Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas

Journal of Clinical Neuroscience 16 (2009) 1119–1130

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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn

Review

Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas Michael L.H. Wong a,b,*, Amy Prawira a, Andrew H. Kaye a,b, Christopher M. Hovens a a b

Department of Surgery, University of Melbourne, Parkville, Victoria, Australia Department of Neurosurgery, Royal Melbourne Hospital, Grattan Street, Parkville 3050, Victoria, Australia

a r t i c l e

i n f o

Article history: Received 9 September 2008 Accepted 3 February 2009

Keywords: Angiogenesis Clinical trials Glioma

a b s t r a c t Angiogenesis is a key event in the progression of malignant gliomas. The presence of microvascular proliferation leads to the histological diagnosis of glioblastoma multiforme. Tumour angiogenesis involves multiple cellular processes including endothelial cell proliferation, migration, reorganisation of extracellular matrix and tube formation. These processes are regulated by numerous pro-angiogenic and antiangiogenic growth factors. Angiogenesis inhibitors have been developed to interrupt the angiogenic process at the growth factor, receptor tyrosine kinase and intracellular kinase levels. Other anti-angiogenic therapies alter the immune response and endogeneous angiogenesis inhibitor levels. Most antiangiogenic therapies for malignant gliomas are in Phase I/II trials and only modest efficacies are reported for monotherapies. The greatest potential for angiogenesis inhibitors may lie in their ability to combine safely with chemotherapy and radiotherapy. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.

1. Introduction Two distinct processes have been described for the formation of vasculature. Vasculogenesis refers to the formation of primitive blood vessels from mesoderm by differentiation of angioblasts during embryonic development.1 After the primary vascular plexus is formed, further expansion of the circulatory network relies on sprouting or splitting from pre-existing vessels in a process termed angiogenesis.2–5 Blood vessels formed in later stages of embryonic development or in adults as a result of tissue demands are predominantly products of angiogenesis.6 The formation of new blood vessels occurs physiologically during embryogenesis, the reproductive cycle in females and wound healing.5,7,8 Angiogenesis also takes place in a variety of pathological states, including ischemic diseases, chronic inflammatory reactions, and cancer.2,9 It was almost a century ago that the association between angiogenesis and cancer was initially observed.10–12 In 1966, Folkman et al. first showed that tumour growth and metastasis required the formation of new blood vessels.13 Sufficient nutrients and waste exchange can be achieved by diffusion if tumour cells are situated within about 100 lm of blood vessels.14,15 However, growth of tumours beyond this limit necessitates the recruitment of a new blood supply and consequently leads to the emergence of an angiogenic phenotype.3,14 Exponential growth of tumours exceeding

* Corresponding author. Tel.: +61 3 93427703; fax: +61 3 93476488. E-mail address: [email protected] (M.L.H. Wong).

1–2 mm3 occurs after a vascular network is established through angiogenesis.10,13,16–20 The hypothesis that tumours produced a diffusible angiogenic substance was proposed in 1968.21,22 Folkman et al. subsequently proposed in 1971 that tumour growth and metastasis were angiogenesis dependent, and hence, blocking angiogenesis could be a strategy to arrest tumour growth.23 In 1976, Gullino showed that cells in pre-malignant tissue acquired angiogenic capacity as part of the transformation to become fully malignant.24 Genetic studies subsequently confirmed that the acquisition of an angiogenic phenotype was one of the hallmarks of cancer.3,25–28 Angiogenesis is recognised as a key event in the progression of glioma.29–31 Among all solid tumours, glioblastoma multiforme (GBM) has been reported to be the most angiogenic by displaying the highest degree of vascular proliferation and endothelial cell hyperplasia.32 Such intense vascularisation is partly responsible for the pathological features of GBM, including peritumoral oedema resulting from the defective blood brain barrier (BBB) in the newly formed tumour vasculature.33–36 These vessels are associated with increased risks of intratumoural haemorrhage37,38 and are also responsible for contrast enhancement on neuroimaging.36,39–41 Unlike tumours in other locations, gliomas rarely metastasise to distant organs and their aggressive behaviour and poor prognosis are determined by their histological grade. Microvascular proliferation is a diagnostic criterion distinguishing low grade from high grade astrocytomas and is a histopathological hallmark of GBM.42–46

0967-5868/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2009.02.009

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Although it is uncertain if microvascular proliferation is the cause or effect of malignant tumour behaviours, neovascularisation in gliomas correlates positively with their biological aggressiveness, degree of malignancy and clinical recurrence and inversely with the post-operative survival of patients.43–45 The angiogenic potential of GBM was first recognised in 1976 by observing new vessel formation elicited by GBM implanted into rabbit corneas.47 Moreover, glioma cells induced endothelial cell proliferation and tube formation in vitro.48,49 Angiogenic factors such as vascular endothelial growth factor (VEGF) have been identified in pseudopalisading tumour cells adjacent to necrotic zones and hyperplastic vessels, implicating their role in glioma angiogenesis.50–54 Hypoxia inducible factor-1 (HIF-1)a is also expressed in pseudopalisading cells in conjunction with VEGF, which provides a link between hypoxia and angiogenesis in malignant glioma.52,54–56 2. The mechanism of angiogenesis Angiogenesis involves a sequence of coordinated events that is initiated by the expression of angiogenic factors such as VEGF with subsequent binding to its cognate receptors on endothelial cells (Fig. 1). VEGF increases vascular permeability, which leads to extravasation of plasma proteins and dissociation of pericyte coverage.50,53 Endothelial cell migration and proliferation then follow in preparation for the new vasculature.57 Local degradation of the vascular basement membrane and extracellular matrix (ECM) occur simultaneously, paving the way for newly sprouting vessels. This breakdown of ECM involves cathepsin B, matrix metalloproteinases (MMP) and other enzymes as well as the expression of matrix proteins such as fibronectin, laminin, tenascin-C and vitronectin.58–62 Several of these ECM molecules enhance phosphorylation of focal adhesion kinase, which is a critical step in glioma angiogenesis.63–65

Formation of the new blood vessel is accomplished by alignment of endothelial cells in bipolar mode, tubular morphogenesis and formation of a lumen. Individual sprouts are then connected to form vascular loops. Once connected, blood begins to flow through the vessel loops. Maturation of the vessel wall then begins by recruitment of pericytes and/or smooth muscle cells to assemble along the endothelial cells outside the new vessel. The angiogenic process is finally completed by the formation of new basement membrane.66–68 Recent evidence suggests that vascular collapse may precede angiogenesis in the development of glioma, thus adding a further layer of complexity to the angiogenic tumour model.69,70 Glioma cells first accumulate around existing cerebral blood vessels and lift off the astrocytic foot processes, which leads to the disruption of the normal contact between endothelial cells and the basement membrane.70 Affected endothelial cells express angiopoietin-2 (Ang-2) resulting in destabilisation of the vessel wall and decreased pericyte coverage.69–71 Subsequently, these blood vessels become apoptotic and undergo involution. This vascular collapse leads to the death of neighbouring tumour cells and the formation of a necrotic area. Hypoxia ensues in the necrotic region triggering the expression of HIF-1a and VEGF that in turn initiate angiogenesis.69,70 Taken together, vascular regression and necrosis constitute necessary events for the subsequent development of angiogenesis in gliomas. 3. Mediators of glioma angiogenesis Vascular homeostasis is governed by a balance between proangiogenic and anti-angiogenic factors. More than 25 different growth factors and cytokines have been identified that are able to induce angiogenesis72 (Fig. 2). The production of angiogenic

Fig. 1. Tumour angiogenesis. Angiogenesis is initiated by the production of angiogenic factors from tumour cells, such as vascular endothelial growth factor (VEGF). Upon binding to its cognate receptors on endothelial cells, VEGF triggers endothelial cell proliferation and migration. Degradation and invasion of extracellular matrix (ECM) then follow. Endothelial cells assemble into a tubular structure. The process is completed by loop formation and vessel wall maturation. (EC = endothelial cell).

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Fig. 2. A schematic diagram of angiogenesis mediators in gliomas. The phosphatidylinositol-30 kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase (MAPK) are seen to converge angiogenic signals for many angiogenic growth factors, including the most important mediator, vascular endothelial growth factor (VEGF). These pathways and others modulate essential cellular processes in angiogenesis, including endothelial cell proliferation, survival, migration, invasion, tube formation and extracellular matrix degradation. CXCR = C-X-C chemokine receptor, CYR6.1 = cysteine-rich angiogenic inducer 61, CTGF = connective tissue growth factor, EGF = epidermal growth factor, FGF = fibroblast growth factor, HGF = hepatocyte growth factor, IL-6 = interleukin-6, IL-8 = interleukin-8, MMP = matrix metalloproteinases, PDGF = platelet-derived growth factor, PI3K = PI3 kinase, SF = scatter factor, TGF-a = transforming growth factor-alpha, TGF-ß = transforming growth factor-beta.

growth factors is either the result of genetic alterations or is induced by hypoxia. 3.1. Vascular endothelial growth factor The VEGF family of growth factors and their receptors are the most important mediators of glioma angiogenesis.73 The VEGF family includes six glycoproteins referred to as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor.51,74–76 VEGF-A and its receptors are the best characterised signalling pathway in angiogenesis.5,51,77,78 Loss of a single VEGF-A allele during embryonic development is lethal.5,77,78 VEGF-A binds to two receptor tyrosine kinases (RTK) – VEGFR-1 (Flt-1) and VEGFR-2 (KDR, Flk-1).51 It is generally agreed that VEGFR-2 is the major receptor mediating the mitogenic, angiogenic and permeability-enhancing effects of VEGF-A. The role of VEGR-1 in angiogenesis is more complex. Binding to VEGFR-1 may prevent VEGF from interacting with VEGFR-2.51 However, recent evidence has suggested that VEGFR-1 participates in haematopoiesis and in the recruitment of monocytes and other bone marrow derived cells to promote tumour angiogenesis.79–81 In addition, VEGFR-1 is involved in the activation of matrix metalloproteinases associated with matrix degradation and in the production of growth factors from endothelial cells.82,83 VEGF-A gene expression is upregulated by hypoxia, mediated by the transcription factor HIF and the product of the von Hippel–Lindau (VHL) tumour suppressor gene.84 Other transcription factors capable of upregulating VEGF transcription include the ETS-1 proto-oncogene and STAT-3.85,86 ETS proteins activate many genes involved in angiogenesis, including those that regulate VEGFR-1 and VEGFR-2, integrin b3, some MMP and urokinase-type plasminogen activator (uPA).87 However, VEGF can induce ETS-1 expression in glioma cells, thereby forming a possible autocrine loop.86 Accordingly, ETS-1 is expressed more frequently in GBM compared with low grade astrocytomas, being most prominently observed in the glomeruloid tufts of GBM.86 In addition to transcription factors, a variety of growth factors can also upregulate VEGF expression, including transforming growth factor (TGF)-b, epidermal growth factor (EGF), platelet-derived growth factor (PDGF)-B and basic fibroblast growth factors (FGF).85,88–93 VEGF-A messenger RNA is highly expressed in many human tumours,94 including in pseudopalisading cells around the necrotic

core in GBM.52,54,95 A broad spectrum of oncogenes is associated with VEGF-A upregulation, including Ras, erbB-2/Her2, activated EGFR and bcr-abl.96,97 The effect of Ras on VEGF expression may be mediated through the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway. The kinase ERK promotes VEGF expression by recruiting the activator protein-2 (AP-2/Sp1) complex onto the promoter region of the VEGF gene.98 Conversely, mutation and inactivation of various other suppressor genes, such as VHL and PTEN, can also result in VEGF upregulation.99–102 Upon binding to its cognate receptors, VEGF promotes the formation of the secondary messenger via hydrolysis of inositol, leading to receptor autophosphorylation in the presence of heparinlike molecules, and initiates phosphatidylinositol metabolic signal transduction pathways.103,104 The biological effects of VEGF are mediated through diverse signalling pathways. VEGF promotes endothelial proliferation via the activation of the MAPK pathway.103 VEGF also enhances vascular permeability through the MAPK signalling cascade by rearranging cadherin/catenin complexes and loosening adhering junctions between endothelial cells.105,106 Apart from MAPK, the Akt and endothelial nitric oxide synthase (eNOS) pathways are also involved in mediating vascular permeability.107 VEGF stimulates endothelial production of uPA, tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor1 (PAI-1).108,109 Plasminogen activators induce the conversion of plasminogen to plasmin, which can break down ECM components, leading to ECM remodelling. In addition, activation of the uPA receptor can lead to phosphorylation of focal adhesion proteins and the activation of MAPK, thus mediating endothelial cell migration and proliferation.110 Alternatively, the angiogenic effect of VEGF can be mediated through integrins, a1b1, a2b1 and avb3, which promote cell migration, proliferation and matrix remodelling.111,112 VEGF is also a potent pro-survival factor for endothelial cells. This pro-survival effect is mediated through the suppression of p53, p21, p16 and p27, proapoptotic protein Bax, and activation of phosphatidylinositol-3’ kinase (PI3K)/Akt, ERK kinases, Bcl-2, A1 and survivin pathways.113–117 The activation of MAPK/ERK is associated with inhibition of the Jun-N terminal kinase (JNK) pathway in mediating the anti-apoptotic effect of VEGF.118 The PI3K/Akt pathway is of central importance in VEGF signalling.119,120 Activated VEGFR-2 mediates the phosphorylation of

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Akt, which potently inhibits endothelial cell apoptosis by interfering with various apoptosis signalling pathways.121,122 Akt also promotes endothelial cell migration,123 and increases the expression of HIF, leading to enhanced VEGF expression.124 eNOS is an important downstream effector of Akt in angiogenesis. Activation of eNOS by Akt leads to the production of nitric oxide, which in turn promotes endothelial cell survival,125,126 proliferation,127,128 migration129–131 and ECM remodelling.128 Furthermore, increased expression of VEGF in response to hypoxia is partly mediated through the activation of the PI3K/Akt cascade.124 3.2. Angiopoietins Angiopoietin-1 (Ang-1) and Ang-2 are important endothelial growth factors that signal via the Tie2 RTK expressed on endothelial cells. Ang-1 and Ang-2 have been implicated in glioma angiogenesis.64,69–71,132,133 Tie2 activation by Ang-1 leads to stabilisation, remodelling and maturation of blood vessels.134 Ang-1 induces phosphorylation of Tie2 and the p85 subunit of PI3K and increases PI3K activity in a dose-dependent manner, leading to endothelial cell survival via Akt signalling.135 Alternatively, the anti-apoptotic effect of Ang-1 can be mediated through the upregulation of survivin.136,137 In addition, Ang-1 stimulates endothelial cell migration via a PI3K-dependent activation of focal adhesion kinase (FAK), which has a key role in regulating dynamic changes in actin cytoskeletal organisation during cell migration.138 Increased plasmin and MMP secretions from endothelial cells secondary to Ang-1 binding are also important for vessel sprouting.138 However, Ang-2 may act as an antagonist to Tie2 phosphorylation, which leads to destabilisation of blood vessels and thus represents a checkpoint on Ang-1/Tie2-mediated angiogenesis.134 However, the biological effect of Ang-2 may depend on VEGF level. In the presence of endogenous VEGF, Ang-2 promotes vessel dilatation, remodelling of the basal lamina, proliferation and migration of endothelial cells, and stimulates sprouting of new blood vessels.139 In the absence of VEGF activity, Ang-2 becomes anti-angiogenic by promoting endothelial cell death and the regression of vessels. 3.3. Fibroblast growth factors The FGF family of proteins and their receptors are overexpressed in various types of cancer. Binding of FGF to its receptor causes transphosphorylation and activation of intrinsic tyrosine kinase, which results in signal transduction. Both acidic FGF (aFGF) and basic FGF (bFGF) are upregulated in GBM140,141 and are responsible for resistance of endothelial cells to apoptosis.142 The anti-apoptotic effect of bFGF is mediated by increased expression of Bcl-XL and Bcl-2 via the MEK-dependent signalling pathway.143 bFGF augments VEGF-mediated angiogenic effects by inducing VEGF expression.144 In addition, bFGF stimulates the expression of VEGFR in endothelial cells.145 Similar to VEGF, aFGF and bFGF induce endothelial cell proliferation and migration. Furthermore, FGF activation leads to remodelling of ECM and degradation of the basement membrane by inducing production of plasminogen activator, collagenase and MMP in endothelial cells.146,147 3.4. Platelet-derived growth factor PDGF-B and platelet-derived growth factor b receptor (PDGFRb) have important roles in the development and differentiation of the vessel wall.148 PDGF-B is required for recruitment of pericytes and maturation of the microvasculature. However, PDGF’s effects on angiogenesis are mediated partly by VEGF.90,93 Inhibition of PDGFR-b signalling renders tumour vasculature particularly vulnerable to withdrawal of VEGF which, if it happens, would lead

to endothelial apoptosis and vascular regression.149 The angiogenic effects of PDGF are mediated through PI3K/Akt, MAPK/ERK and STAT3 signalling.150 In particular, PDGF-B can also induce the expression of VEGF via a PI3K/Akt dependent mechanism.151 3.5. Epidermal growth factor/transforming growth factor-a EGF and TGF-a are potent mitogenic factors for endothelial cells mediated by binding to the epidermal growth factor receptor (EGFR).152 Similar to EGF and EGFR, TGF-a is overexpressed in primary human astrocytomas.153 EGFR and TGF-a are frequently expressed on tumour endothelial cells.152 EGF stimulates VEGF production in glioma cells, acting in an autocrine and paracrine fashion.92,154 Moreover, the constitutively active EGFR mutant, EGFRvIII, induces VEGF expression through Ras/MAPK and NF-jB signalling.155,156 3.6. Transforming growth factor (TGF)-b TGF-b and its receptors are highly expressed in malignant gliomas, especially in areas of vascular hyperplasia and around necrotic regions.157,158 Although TGF-b inhibits endothelial cell proliferation in vitro,159 a high level of TGF-b promotes angiogenesis in vivo.160 In glioma cells, the angiogenic effect of TGF-b is probably mediated through the enhanced expression of VEGF.161 Molecular inhibition of TGF-b receptor results in reduced VEGF expression and inhibition of PAI-1 by glioma cells.162 In addition, TGF-b induces endothelial production of PDGF-A and PDGF-B chains.152 TGF-b also promotes angiogenesis via the integrin signalling pathway. TGF-b upregulates expression of avb3 integrin that, in turn, binds to MMP-2, which leads to degradation of the ECM and enhanced endothelial cell invasion.163,164 3.7. Scatter factor/hepatocyte growth factor Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic cytokine with diverse biological functions. Expression of SF/HGF and its receptor c-MET is increased in both tumour and endothelial cells in GBM specimens. As a result, an autocrine or paracrine loop is believed to exist between glioma and endothelial cells, contributing to tumour progression and angiogenesis.165 Higher levels of SF/HGF correlate significantly with angiogenic activity in malignant glioma.140 Inhibition of SF/HGF/c-MET expression and signalling results in suppression of tumour growth and angiogenesis in vivo.166,167 3.8. Interleukin-6 and interleukin-8 Interleukin (IL)-6 and IL-8 are cytokines produced by gliomas168,169 and their expressions correlate with the malignant behaviours in these tumours.170,171 IL-6 induces transcriptional activation of VEGF and regulates VEGF promoter activity via direct interaction with STAT3.85 IL-8, however, stimulates angiogenesis via the interaction with the C-X-C chemokine receptor 1 (CXCR1), CXCR2 and Duffy antigen receptor for cytokines (DARC).170–173 DARC expression has been detected on tumour-associated endothelial cells, whereas CXCR1 and CXCR2 are found on infiltrating leukocytes near blood vessels. IL-8 is postulated to have a role in angiogenesis, chemotaxis and leukocyte activation through paracrine functions.174 IL-8 is probably an independent inducer of endothelial cell tubular formation.175 IL-8 expression is upregulated during hypoxia in glioblastoma, and this is mediated by the AP-1 site on the IL-8 promoter.174,176 It is also possible that IL-8 synthesis is increased by EGFR activation via NF-jB dependent signal transduction.170

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3.9. Tumour necrosis factor-a Tumour necrosis factor (TNF)-a is a potent inflammatory cytokine that is found in malignant gliomas and other cells including reactive astrocytes, endothelial cells, and infiltrating macrophages.177,178 The TNF-a receptor (TNFR) is expressed by glioma and endothelial cells.179,180 TNF-a induces tumour angiogenesis indirectly via the activation of other angiogenic factors, the most important of which is VEGF. Expression of VEGF is upregulated in human glioma cells upon TNF-a treatment mediated in part through the transcription factor Sp1.181 In addition, TNF-a enhances VEGF, IL-8 and bFGF production in human microvascular endothelial cells and induces tubular morphogenesis in vitro.182 The angiogenic effects of TNF-a are dependent on Sp1, NF-jB and the JNK signalling cascades. 3.10. Cysteine-rich angiogenic inducer 61, connective tissue growth factor and insulin-like growth factor-1 Cysteine-rich angiogenic inducer 61 (CYR61) and connective tissue growth factor (CTGF) are members of the CCN (CTGF/ CYR61/Cef10/NOVH) family that induce endothelial cell proliferation, migration and tube formation in vitro and promote angiogenesis in vivo.183,184 Their effects on endothelial cell adhesion and migration are mediated through binding to avb3 integrin expressed on the endothelial cell surface.185 Increased expression of CYR61 and CTGF are commonly found in high grade gliomas.186 Insulin-like growth factor-1 (IGF-1) has also been implicated in glioma-induced angiogenesis. Expression of IGF-1 and IGF-1 receptor correlates with histological grade in astrocytomas.187 Furthermore, IGF-1 immunoreactivity is more intense in the tumour cells surrounding microvascular hyperplasia and in reactive astrocytes at the margins of tumour infiltration. In addition, tumourassociated endothelial cells are also immunopositive for IGF-1.187 These results imply an association between microvascular proliferation and IGF-1 expression in glioma cells. 3.11. Integrins Integrins are transmembrane receptor molecules that are responsible for the interaction of endothelial and tumour cells with the ECM. Integrin signal transduction mediates endothelial cell migration and invasion.188 Integrin-avb3 is of particular importance in glioma angiogenesis because its expression correlates positively with tumour grade and glioma cell proliferation.189,190 3.12. Matrix metalloproteinases The MMP family consists of four groups according to their substrates: collagenases, gelatinases, stromelysins and membraneassociated MMP. Gelatinases-A (MMP-2) and gelatinases-B (MMP-9) are highly expressed in astrocytomas and their levels correlate with histological grade, especially those of MMP-9. Both MMP-2 and MMP-9 were detected in blood vessels as well as in tumour cells.191,192 MMPs are involved in the proteolytic degradation of ECM components and facilitate cell motility during invasion and angiogenesis.193 Angiogenic effects of TGF-b and VEGF are partially mediated via the upregulation of MMP-2 and suppression of tissue inhibitor of metalloproteinases (TIMP)-2.194,195 Conversely, MMP-2 and MMP-9 proteolytically cleave and activate latent TGF-b, and promote tumour invasion and angiogenesis.196 3.13. Endothelial progenitor cells Bone marrow-derived endothelial progenitor cells (EPC) participate in angiogenic processes, although their precise roles remain

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to be elucidated. EPC were originally isolated from human peripheral blood on the basis of cell surface expression of CD34 and other endothelial markers.197 These cells differentiated into endothelial cells in vitro and seemed to be recruited to sites of active angiogenesis in in vivo models of ischaemia. Thus, they might complement resident endothelial cells in sprouting new vessels. Various growth factors, such as VEGF and granulocyte macrophage-colony stimulating factor (GM-CSF), were reported to mobilise EPC into angiogenic sites.198 Angiogenic factors might induce mobilisation of EPC from bone marrow by activating MMP-9 and releasing the soluble KIT ligand which, in turn, promotes proliferation and motility of EPC within the bone marrow substance, ultimately leading to the release of EPC into the peripheral circulation.199 It is, however, uncertain of the extent to which EPC participate in tumour angiogenesis. In angiogenic-defective Id mutant mice, EPC contribute to neovasculature of some, but not all, PTEN+/ tumours.200 Furthermore, most bone-marrow derived cells recruited to tumour vasculature are adherent perivascular mononuclear cells rather than endothelial cells.201 The percentage of EPC involved in tumour vasculature was estimated at only about 5% of the total endothelial cell population in tumours.202

3.14. Endogenous angiogenesis inhibitors Endogenous angiogenesis inhibitors have been broadly categorised into 4 groups: interferons (IFN), ILs, TIMP, and proteolytic fragments.203 IFN-a/b suppress the expression of pro-angiogenic factors MMP-9 and IL-8 in different types of cancers.204–207 IFNa/b also decrease bFGF activity, resulting in endothelial apoptosis.205–208 Moreover, IFN-c is believed to induce its anti-angiogenic effects through the secretion of IFN-c inducible protein 10 (IP-10) and monokine induced by IFN-c (Mig).209 Several members of the IL family have been found to inhibit angiogenesis. IL-4 reduces in vivo neovascularisation induced by bFGF and blocks the migration of endothelial cells in vitro.210 In addition, IL-12 suppresses the expression of VEGF mRNA, bFGF and MMP-9 mRNA.211,212 IL-10 may also downregulate the synthesis of VEGF, IL-1b, TNF-a, IL-6, and MMP-9 in tumour-associated macrophages.213 TIMP inhibits the activities of MMP-1, MMP-2 and MMP-9, which leads to reduced ECM remodelling and suppression of endothelial cell migration and invasion.214 Overexpression of TIMP-1 inhibits endothelial cell migration in vitro.215 Apart from its effect in ECM, TIMP-2 also downregulates bFGF-induced endothelial cell proliferation.216 Furthermore, the anti-angiogenic effects of TIMP-3 appear to be mediated, in part, by decreased expression of vascular endothelial-cadherin in endothelial cells.217 Angiostatin is an internal fragment of plasminogen that is able to downregulate VEGF expression in tumour cells.218 Angiostatin also exerts its anti-angiogenic effects via the disruption of HGF/cmet signalling.219 The effects of angiostatin in endothelial cells include inhibition of proliferation, migration and induction of apoptosis.220–222 Endostatin is a fragment of type XVIII collagen that has shown inhibitory action in endothelial cell proliferation, migration and angiogenesis. Endostatin blocks VEGFR-2 activation, leading to suppression of ERK, p38 MAPK and p125FAK signalling.223 Endostatin also directly interacts with VEGFR-2 and inhibits VEGF binding. The anti-migratory effect of endostatin is believed to rely on suppression of eNOS activity.224 Endostatin also inhibits integrin function,225 bFGF binding,226 and MMP-2 activity in endothelial cells.227 Endothelial cell apoptosis is also enhanced by endostatin via the suppression of Bcl-2 and Bcl-XL.228

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4. Anti-angiogenic therapies in malignant gliomas Strategies have been devised to inhibit angiogenesis in malignant gliomas: blocking growth factor production, neutralisation of circulating growth factors, inhibition of RTK activation and suppression of intracellular signalling cascades. Although no antiangiogenic drug has been approved for the treatment of malignant gliomas, many have undergone Phase I/II clinical trials (Table 1, Fig. 3). 4.1. Monoclonal antibodies Monoclonal antibodies to circulating angiogenic factors are the effective means of reducing pro-angiogenic stimuli. The most extensively developed drug in this class is the anti-VEGF antibody. Unlike antibodies that target tumour cells, anti-VEGF antibodies do not need to cross the BBB to exert their effects, thus circumventing a major obstacle in neurotherapeutics. It is, however, uncertain to what extent anti-VEGF antibodies are able to neutralise the paracrine production of VEGF by glioma cells that may occur in the protected zone of the BBB. Bevacizumab (AvastinÒ; Roche, Basel, Switzerland) is a humanised IgG1 monoclonal antibody that neutralises VEGF. In 2004, it became the first drug approved solely as an angiogenesis inhibitor, originally for the treatment of colorectal cancer, and it was later also approved for lung cancer use.229 In a Phase II trial involving 35 patients with recurrent GBM, bevacizumab, in combination with irinotecan, achieved a 57% response rate.230 The 6 month progression-free survival (PFS) among all 35 patients was 46%. The 6 month overall survival was 77%. One patient developed an intracerebral haemorrhage and four patients developed thromboembolic complications. These results are significantly better than for temozolomide, which achieves a 6 month PFS of 21% and a 6 month overall survival of 60% in patients with recurrent GBM. In another group of 10 patients with recurrent GBM, four patients showed a partial response when treated with bevacizumab Table 1 Clinical trials of anti-angiogenic agents in malignant gliomas (March 2009) Mechanism of action

Drug

Trialsref

Monoclonal antibodies Anti-VEGF

Bevacizumab

Phase II230–232

RTK inhibitors VEGFR, PDGFR, Raf, c-Kit VEGFR VEGFR, PDGFR, c-Kit, c-Fms VEGFR2, EGFR, HER2

Sorafenib AZD2171 Vatalanib AEE788

Phase Phase Phase Phase

Other inhibitors mTOR inhibitor mTOR inhibitor mTOR inhibitor

Temsirolimus Everolimus AP23573

Proteosome inhibitor PKC inhibitor Inhibits VEGF, IL-6 expression Inhibits VEGF, IL-6 expression Endostatin enhancer Inhibits MMP-9, IL-8, bFGF Integrin avb3 and avb5 antagonist Integrin avb3 and a5b1 antagonist

Bortezomib Enzastaurin Thalidomide Lenalidomide Celecoxib IFN-a Cilengitide ATN-161

MMP inhibitor Inhibits HIF-1a and tubulin polymerisation

Prinomastat 2-methoxyestradiol

Phase II244,245 Phase I/II246 Phase I (no published data) Phase I247,248 Phase I/II251,252 Phase II255–257 Phase I259 Phase I/II261 Phase I/II266,267 Phase I/II270,271 Phase I/II (no published data) Phase II274 Phase II276

I/II235 II236 I240 I242

See text for details of drugs and clinical trials. bFGF = fibroblast growth factor, EGFR = epidermal growth factor receptor, HIF = hypoxia inducible factor, IL = interleukin, IFN-a = interferon-alpha, PKC = protein kinase C, PDGFR = plateletderived growth factor, MMP = matrix metalloproteinases, RTK = receptor tyrosine kinase, VEGF = vascular endothelial growth factor.

plus carboplatin, irinotecan or etoposide.231 In a recent series of 10 patients with recurrent malignant gliomas (nine World Health Organization [WHO] grade 4 and one WHO grade 3) who have failed additional resection, chemotherapy and radiation after their initial relapse, bevacizumab plus irinotecan therapy produced an objective response rate of 80%.232 The median progression-free interval on this treatment was 25 weeks. These results are again superior than for temozolomide, which leads to a response rate of 46% and median PFS of about 12 weeks in recurrent GBM.233 However, the efficacy of bevacizumab in achieving a radiological response and prolonging survival in patients with malignant gliomas is yet to be confirmed in a larger Phase III trial. 4.2. RTK inhibitors Sorafenib (NexavarÒ; Bayer Schering Pharma, Berlin, Germany; Onyx Pharmaceuticals, Emeryville, CA, USA) is a multi-kinase inhibitor which inhibits Raf, VEGFR, PDGFR-b and c-Kit. It inhibits the kinase activity of both C-Raf and B-Raf, which leads to downregulation of MEK and ERK activities in tumours cells, and also suppresses angiogenesis via inhibition of VEGFR and PDGFR activity in endothelial cells.234 It has been approved for the treatment of kidney cancer.229 A Phase I trial has reported good safety and tolerability of sorafenib in patients with recurrent malignant gliomas up to a dose of 800 mg twice daily.235 Adverse effects include hand foot syndrome, pruritis, hypophosphataemia, and joint pain. Phase II trials of sorafenib in patients with malignant gliomas are ongoing. AZD2171 (AstraZeneca, London, UK) is a potent, oral pan-VEGF RTK inhibitor. Daily dosing of AZD2171 results in rapid normalisation of glioma vessels and is associated with improvement of cerebral oedema.236 In a Phase II study of 30 patients with recurrent GBM, AZD2171 had a steroid-sparing effect in alleviating tumour-associated oedema.237 However, the effect of AZD2171 on survival is only modest, with a 6 month PFS of 28% and a median PFS of 16 weeks. Vatalanib (Novartis, Basel, Switzerland) is a small anti-angiogenic molecule which inhibits all 3 subtypes of VEGFR, PDGFR, cKit and c-Fms.238,239 Vatalanib in combination with imatinib and hydroxyurea have been evaluated in a recent Phase I study of 35 patients with recurrent GBM.240 Adverse effects were thrombocytopenia, hypertension, elevated liver enzymes, and fatigue. About 29% of the patients had partial response to the treatment. AEE788 (Novartis) is a multi-kinase inhibitor that suppresses the activation of EGFR, HER2, and VEGFR2.241 In a Phase I study of 26 patients with recurrent GBM, 27% had stable disease after AEE788 treatment.242 The 6 month PFS was 14% among this group. The most common side effects included diarrhoea, skin rash, fatigue, nausea and anorexia, thrush, and vomiting. A Phase II trial in combination with everolimus is continuing. 4.3. Intracellular kinase inhibitors Due to the common signalling pathways for oncogenesis and angiogenesis, many kinase inhibitors targeting tumour cells also have an anti-angiogenic effect.243 These include mTOR inhibitors (temsirolimus,244,245 everolimus246 and AP23573), bortezomib247,248 and protein kinase C (PKC) inhibitors.229 Of particular interest in this group is enzastaurin (Eli Lilly, Indianapolis, IN, USA) which is a selective PKCb inhibitor. It suppresses the phosphorylation of GSK3b, ribosomal S6 and Akt in GBM xenografts.249 It is also a potent inhibitor of endothelial cell proliferation in vitro and VEGF or bFGF-induced angiogenesis in vivo.250 In a Phase II study of enzastaurin in patients with recurrent malignant glioma, a 16% response rate was reported,251 which was significantly better than the response rate seen with temozolo-

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Fig. 3. Anti-angiogenic agents for malignant gliomas in clinical trials as of March 2009 and their sites of action. See Table 1 and text for references to drugs and clinical trials. HIF = hypoxia inducible factor, PKC = protein kinase C, MMP = matrix metalloproteinases, mTOR = mammalian target of rapamycin, PI3K = phosphotidylinositol 3-kinase, VEGF = vascular endothelial growth factor.

mide.233 In an ongoing Phase I/II study, enzastaurin was able to combine with temozolomide and concurrent radiotherapy without any dose limiting toxicity.252 4.4. Immunomodulatory agents Thalidomide (ThalomidÒ, Celgene Corporation, summit, NJ, USA) is an immunomodulatory agent that inhibits angiogenesis. Its anti-angiogenic mechanism is not yet fully understood, but is believed to involve inhibition of VEGF and IL-6 expression.253 Recent evidence also indicates its probable suppression of nitric oxide-induced migration of endothelial cells at the initial phase of angiogenesis.254 In a Phase II trial using thalidomide as a monotherapy in patients with recurrent malignant glioma, the objective response rate was 6% and the 12 month overall survival was 22%.255 The response rate improved to 24% when thalidomide was combined with bis-chloronitrosourea (BCNU).256 In another study, patients with recurrent GBM who have also failed temozolomide or nitrosourea therapy were given thalidomide in conjunction with irinotecan. The efficacy of this treatment was better than monotherapy, and resulted in a 6-PFS of 28% and a 82% 6 month overall survival.257 Lenalidomide (RevlimidÒ, Celgene) is a derivative of thalidomide with enhanced immunological and anti-angiogenic properties but lacking toxicities associated with thalidomide.258 Unfortunately the efficacy of lenalidomide as a monotherapy in malignant gliomas is, so far, disappointing. In a study of 24 patients with recurrent GBM, no objective radiographic response was seen, and only 12.5% of patients were progression-free at 6 months.259 4.5. Endogenous angiogenesis inhibitors Celecoxib (Pfizer, New York, USA) is a selective cyclo-oxygenase-2 inhibitor. It suppresses proliferation and increases apoptosis in endothelial cells by upregulating the endogenous synthesis of

endostatin.260 The efficacy of celecoxib in combination with temozolomide was assessed in patients with recurrent malignant astrocytomas.261 Overall response rate was 72%. The median survival from initial diagnosis was 15 months for GBM and 23 months for anaplastic astrocytoma, which appears to be superior than temozolomide alone.233 IFN-a/b function as direct anti-tumour,262 immunomodulator263 and anti-angiogenic agents.264,265 In a Phase II study of long-acting IFN-a plus temozolomide in recurrent GBM, 6 month PFS was 38%, which was better than temozolomide alone.266 IFNa has also been used in combination with BCNU Gliadel wafer to treat patients with recurrent GBM and an overall response rate of 20% was reported.267 4.6. Other inhibitors of angiogenesis Cilengitide (EMD Pharmaceuticals, Raleigh-Durham, NC, USA) is a cyclic RGD pentapeptide inhibitor of integrins avb3 and avb5, which has shown promising anti-tumour and anti-angiogenic effects in vivo.268,269 As a monotherapy in patients with recurrent GBM, cilengitide was moderately effective in achieving a 6 month PFS of 16% and a median overall survival of 6.5 months.270 The efficacy of cilengitide has also been assessed in combination with temozolomide plus radiotherapy in newly diagnosed GBM.271 This combination therapy was well tolerated. The 6 month PFS was 65%,which was superior to 54% achieved by concurrent temozolomide and radiotherapy alone.272 A larger Phase III trial is required to confirm these results. ATN-161 (Attenuon, San Diego, USA) is non-RGD-based integrin binding peptide which antagonises avb3 and a5b1. A Phase I/II study of ATN-161 and carboplatin in patients with recurrent malignant glioma is ongoing. Prinomastat (Agouron Pharmaceuticals, La Jolla, CA, USA) is a selective oral inhibitor of MMP-2, MMP-9, MMP-13 and MMP-14. This drug has been shown to inhibit tumour growth and angiogenesis in vivo.273 Unfortunately, the results from the Phase II study of

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prinomastat in GBM patients have been disappointing. Prinomastat in combination with temozolomide and radiotherapy did not improve median survival or PFS compared to temozolomide and radiotherapy alone.274 The compound 2-methoxyestradiol (2ME2) (EntreMed, Rockville, MD, USA) is an estrogen derivative. It inhibits tumour cell proliferation and induces apoptosis by suppressing microtubule polymerisation and by increasing the reactive oxygen species-induced cell damage.275 In addition, 2ME2 downregulates HIF-1a expression at the post-transcriptional level and inhibits HIF-1amediated VEGF expression. In an ongoing Phase II study, 2ME2 as a single agent achieved a 44% response rate in patients with recurrent GBM.276 No survival data are available at the time of writing. 5. Conclusions

16.

17. 18. 19.

20.

21.

22.

Tumour-related angiogenesis is a fertile ground for developing effective anti-cancer treatments. Anti-angiogenic agents have special roles in the treatment of central nervous system tumours because they can bypass the BBB in exerting their effects. In addition, GBM is one of the most angiogenic tumours in humans, thus rendering it an ideal target for anti-angiogenic treatment.32 Most angiogenesis inhibitors are not highly effective as a monotherapy. Fortunately, many of these agents are able to be combined safely with other adjuvant therapies, in particular temozolomide and concurrent radiotherapy. Such combinations may hold the greatest potential for superior therapeutic efficacy because each component therapy is attacking a slightly different part of the oncogenic machinery.277 At the time of writing, no angiogenesis inhibitor is approved for the treatment of malignant gliomas. Ongoing clinical trials of potential anti-angiogenic drugs may provide the next new modality in addition to surgery, radiotherapy and cytotoxic chemotherapy for the treatment of malignant gliomas.

23.

Acknowledgements

34.

We thank the Royal Australasian College Surgeons Surgeon Scientist Scholarship and the Friends of Royal Melbourne Hospital Neuroscience Foundation for their support.

35.

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