
J. Wang, Y. Sun, Y. Liu et al., “Results of randomized, multicenter, double-blind phase III trial of rh-endostatin (YH-16) in treatment of advanced non-small cell lung cancer patients,” Chinese Journal of Lung Cancer, vol. 8, no. 4, pp. 283–290, 2005.
[68]
M. R. Gilbert, J. Kuhn, K. R. Lamborn et al., “Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery,” Journal of Neuro-Oncology, pp. 1–7, 2011.
[69]
R. Stupp, M. E. Hegi, B. Neyns et al., “Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma,” Journal of Clinical Oncology, vol. 28, no. 16, pp. 2712–2718, 2010.
[70]
C. Delbaldo, E. Raymond, K. Vera et al., “Phase I and pharmacokinetic study of etaracizumab (Abegrin？), a humanized monoclonal antibody against αvβ3 integrin receptor, in patients with advanced solid tumors,” Investigational New Drugs, vol. 26, no. 1, pp. 35–43, 2008.
[71]
P. Hersey, J. Sosman, S. O'Day et al., “A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin αvβ3, ± dacarbazine in patients with stage IV metastatic melanoma,” Cancer, vol. 116, no. 6, pp. 1526–1534, 2010.
[72]
K. M. Bell-Mcguinn, C. M. Matthews, S. N. Ho et al., “A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal Cancer,” Gynecologic Oncology, vol. 121, no. 2, pp. 273–279, 2011.
[73]
V. A. Levin, S. Phuphanich, W. K. A. Yung et al., “Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation,” Journal of Neuro-Oncology, vol. 78, no. 3, pp. 295–302, 2006.
[74]
F. A. Shepherd, G. Giaccone, L. Seymour et al., “Prospective, randomized, double-blind, placebo-controlled trial of marimastat after response to first-line chemotherapy in patients with small-cell lung Cancer: a trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer,” Journal of Clinical Oncology, vol. 20, no. 22, pp. 4434–4439, 2002.
[75]
D. A. Reardon, J. J. Vredenburgh, A. Coan et al., “Phase i study of sunitinib and irinotecan for patients with recurrent malignant glioma,” Journal of Neuro-Oncology, vol. 105, no. 3, pp. 621–627, 2011.
[76]
L. B. Nabors, J. G. Supko, M. Rosenfeld et al., “Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma,” Neuro-Oncology, vol. 13, no. 12, pp. 1324–1330, 2011.
[77]
L. L. Garland, K. Chansky, A. J. Wozniak et al., “Phase II study of cediranib in patients with Malignant pleural mesothelioma: SWOG S0509,” Journal of Thoracic Oncology, vol. 6, no. 11, pp. 1938–1945, 2011.
[78]
S. R. Alberts, T. R. Fitch, G. P. Kim et al., “Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II north central Cancer treatment group clinical trial,” American Journal of Clinical Oncology, 2011.
[79]
T. T. Batchelor, D. G. Duda, E. Di Tomaso et al., “Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma,” Journal of Clinical Oncology, vol. 28, no. 17, pp. 2817–2823, 2010.
[80]
B. Neyns, J. Sadones, C. Chaskis et al., “Phase II study of sunitinib malate in patients with recurrent high-grade glioma,” Journal of Neuro-Oncology, vol. 103, no. 3, pp. 491–501, 2011.
[81]
D. A. Reardon, G. Dresemann, S. Taillibert et al., “Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma,” British Journal of Cancer, vol. 101, no. 12, pp. 1995–2004, 2009.
[82]
E. Razis, P. Selviaridis, S. Labropoulos et al., “Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of the treatment,” Clinical Cancer Research, vol. 15, no. 19, pp. 6258–6266, 2009.
[83]
G. Dresemann, M. Weller, M. A. Rosenthal et al., “Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide,” Journal of Neuro-Oncology, vol. 96, no. 3, pp. 393–402, 2010.
[84]
J. J. Vredenburgh, A. Desjardins, J. E. Herndon et al., “Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma,” Clinical Cancer Research, vol. 13, no. 4, pp. 1253–1259, 2007.
[85]
A. D. Norden, J. Drappatz, A. Muzikansky et al., “An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma,” Journal of Neuro-Oncology, vol. 92, no. 2, pp. 149–155, 2009.
[86]
T. Xu, J. Chen, Y. Lu, and J. E. A. Wolff, “Effects of bevacizumab plus irinotecan on response and survival in patients with recurrent malignant glioma: a systematic review and survival-gain analysis,” BMC Cancer, vol. 10, article 252, 2010.
[87]
O. Keunen, M. Johansson, A. Oudin et al., “Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 9, pp. 3749–3754, 2011.
[88]
A. K. Lucio-Eterovic, Y. Piao, and J. F. De Groot, “Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy,” Clinical Cancer Research, vol. 15, no. 14, pp. 4589–4599, 2009.
[89]
V. Lorgis, et al., “Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts,” Journal of Neurooncol, vol. 107, no. 2, pp. 351–358, 2012.
[90]
S. M. Sweeney, G. DiLullo, S. J. Slater et al., “Angiogenesis in collagen I requires α2β1 ligation of a GFP*GER sequence and possibly p38 MAPK activation and focal adhesion disassembly,” The Journal of Biological Chemistry, vol. 278, no. 33, pp. 30516–30524, 2003.
[91]
D. R. Senger, C. A. Perruzzi, M. Streit, V. E. Koteliansky, A. R. De Fougerolles, and M. Detmar, “The α1β1 and α2β1 integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis,” American Journal of Pathology, vol. 160, no. 1, pp. 195–204, 2002.
[92]
P. C. Brooks, R. A. F. Clark, and D. A. Cheresh, “Requirement of vascular integrin α(v)β3 for angiogenesis,” Science, vol. 264, no. 5158, pp. 569–571, 1994.
[93]
M. Friedlander, P. C. Brooks, R. W. Shaffer, C. M. Kincaid, J. A. Varner, and D. A. Cheresh, “Definition of two angiogenic pathways by distinct αv integrins,” Science, vol. 270, no. 5241, pp. 1500–1502, 1995.
[94]
C. J. Drake, D. A. Cheresh, and C. D. Little, “An antagonist of integrin α(v)β3 prevents maturation of blood vessels during embryonic neovascularization,” Journal of Cell Science, vol. 108, no. 7, pp. 2655–2661, 1995.
[95]
Y. Fu, M. L. Ponce, M. Thill, P. Yuan, S. W. Nam, and K. G. Csaky, “Angiogenesis inhibition and choroidal neovascularization suppression by sustained delivery of an integrin antagonist, EMD478761,” Investigative Ophthalmology and Visual Science, vol. 48, no. 11, pp. 5184–5190, 2007.
[96]
D. A. Reardon, K. L. Fink, T. Mikkelsen et al., “Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme,” Journal of Clinical Oncology, vol. 26, no. 34, pp. 5610–5617, 2008.
[97]
J. B. Vermorken, J. Guigay, R. Mesia et al., “Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell Cancer of the head and neck: findings of the phase i part,” British Journal of Cancer, vol. 104, no. 11, pp. 1691–1696, 2011.
[98]
D. A. Reardon, B. Neyns, M. Weller, J. C. Tonn, L. B. Nabors, and R. Stupp, “Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies,” Future Oncology, vol. 7, no. 3, pp. 339–354, 2011.
[99]
W. Cai, Y. Wu, K. Chen, Q. Cao, D. A. Tice, and X. Chen, “In vitro and in vivo characterization of 64Cu-labeled Abegrin？, a humanized monoclonal antibody against integrin αvβ3,” Cancer Research, vol. 66, no. 19, pp. 9673–9681, 2006.
[100]
A. D. Ricart, A. W. Tolcher, G. Liu et al., “Volociximab, a chimeric monoclonal antibody that specifically binds α5β1 integrin: a phase l, pharmacokinetic, and biological correlative study,” Clinical Cancer Research, vol. 14, no. 23, pp. 7924–7929, 2008.
[101]
M. D. Groves, V. K. Puduvalli, K. R. Hess et al., “Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme,” Journal of Clinical Oncology, vol. 20, no. 5, pp. 1383–1388, 2002.
[102]
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.
[103]
M. L. Maitland, K. E. Kasza, T. Karrison et al., “Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment,” Clinical Cancer Research, vol. 15, no. 19, pp. 6250–6257, 2009.
[104]
W. Fiedler, R. Mesters, M. Heuser et al., “An open-label, Phase I study of cediranib (RECENTIN？) in patients with acute myeloid Leukemia,” Leukemia Research, vol. 34, no. 2, pp. 196–202, 2010.
[105]
R. J. Motzer, T. E. Hutson, P. Tomczak et al., “Sunitinib versus interferon alfa in metastatic renal-cell carcinoma,” The New England Journal of Medicine, vol. 356, no. 2, pp. 115–124, 2007.
[106]
E. Raymond, L. Dahan, J.-L. Raoul et al., “Sunitinib malate for the treatment of pancreatic neuroendocrine tumors,” The New England Journal of Medicine, vol. 364, no. 6, pp. 501–513, 2011.
[107]
G. D. Demetri, A. T. van Oosterom, C. R. Garrett et al., “Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial,” The Lancet, vol. 368, no. 9544, pp. 1329–1338, 2006.
[108]
S. Matsumoto, S. Batra, K. Saito et al., “Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia,” Cancer Research, vol. 71, no. 20, pp. 6350–6359, 2011.
[109]
E. Ranza, G. Mazzini, A. Facoetti, and R. Nano, “In-vitro effects of the tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation,” Journal of Neuro-Oncology, vol. 96, no. 3, pp. 349–357, 2010.
[110]
P. Y. Wen, W. K. A. Yung, K. R. Lamborn et al., “Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American brain tumor consortium study 99-08,” Clinical Cancer Research, vol. 12, no. 16, pp. 4899–4907, 2006.
[111]
Y. Jin, J.-P. Li, L.-Y. Tang et al., “Protein expression and significance of VEGF, EGFR and MMP-9 in non-small cell lung carcinomas,” Asian Pacific Journal of Cancer Prevention, vol. 12, no. 6, pp. 1473–1476, 2011.
[112]
A. Kamat, S. Rajoria, A. George et al., “Estrogen-mediated angiogenesis in thyroid tumor microenvironment is mediated through VEGF signaling pathways,” Archives of Otolaryngology, vol. 137, no. 11, pp. 1146–1153, 2011.
[113]
L. B. Saltz, H. J. Lenz, H. L. Kindler et al., “Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal Cancer: the BOND-2 study,” Journal of Clinical Oncology, vol. 25, no. 29, pp. 4557–4561, 2007.
[114]
H. L. Kindler, D. Niedzwiecki, D. Hollis et al., “Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic Cancer: phase III trial of the Cancer and Leukemia group B (CALGB 80303),” Journal of Clinical Oncology, vol. 28, no. 22, pp. 3617–3622, 2010.
[115]
O. Casanovas, D. J. Hicklin, G. Bergers, and D. Hanahan, “Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors,” Cancer Cell, vol. 8, no. 4, pp. 299–309, 2005.
[116]
T. Kamba and D. M. McDonald, “Mechanisms of adverse effects of anti-VEGF therapy for Cancer,” British Journal of Cancer, vol. 96, no. 12, pp. 1788–1795, 2007.
[117]
S. Kourembanas, R. L. Hannan, and D. V. Faller, “Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells,” Journal of Clinical Investigation, vol. 86, no. 2, pp. 670–674, 1990.
[118]
D. V. Faller, “Endothelial cell responses to hypoxic stress,” Clinical and Experimental Pharmacology and Physiology, vol. 26, no. 1, pp. 74–84, 1999.
[119]
J. Huang, S. Z. Softer, E. S. Kim et al., “Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis,” Molecular Cancer Research, vol. 2, no. 1, pp. 36–42, 2004.
[120]
J. L. Rubenstein, J. Kim, T. Ozawa et al., “Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption,” Neoplasia, vol. 2, no. 4, pp. 306–314, 2000.
[121]
J. Glade Bender, E. M. Cooney, J. J. Kandel, and D. J. Yamashiro, “Vascular remodeling and clinical resistance to antiangiogenic Cancer therapy,” Drug Resistance Updates, vol. 7, no. 4-5, pp. 289–300, 2004.
[122]
L. Hiatky, C. Tsionou, P. Hahnfeldt, and C. N. Coleman, “Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia—induced vascular endothelial growth factor up—regulation and protein expression,” Cancer Research, vol. 54, no. 23, pp. 6083–6086, 1994.
[123]
M. B. Ruzinova, R. A. Schoer, W. Gerald et al., “Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors,” Cancer Cell, vol. 4, no. 4, pp. 277–289, 2003.
[124]
A. S. Bailey, H. Willenbring, S. Jiang et al., “Myeloid lineage progenitors give rise to vascular endothelium,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 35, pp. 13156–13161, 2006.
[125]
F. Shojaei, X. Wu, A. K. Malik et al., “Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells,” Nature Biotechnology, vol. 25, no. 8, pp. 911–920, 2007.
[126]
R. D. Leek, C. E. Lewis, R. Whitehouse, M. Greenall, J. Clarke, and A. L. Harris, “Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma,” Cancer Research, vol. 56, no. 20, pp. 4625–4629, 1996.
[127]
C. E. Lewis and J. W. Pollard, “Distinct role of macrophages in different tumor microenvironments,” Cancer Research, vol. 66, no. 2, pp. 605–612, 2006.
[128]
E. Y. Lin, A. V. Nguyen, R. G. Russell, and J. W. Pollard, “Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy,” Journal of Experimental Medicine, vol. 193, no. 6, pp. 727–739, 2001.
[129]
L. Bingle, N. J. Brown, and C. E. Lewis, “The role of tumour-associated macrophages in tumour progression: implications for new antiCancer therapies,” Journal of Pathology, vol. 196, no. 3, pp. 254–265, 2002.
[130]
M. Platten, A. Kretz, U. Naumann et al., “Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas,” Annals of Neurology, vol. 54, no. 3, pp. 388–392, 2003.
[131]
M. M. Mueller and N. E. Fusenig, “Constitutive expression of G-CSF and GM-CSF in human skin carcinoma cells with functional consequence for tumor progression,” International Journal of Cancer, vol. 83, no. 6, pp. 780–789, 1999.
[132]
T. W. Briers, C. Desmaretz, and E. Vanmechelen, “Generation and characterization of mouse microglial cell lines,” Journal of Neuroimmunology, vol. 52, no. 2, pp. 153–164, 1994.
[133]
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.
[134]
L. Zhang, T. Himi, and S. Murota, “Induction of hepatocyte growth factor (HGF) in rat microglial cells by prostaglandin E(2),” Journal of Neuroscience Research, vol. 62, no. 3, pp. 389–395, 2000.
[135]
P. Kunkel, S. Müller, P. Schirmacher et al., “Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas,” Neuro-Oncology, vol. 3, no. 2, pp. 82–88, 2001.
[136]
C. Hao, I. F. Parney, W. H. Roa, J. Turner, K. C. Petruk, and D. A. Ramsay, “Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation,” Acta Neuropathologica, vol. 103, no. 2, pp. 171–178, 2002.
[137]
H. Galarneau, J. Villeneuve, G. Gowing, J. P. Julien, and L. Vallières, “Increased glioma growth in mice depleted of macrophages,” Cancer Research, vol. 67, no. 18, pp. 8874–8881, 2007.
[138]
A. Ghosh and S. Chaudhuri, “Microglial action in glioma: a boon turns bane,” Immunology Letters, vol. 131, no. 1, pp. 3–9, 2010.
[139]
A. Persson and E. Englund, “The glioma cell edge—winning by engulfing the enemy?” Medical Hypotheses, vol. 73, no. 3, pp. 336–337, 2009.
[140]
T. N. Seyfried, M. A. Kiebish, J. Marsh, L. M. Shelton, L. C. Huysentruyt, and P. Mukherjee, “Metabolic management of brain Cancer,” Biochimica et Biophysica Acta, vol. 1807, no. 6, pp. 577–594, 2011.
[141]
M. Rachkovsky, S. Sodi, A. Chakraborty et al., “Melanoma x macrophage hybrids with enhanced metastatic potential,” Clinical and Experimental Metastasis, vol. 16, no. 4, pp. 299–312, 1998.
[142]
J. M. Pawelek and A. K. Chakraborty, “Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis,” Nature Reviews Cancer, vol. 8, no. 5, pp. 377–386, 2008.
[143]
T. Strojnik, R. Kavalar, and T. T. Lah, “Experimental model and immunohistochemical analyses of U87 human glioblastoma cell xenografts in immunosuppressed rat brains,” AntiCancer Research, vol. 26, no. 4 B, pp. 2887–2900, 2006.
[144]
I. Shabo, H. Olsson, X. F. Sun, and J. Svanvik, “Expression of the macrophage antigen CD163 in rectal Cancer cells is associated with early local recurrence and reduced survival time,” International Journal of Cancer, vol. 125, no. 8, pp. 1826–1831, 2009.
[145]
T. Browder, C. E. Butterfield, B. M. Kr？ling et al., “Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant Cancer,” Cancer Research, vol. 60, no. 7, pp. 1878–1886, 2000.
[146]
M. Kioi, H. Vogel, G. Schultz, R. M. Hoffman, G. R. Harsh, and J. M. Brown, “Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice,” Journal of Clinical Investigation, vol. 120, no. 3, pp. 694–705, 2010.
[147]
M. Frontczak-Baniewicz, D. Czajkowska, J. Andrychowski, and M. Walski, “The immature endothelial cell in human glioma. Ultrastructural features of blood capillary vessels,” Folia Neuropathologica, vol. 46, no. 1, pp. 49–56, 2008.
[148]
M. W. Kieran, C. D. Turner, J. B. Rubin et al., “A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive Cancer,” Journal of Pediatric Hematology/Oncology, vol. 27, no. 11, pp. 573–581, 2005.
[149]
Y. Soda, T. Marumoto, D. Friedmann-Morvinski et al., “Transdifferentiation of glioblastoma cells into vascular endothelial cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 11, pp. 4274–4280, 2011.
[150]
N. T. Fernando, M. Koch, C. Rothrock et al., “Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors,” Clinical Cancer Research, vol. 14, no. 5, pp. 1529–1539, 2008.
[151]
T. T. Batchelor, A. G. Sorensen, E. di Tomaso et al., “AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients,” Cancer Cell, vol. 11, no. 1, pp. 83–95, 2007.
[152]
M. Hagedorn, L. Zilberberg, J. Wilting et al., “Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors,” Cancer Research, vol. 62, no. 23, pp. 6884–6890, 2002.
[153]
L. Bello, V. Lucini, F. Costa et al., “Combinatorial administration of molecules that simultaneously inhibit angiogenesis and invasion leads to increased therapeutic efficacy in mouse models of malignant glioma,” Clinical Cancer Research, vol. 10, no. 13, pp. 4527–4537, 2004.
[154]
D. L. Dai, N. Makretsov, E. I. Campos et al., “Increased expression of integrin-linked kinase is correlated with melanoma progression and poor patient survival,” Clinical Cancer Research, vol. 9, no. 12, pp. 4409–4414, 2003.
[155]
A. A. Troussard, P. Costello, T. N. Yoganathan, S. Kumagai, C. D. Roskelley, and S. Dedhar, “The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9),” Oncogene, vol. 19, no. 48, pp. 5444–5452, 2000.
[156]
L. A. Edwards, J. Woo, L. A. Huxham et al., “Suppression of VEGF secretion and changes in glioblastoma multiforme microenvironment by inhibition of Integrin-linked kinase (ILK),” Molecular Cancer Therapeutics, vol. 7, no. 1, pp. 59–70, 2008.
[157]
C. Verpelli, G. Bertani, V. Cea et al., “Anti-angiogenic therapy induces integrin-linked kinase 1 up-regulation in a mouse model of glioblastoma,” PLoS ONE, vol. 5, no. 10, Article ID e13710, 2010.
[158]
A. Saidi, M. Hagedorn, N. Allain et al., “Combined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness,” International Journal of Cancer, vol. 125, no. 5, pp. 1054–1064, 2009.
[159]
A. Quintas-Cardama, H. Kantarjian, D. Jones et al., “Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous Leukemia after imatinib and nilotinib (AMN107) therapy failure,” Blood, vol. 109, no. 2, pp. 497–499, 2007.
[160]
H. Kantarjian, F. Giles, L. Wunderle et al., “Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL,” The New England Journal of Medicine, vol. 354, no. 24, pp. 2542–2551, 2006.
[161]
J. C. Reubi and B. Waser, “Unexpected high incidence of cholecystokinin-B/gastrin receptors in human medullary thyroid carcinomas,” International Journal of Cancer, vol. 67, no. 5, pp. 644–647, 1996.
[162]
T. A. Slastnikova, A. A. Rosenkranz, P. V. Gulak et al., “Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery,” International Journal of Nanomedicine, vol. 7, pp. 467–482, 2012.
[163]
J. R. Kanwar, G. Mahidhara, and R. K. Kanwar, “Antiangiogenic therapy using nanotechnological-based delivery system,” Drug Discovery Today, vol. 16, no. 5-6, pp. 188–202, 2011.
[164]
E. W. M. Ng, D. T. Shima, P. Calias, E. T. Cunningham, D. R. Guyer, and A. P. Adamis, “Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease,” Nature Reviews Drug Discovery, vol. 5, no. 2, pp. 123–132, 2006.
