Invasion as target for therapy of glioblastoma multiforme

BBACAN-87921; No. of pages: 9; 4C: 4 Biochimica et Biophysica Acta xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbacan

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Review

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Invasion as target for therapy of glioblastoma multiforme a b c

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Anne Vehlow a, Nils Cordes a,b,c,⁎

OncoRay — National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf, 01314 Dresden, Germany

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Article history: Received 16 May 2013 Received in revised form 9 July 2013 Accepted 18 July 2013 Available online xxxx

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The survival of cancer patients suffering from glioblastoma multiforme is limited to just a few months even after treatment with the most advanced techniques. The indefinable borders of glioblastoma cell infiltration into the surrounding healthy tissue prevent complete surgical removal. In addition, genetic mutations, epigenetic modifications and microenvironmental heterogeneity cause resistance to radio- and chemotherapy altogether resulting in a hardly to overcome therapeutic scenario. Therefore, the development of efficient therapeutic strategies to combat these tumors requires a better knowledge of genetic and proteomic alterations as well as the infiltrative behavior of glioblastoma cells and how this can be targeted. Among many cell surface receptors, members of the integrin family are known to regulate glioblastoma cell invasion in concert with extracellular matrix degrading proteases. While preclinical and early clinical trials suggested specific integrin targeting as a promising therapeutic approach, clinical trials failed to deliver improved cure rates up to now. Little is known about glioblastoma cell motility, but switches in invasion modes and adaption to specific microenvironmental cues as a consequence of treatment may maintain tumor cell resistance to therapy. Thus, understanding the molecular basis of integrin and protease function for glioblastoma cell invasion in the context of radiochemotherapy is a pressing issue and may be beneficial for the design of efficient therapeutic approaches. This review article summarizes the latest findings on integrins and extracellular matrix in glioblastoma and adds some perspective thoughts on how this knowledge might be exploited for optimized multimodal therapy approaches. © 2013 Published by Elsevier B.V.

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Keywords: Glioblastoma multiforme Extracellular matrix Invasion Integrins Proteases Radiochemotherapy

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. ECM modifications in the brain microenvironment affect glioblastoma cell invasion 3. ECM degradation in favor of glioblastoma cell invasion . . . . . . . . . . . . . 4. Integrins in control of glioblastoma cell invasion . . . . . . . . . . . . . . . . 5. Effects of radiochemotherapy on glioblastoma cell invasion mechanisms . . . 6. Clinical targeting glioblastoma cell invasion . . . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

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Glioblastoma multiforme (GBM) is the most malignant form of primary astrocytic brain tumors in adults [1]. The current treatment standard is a multimodal approach combining neurosurgery,

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⁎ Corresponding author at: OncoRay — National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74/PF 41, 01307 Dresden, Germany. Tel.: +49 351 458 7401; fax: +49 351 458 7311. E-mail address: [email protected] (N. Cordes).

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fractionated radiation therapy and chemotherapy with the DNA methylating agent temozolomide [2,3,6]. But despite continuous improvements in the treatment of GBM during the past decade, these tumors are still associated with a poor prognosis and rare long-term survival of the patients [4–6]. Recent effort to better understand the biology of GBM tumors has particularly led to the discovery of molecular gene signatures [7–12]. Frequent mutations in the p53 and isocitrate dehydrogenase (IDH) gene, alterations of genes regulating retinoblastoma (RB) protein function and control receptor tyrosine kinase signaling (including

0304-419X/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.bbcan.2013.07.001

Please cite this article as: A. Vehlow, N. Cordes, Invasion as target for therapy of glioblastoma multiforme, Biochim. Biophys. Acta (2013), http:// dx.doi.org/10.1016/j.bbcan.2013.07.001

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Functioning as a reservoir of growth factors and matrix proteins, as well as providing structural support [31], the ECM is crucial in promoting GBM progression [32,33]. In the brain, the major cellular components such as neurons, glia and blood vessels are held in place by a unique ECM scaffold approximately accounting for up to 15–20% of the brain volume [34]. The ECM of a healthy brain mainly consists of the large space-filling non-protein-bound glycosaminoglycan hyaluronic acid (HA) and in addition proteoglycans and glycoproteins, which interact to organize the extracellular space [35]. Apart from moving along myelinated axons, glioblastoma cells disseminate into healthy brain regions along the vascular basement membrane and the glia limitans externa where fibrous proteins such as collagens, fibronectin, laminins and vitronectin are expressed [35,36]. Intriguingly, these ECM components have been detected throughout GBM tumors [32], where they may act as promoters of treatment resistance and invasion. Mostly, laminin, fibronectin, collagen-III and collagen-IV expression is restricted to blood vessel walls within the neoplastic area of GBM [37–45]. Vitronectin and fibronectin expression increases in line with a more infiltrative tumor grade [37,39] and especially fibronectin isoforms containing extra domain A (EDA) and extra domain B (EDB) seem to be confined to tumor while absent in healthy brain regions [46]. Laminin was also observed at the invasive edge of the GBMs [47–50] and

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2. ECM modifications in the brain microenvironment affect glioblastoma cell invasion

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vitronectin surrounds islands of tumor cells that have invaded the normal brain parenchyma [51,52]. This strongly indicates a role for both proteins in GBM progression. Collagen-I expression was detected within extratumoral and intratumoral interstitial connective tissue and may act as a pro-invasive guidance cue [41,42]. Furthermore, the first fibrilassociated collagen with interrupted triple helices (FACIT), i.e. collagenXVI, was identified in GBM patient samples to be highly expressed on brain vessels and glioblastoma cells in comparison to normal brain cortex [53,54] and may promote glioblastoma cell invasion [55]. Interestingly, glioblastoma cells are suggested to express and secrete ECM proteins into the surrounding microenvironment and this action may depend on 3D in vivo and in vitro growth conditions [56–58]. Cultured glioblastoma cells generate basement membrane components, such as laminin [38,47], vitronectin [39,59], fibronectin [58,60,61], collagen-I [58,62,63], collagen-IV [41,58] or collagen-VI [64,65]. Interestingly, crosstalk with the cerebral microenvironment may alter this glioblastoma cell-mediated expression of ECM proteins [56,66] through additional or complimentary ECM production and secretion by the normal brain tissue [48,59,67]. Recent studies identified a switch from laminin-9 to predominantly laminin-8 expression in high grade glioblastoma cells [68] and this was associated with rapid tumor recurrence and a shorter survival time of patients [69,70]. Based on in vitro examinations showing reduced glioblastoma cell invasion upon inhibition of laminin8 expression [71], laminin-8 secretion by glioblastoma cells may further facilitate their own motility. Hence, invasion might be made feasible or even fostered by the autonomous secretion of ECM proteins.

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3. ECM degradation in favor of glioblastoma cell invasion

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Apart from the secretion of matrix proteins into the microenvironment, glioblastoma cells express and release ECM-degrading enzymes for ECM remodeling and infiltration. The function of these proteases is controlled by specific inhibitors and an imbalance in their expression levels facilitates invasion. In glioblastoma, three groups of proteases are linked to aggressive infiltration by degrading various constituents of the ECM: (1) serine proteases, (2) cysteine proteases, and (3) matrix metalloproteinases (MMP) [29]. Among the group of serine proteases, the urokinase-type plasminogen activator (uPA) and its membrane-bound receptor (uPAR) have attracted much attention. By converting plasminogen to active plasmin, uPA induces the degradation of various ECM proteins such as fibronectin and laminin and contributes to the activation of the adhesive and invasive properties of glioblastoma cells [72]. uPA localization has been detected predominantly at the tumor margin [73–75], while uPAR can be found throughout the tumor [76]. uPA transcripts, protein expression and activity correlate with increasing brain tumor grade [74,75,77,78]. Targeted inhibition of uPA or its receptor reduces tumor growth and glioblastoma cell invasion in vitro [79–85] and tumorigenicity in nude mice [81,86]. Also, the lysosomal cysteine protease Cathepsin B is linked to glioblastoma invasion by the degradation of laminins and collagens [87] and is secreted by glioblastoma cells in vitro [88]. Elevated Cathepsin B expression on the cell surface and enzyme activity correlate with tumor grade [89–91] and are associated with an increased invasiveness of glioblastoma cells [92]. Furthermore, enhanced Cathepsin B expression correlates with significant shorter overall survival of GBM patients [73,93] and downregulation of Cathepsin B expression impairs invasive and tumorigenic potential of human glioblastoma cell lines [80,94,95]. MMP endopeptidases can be grouped according to their structure and substrate specificity into collagenases, gelatinases, stromelysins, matrilysins and membrane-type MMP [96]. All require activation of their inactive proenzyme by enzymatic cleavage before concerting their degradative activity on matrix proteins [96]. Several MMP are overexpressed in GBM tumors, but in line with the vascular basement membrane being the typical invasion route of glioblastoma cells, much research has been focused on elucidating the function

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epidermal growth factor receptor (EGFR), phosphatidylinositide 3-kinase (PI3K) and phosphatase and tensin homologue (PTEN)) [8–11,13], as well as an unmethylated O6-methylguanine methyltransferase (MGMT) promoter have been identified to contribute to a resistance phenotype to radio- and chemotherapy and also correlate with poor overall survival [5,14–17]. Beyond this plethora of genetic and epigenetic modifications, there is another additional characteristic aggravating eradication of GBM, which is the infiltrative growth pattern. This phenomenon complicates complete surgical resection allowing tumor regrowth and further invasion of surviving tumor cells in close proximity to the resection area [18]. How to optimize the treatment tailored to invading cells appears rather easy at first glance. On closer inspection, the complexity of the cell migration process becomes more obvious and the fact that tumor cells have the ability to use and switch between different migration modes, i.e. collective, mesenchymal and ameboid, complicates treatment development [19–21]. Another key point is the cell–extracellular matrix (ECM) interactions that govern cell motility as well as additional eminent cell functions associated with treatment resistance. We and others have shown that glioblastoma cell invasion, proliferation and therapy resistance depend on an integrin-based interaction with the ECM and the consequential modulation of intracellular signal transduction pathways [22–26]. Apart from integrins, secretion of proteases by glioblastoma cells into the surrounding brain microenvironment further facilitates infiltration of healthy brain areas thereby augmenting disease progression [27–29]. Although it seems promising to therapeutically target integrins and proteases to restrict infiltration of GBM tumors, inhibitors of these proteins failed to improve patient's outcome in late stage clinical trials [30]. In this respect, the mechanistic processes that underlie glioblastoma cell invasion are still unclear. Most in vitro studies addressing this issue employ cell lines cultured on 2-dimensional (2D) substrates, which do not integrate additional effects of tumor cell and ECM interactions as 3dimensional (3D) microenvironments. Furthermore, whether infiltration of glioblastoma cells into the surrounding brain tissue is affected by radio- and chemotherapeutic treatment is highly debated and only little is known about the effects of the treatment regimen on the interactions of glioblastoma cells within the specialized brain microenvironment. With regard to being the standard of care for patients suffering from GBM, this review discusses the effects of radiochemotherapy in the context of integrin-based glioblastoma cell invasion and survival.

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5. Effects of radiochemotherapy on glioblastoma cell invasion mechanisms

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Depending on the tissue environment and the tumor entity, cancer cells may invade as single cells using mesenchymal or ameboid modes or collectively as cell groups [20]. Tumor cells may switch between mesenchymal and ameboid movement, collective and single cell invasion by the process of epithelial-to-mesenchymal transition or by forming cell collectives from single cells [20]. Apart from overcoming microenvironmental challenges, these switches are suggested to contribute to therapy resistance of tumor cells [19]. Glioblastoma cells mainly appear to invade using the mesenchymal form of motility in vivo, which is dependent on the adhesive interaction of integrins with the ECM and the remodeling of the surrounding tissue by the secretion of proteases [21,144,145] (Fig. 1). In contrast, ameboid invasion of glioblastoma cells, which is largely independent of integrins and matrix degradation, has so far only been described in vitro

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Interactions with the ECM are mediated by integrins, a protein family of heterodimeric transmembrane adhesion receptors that bidirectionally link the ECM with intracellular signaling networks [21,32,123]. Integrins are comprised of one of 18 α and one of 8 β subunits, forming 24 known α/β integrin pairs with specificity for different ECM proteins [123,124]. These integrin receptors contribute to the regulation of cell proliferation, differentiation, motility and tissue organization apart from cancer cell survival and invasion [123]. Concomitant with an upregulation of pro-migratory ECM proteins, elevated expression of the respective integrin receptors has been detected in GBM tumor samples, suggestive of important functions of integrins during GBM progression. Expression of several integrin subunits such as β1, β3, β4 or β8 in combination with α2,

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α3, α5 or αv is upregulated in GBM tumors compared to normal brain or in cell lines derived from GBM tumors [38,125–128]. In addition, the integrins α2β1, α5β1, α6β1 α9β1 and αvβ3 are strongly expressed in GBM samples in contrast to normal brain tissue [126,129,130]. Furthermore, glioblastoma cells and blood vessels in GBM tumors express high levels of integrins αvβ3 and αvβ5, which serve as adhesive receptors in the periphery of and throughout GBM neoplasms [130–132]. In addition, both integrins are linked to glioblastoma progression as their expression positively correlates with the histological tumor grade [39,51,130,131]. Importantly, several studies by us and others have shown that integrins are crucial regulators of glioblastoma cell invasion, as small interfering RNA (siRNA) directed against various integrin subunits or integrin blocking antibodies and peptides decrease the invasive ability of glioblastoma cell lines in vitro and in vivo [33,116,120,127,129,133–138]. Along with their increased expression, crosstalk of integrins and proteases links glioblastoma cell invasion to the availability of ECM substrates. With this regard, uPA and uPAR were found to colocalize to focal adhesion containing αvβ3 indicating a role for glioblastoma cell adhesion and invasion by regulating matrix degradation at sites of contact [76]. MMP-2 also colocalizes with αvβ3 to a bigger extent in the periphery than in their center of GBM tumors further supporting the role of these enzymes for the infiltrative phenotype of GBM [51]. On the cellular level, αvβ3 and MMP-2 bind to each other and form protein complexes with p21 protein-activated kinase 4 (PAK4) directly linking these proteins to the invasion process [106]. Also β1 integrins colocalize with MMP-2 in focalized contacts at the lamellipodium pointing at a prominent function during progressive invasion [139]. Intriguingly, decreasing α3β1 and α5β1 expression by treatment with specific antibodies showed contradictory results. While Chintala et al. demonstrated enhanced MMP-2 activity and invasion of glioblastoma cells [140], we exhibited diminished MMP-2 activity and invasion [22]. Nonetheless, both studies point at a regulatory and mutual function between integrins and MMP-2. Inhibition of MMP-2 by siRNA reduced the invasive potential of glioblastoma cell lines in vitro and tumor growth in vivo [106,107] and these effects may be related to a deregulation of β1 and β3 integrin expression and their associated downstream signaling [105,106]. Previously, we have established that ionizing radiation induces expression of β1 integrins in glioblastoma cell lines rendering them more resistant to irradiation, and that inhibition of β1 integrin successfully reduces glioblastoma cell invasion and survival in response to irradiation [22,116,141]. Also expression of β3 and β5 containing integrin receptors showed the tendency to increase after Xray irradiation and was suggested to be linked to hypermigration of glioblastoma cells [120,133,142,143]. But despite modulation of the invasion capability of GBM cells in these preclinical studies, clinical data are not supportive of this paradigm.

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of the gelatinases MMP-2 and MMP-9 as promoters of glioblastoma cell invasion [97]. MMP-2 activity is highly increased in GBM tumors compared to normal brain and expression levels correlate with malignant progression in vivo [98–101]. In concert with this, MT1-MMP and MT2-MMP, which are thought to regulate activation of MMP-2 on the cell surface [102], are also expressed at higher levels in GBM tissues and this correlates with MMP-2 activation [99,103,104] and glioblastoma cell migration [102]. Inhibition of MMP-2 activity or downregulation of MMP-2 protein levels decreases migration and invasion of glioblastoma cell lines in vitro and in nude mice [84,105–107]. Active MMP-9 is primarily associated with glioblastoma subtypes expressing the ligand-independent EGFR variant III [108]. MMP-9 expression was detected at tumor margins and at sites of endothelial proliferation, pointing at a prominent role in mediating angiogenesis and associated glioblastoma cell invasion [98,109]. Furthermore, its activity and expression increase with tumor grade [73,99,101,110–112] and downregulation of the MMP-9 protein inhibits glioblastoma infiltration in vitro [113] and in nude mice [94,114] suggesting a major role of MMP-9 for glioblastoma tumor growth [115]. Whether radiochemotherapeutic treatment affects the constitution of the microenvironment in GBM tumors by altering expression and secretion of ECM proteins and proteases is far from understood. Studies by us and others have shown that X-ray irradiation indeed induces an increased expression and activity of MMP-2 along with an increase in MT1-MMP and a decrease of inhibitory TIMP-2 protein levels in vitro [107,116–118]. We also showed that linked to these changes was an increase in MMP-2 gelatinase activity at lethal irradiation doses (≥3 Gy), which negatively affected cellular invasiveness [116]. Furthermore, a recent study investigated the effect of a single dose and clinically relevant fractionated irradiation on MMP expression and ECM degradation in normal rat brain [119]. Both irradiation regimes caused an upregulation of MMP-2 mRNA associated with an increased activity and a decrease in collagen-IV levels 24 h after irradiation [119]. Others reported an induction of MMP-2, MMP-9 and MT1-MMP expression and activity levels after sublethal irradiation (≤3 Gy) in vitro, which associated with a concomitant increase in MMP-2 expression and tumor satellite formation in the rat brain [120]. Differential results exist about the effects of temozolomide (TMZ) treatment on glioblastoma cell invasion in vitro. At doses below 50 μM, TMZ resulted in enhanced expression and activity of MMP-2 along with an increase in MT1-MMP and a decrease of inhibitory TIMP-2 protein levels in vitro, which could favor invasion [121]. However, TMZ doses above 50 μM counteracted radiationinduced changes in MMP expression via caspase 3-mediated focal adhesion kinase (FAK) cleavage and reduced glioblastoma cell invasion in matrigel assay and rat brain aggregates [118]. Interestingly, X-rays also enhanced glioblastoma cell-induced angiogenesis in the chicken embryo chorioallantoic membrane model, but mediators of this effect remain uncertain [122]. Thus, radiochemotherapy treatment may indirectly affect glioblastoma cell invasion, as the secretion of ECM proteins and proteases impacts on GBM infiltration.

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hugely, not only in terms of cell shape but also in the requirement of proteases, integrins and certain signaling pathways for glioblastoma cell motility. For example, glioblastoma cells exhibit broad lamellipodia and a prominent cell surface ruffling on 2D surfaces, while they stretch out in 3D environments and extend long narrow processes with some ruffling activity at their tips [144,145]. In addition, inhibition of proteases had no effect on migration on 2D substrates, but affected glioblastoma cell invasion in dense 3D collagen-I matrices [154]. Moreover, migration of glioblastoma cells can occur in the absence of myosin II phosphorylation on 2D substrates, while myosin II-dependent cell contractility is required for their movement through 3D pores that are smaller than the nuclear diameter [144]. Whether radiochemotherapy affects glioblastoma cell motility and invasion is far from understood and highly debated. Experimental systems evaluating glioblastoma cell migration and the effect of radioand chemotherapy on invasion of these tumor cells include scratch assays, single cell or spheroid motility assays on flat surfaces and transwell migration assays, all equipped with varying densities or types of extracellular matrix proteins [107,116,118,120,133,142,143,155]. In concert with these diverse approaches, varying results exist in the literature and their impact for a better understanding of the mechanisms as well as their impact on translation from bench to bedside remains vague. Own data show no change or reduction of glioblastoma cell migration in laminin-rich ECM (lrECM) after a lethal dose of X-rays [116]. However, an increase of glioblastoma cell migration at sublethal or lethal doses of X-rays was reported in several studies using lrECM-dependent transwell assays [107,120] and this effect was reversed by addition of

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[146–148] (Fig. 1). Importantly, it is unknown whether glioblastoma cells can evade radiochemotherapy treatment by switching invasion modes (Fig. 1). On the single cell level, invasive migration is the result of a multistep mechanism combining changes in cell shape, position and tissue architecture that are controlled by a complex interplay between intracellular signaling networks such as activation of PI3K and small GTPases, tumor cell intrinsic and extracellular stimuli and extracellular cues [149,150]. Thereby, a tumor cell first forms a leading edge protrusion by polarization of the actin polymerization machinery. This protrusion engages with ECM substrates via integrins that cluster to couple adhesion to intracellular force generation in focal adhesion complexes, which also contain other surface proteins, such as proteases and receptor tyrosine kinases. Activation of myosin II by the small GTPase Rho and Rho-associated protein kinase (ROCK) then leads to actomyosin-mediated contraction and focal adhesion disassembly at the cell rear, which subsequently moves the cell forward. The whole process is facilitated by the local degradation of ECM substrates by cell surface proteases making way for the advancing cell body [151]. In contrast, ameboid invading cells form bleb-like pseudopodia or smooth membrane protrusions at the leading edge and squeeze through the ECM meshwork utilizing a Rho/ROCK-dependent actomyosin-mediated contraction at the back of the cell [152]. In this respect, the mechanistic processes that underlie glioblastoma cell invasion are still unclear. Most in vitro studies addressing this issue employ cell lines cultured on 2D substrates [107,116,120], which do not integrate additional effects of tumor cell and ECM interactions as 3D matrices [23,153]. Furthermore, 2D and 3D growth conditions differ

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new targeted strategies Fig. 1. Targeting mesenchymal and ameboid invasion of glioblastoma cells. Mesenchymal invasion (left) is characterized by cell elongation in concert with the reorganization of ECM fibers and depends on integrin and protease function. Ameboid invasion (right) depends on the Rho/ROCK signaling axis and allows cells to squeeze through the ECM meshwork by utilizing actomyosin contractility. Invasion mode switches may contribute to therapy resistance and should be considered when designing new targeted strategies in addition to the current multimodal therapy consisting of surgery, radiotherapy and TMZ.

Please cite this article as: A. Vehlow, N. Cordes, Invasion as target for therapy of glioblastoma multiforme, Biochim. Biophys. Acta (2013), http:// dx.doi.org/10.1016/j.bbcan.2013.07.001

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Taken together, the recent results from basic and clinical research further highlight that the successful treatment of GBM patients will require the combination of different treatment modalities depending on the progression status of the GBM tumor and history of the patient. As glioblastoma cells have the capacity to adopt their invasion mode to changing conditions such as microenvironmental changes after radiochemotherapeutic treatment, it seems necessary to consider multimodal treatment options that target specifically the heterogeneity of individual GBM tumors including invasion, angiogenesis and other factors. Thereby, thorough understanding the effects of radiochemotherapy on glioblastoma cell invasion and survival and identification

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The use of surgery for GBM tumor resection is limited and depends on the location and infiltrative behavior of the GBM tumor in the brain. The application of radiotherapy is restricted to the area surrounding the GBM tumor because radiation-induced injury to normal brain tissue may cause severe normal tissue effects in patients after therapy. Thus, not all tumor cells may be removed by these approaches. Although the combination of radiotherapy with the chemotherapeutic agent temozolomide is the current treatment standard for GBM patients

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(Table 1), success is hampered by expression of the MGMT protein and the development of resistances to repeated alkylating chemotherapy [163]. Of central importance for the cure of GBM patients could be the inhibition of tumor infiltration into other brain regions in addition to controlling tumor cell proliferation. Inhibiting MMP as mediators of glioblastoma cell invasion appeared to be a promising treatment modality for GBM in in vitro studies and mouse models [164–166]. In a phase II clinical study, the combination of the MMP inhibitor Marimastat with TMZ increased progression-free patient survival in comparison to TMZ alone [167]. However, further application of Marimastat for GBM treatment evoked severe normal tissue effects in patients and failed to improve patient survival in a phase III clinical trial (Table 1) [30]. Targeting integrins and integrin-associated signaling molecules is a promising strategy for inhibiting invasion of GBM cells and angiogenesis in combination with radio- and chemotherapy [168]. Cilengitide (CGT), an arginine–glycine–aspartic acid (RGD) containing peptide that antagonizes the function of integrins containing αv subunits found in αvβ3 and αvβ5 integrin receptors, is a potent therapeutic agent currently trialed for GBM therapy [169]. In in vitro experiments and orthotopic animal models CGT enhanced the effects of radiotherapy or TMZ on glioblastoma cell survival [170,171]. Results of early phase I/II clinical trials also suggested that CGT may be a beneficial addition to standard radiochemotherapy as it modestly improved overall survival of patients with recurrent GBM with only minimal toxicity [172,173]. Indeed, later phase I/II trials showed an enhanced median overall survival for patients with newly diagnosed GBM after combined treatment with radiotherapy, TMZ and CGT (Table 1) [174,175]. Thereby, prolonged overall survival seemed to correlate with a methylated MGMT promoter [175]. However, Merck KGaA recently stated that patients with newly diagnosed glioblastoma and methylated MGMT gene promoter status did not live significantly longer when treated with CGT plus radiochemotherapy in the follow-up CENTRIC phase III trial (www.merckgroup.com). One reason out of many for this failure could be that mainly αvβ3 and αvβ5, which are predominantly expressed on endothelial cells, were targeted and leaving tumor cell expressed integrins more or less inefficiently blocked. Although discouraging, these news do not exclude a beneficial action of other integrin inhibitors in GBM therapy. For example targeting of β1 integrin in combination with radiochemotherapy was highly effective in inducing efficient tumor cell kill and invasiveness in in vitro studies [23,116]. In addition, the development of novel therapies such as carbon ion radiotherapy and the combination with inhibitors of glioblastoma cell motility might enable an increase in local control, progression-free and overall survival of patients. Recent data indicated that carbon ion radiation effectively reduces treatment resistance of glioblastoma cells in vitro [176,177] and increases progression-free and overall survival of patients [178]. Carbon ion radiotherapy is therefore being further evaluated in phase I/II clinical trials as a new treatment alternative for patients with recurrent [179] and primary GBM [180].

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TMZ [118]. Others reported no effect of X-rays on the collagen-IV dependent transmigration of U87 cells [143]. X-ray irradiation also increased spheroid migration on tissue culture plastic [120] or on vitronectin [107]. Additionally, vitronectin-, collagen-I- and collagenIV-mediated glioblastoma cell transmigration through porous membranes was enhanced after sublethal irradiation [133,142]. In general, stimulation of glioblastoma hypermigration seems to depend on the type of irradiation, as carbon ion irradiation has been demonstrated to decrease migration in vitronectin-, fibronectin- and collagen-IV based transwell assays [142,143,155]. In contrast to 2D assays, very few studies involve more physiological 3D systems to evaluate glioblastoma cell invasion, such as spheroid or single cell invasion assays and xenograft assays in nude mice [23,153,156,157]. As it is becoming clearer that cells behave differently in 2D and 3D environments, the application of 3D-based assays in GBM-directed research is crucial to understanding glioblastoma cell biology and the development of successful therapies [156,158]. In this respect, recent data from our lab shows that X-ray and carbon ion radiation at clinically relevant doses do not affect early glioblastoma cell invasion in collagen-I gels [23]. While both types of irradiation induce DNA double strand breaks and successfully reduce clonogenic survival, only inhibition of signaling axes known to cofunction in cell motility dramatically attenuated invasion. Furthermore, administration of an inhibitory β1 integrin antibody, which inhibits 2D glioblastoma cell migration, did not affect early invasion in 3D collagen-I gels but instead seemed to cause the cells to switch from mesenchymal to ameboid migration [23]. In line with this, depletion of the adapter protein p130 Crk-associated substrate (p130Cas) that is suggested to regulate invasion as part of the integrin signaling machinery induced a mesenchymal to ameboid transition in the U87 glioblastoma cell line [148]. Furthermore, a misbalance of the epithelial cell transforming factor 2 (ECT2) guanine nucleotide exchange factor and RAS protein activator-like 2 (RASAL2) GTPase activating protein triggers ameboid motility in glioblastoma cells by regulating Rac and Cdc42 activity [146]. In addition, increases in RhoA/ROCK signaling after downregulation of the SRY-box 2 (SOX2) transcription factor are associated with a switch to ameboid motility and further invasion in vivo [147]. These findings may be relevant for the treatment of GBM by means of radiation therapy, as X-ray irradiation increases activation of signaling molecules such as RhoA and Rac1 [159] and RhoB downstream of integrins [160]. Earlier studies reported a reduction of rat astrocytoma spheroid invasion into collagen-I gels within 5 days of treatment with higher doses of single or fractionated X-rays [153]. However, in contrast to the rat astrocytoma cells, irradiation of human glioblastoma cell lines or primary human glioblastoma explants alone failed to significantly decrease the invasiveness unless combined with bis-chlorethylnitrosourea (BCNU) or dexamethasone suggesting an anti-survival rather than an anti-invasive effect [161]. Furthermore, although a slight reduction of invasion could be observed, tumor spheroids from two human glioblastoma cell lines retained their ability to invade brain tissue even at higher irradiation doses [162]. Taken together, these studies highlight the importance of understanding the effects of targeted therapies on glioblastoma cell biology as the mechanistic effects of radiochemotherapy on glioblastoma cell invasion and how they translate in vivo is still unclear.

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5

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447 448 449 450 451 452 453 454 455 456 457 458 459 460 Q5 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496

500 501 502 503 504 505 506 507 508

6

509 510

Patients

Treatment

Schedule

MOS

Radiotherapy (RT) plus temozolomide (TMZ) Stupp et al. [6] 286 287

RT RT + TMZ

2 Gy X-ray on 5 days for 6 weeks 2 Gy X-ray on 5 days for 6 weeks +75 mg/m2 TMZ for 6 weeks +150–200 mg/m2 TMZ for 5 days every 28 days (6×) 2 × 1.8 Gy X-ray on 5 days for 3 weeks 2 × 1.8 Gy X-ray on 5 days for 3 weeks + TMZ as in [6]

12.1 months 14.6 months

Guckenberger et al. [4]

41 45

Accelerated RT Accelerated RT + TMZ

Matrix metalloproteinase inhibitor Marimastat (MRM) Groves et al. [167] 44 TMZ + MRM Placebo MRM

αvβ3/αvβ5 integrin inhibitor Cilengitide (CGT) Stupp et al. [175] 52 Nabors et al. [173] 46 48 Carbon ion therapy (CRT) and proton therapy (PT) Mizoe et al. [178] 4 23 5 75 75 152 228

Combs et al. [180] Combs et al. [179]

RT + TMZ + CGT RT + TMZ + CGT

RT + TMZ as in [6] + 500 mg CGT 2× weekly for 35 weeks RT + TMZ as in [6] +500 mg CGT 2× weekly for 4 weeks +2000 mg CGT 2× weekly for 4 weeks

RT + ACNU + CRT

2 Gy X-ray on 5 days for 5 weeks +100 mg/m2 ACNU on days 1, 4, 5 of RT +16.8 GyE on 4 days for 2 weeks +18.4–22.4 GyE on 4 days for 2 weeks +24.8 GyE on 4 days for 2 weeks TMZ as in [6] + 6 × 3 GyE carbon ions TMZ as in [6] + 5 × 2 GyE protons 18 × 2 Gy X-ray 10–16 × 3 GyE carbon ions

CRT + TMZ PT + TMZ Fractionated stereotactic RT CRT

512

Acknowledgements

513

518 519

The research and authors were in part supported by a grant from the Deutsche Forschungsgemeinschaft (CO668/6-1 to N.C.), Bundesministerium für Bildung und Forschung (BMBF Contracts 03ZIK041 to N.C.), and the EFRE Europäische Fonds für regionale Entwicklung, Europa fördert Sachsen (100066308). We would like to thank Katja Storch, Katja Zscheppang and Anett Jandke for critical reading of the manuscript.

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U

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38 weeks 44 weeks

16.1 months 17.4 months 20.8 months

7 months 19 months 26 months Ongoing Ongoing

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511

of integrin-related invasion-specific targets in more physiological 3D or in vivo preclinical studies is a prerequisite for the development of novel therapeutic agents with higher potency.

11.3 months 16 months

45 weeks

O

79 83

R O

Levin et al. [30]

150–200 mg/m2 TMZ on days 1–5 +50 mg/day MRM on days 8–28 (repeat) 20 mg/day Placebo (4 weeks after RT) 20 mg/day MRM (4 weeks after RT)

F

Clinical study

P

t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26 t1:27 t1:28 t1:29 t1:30 t1:31 t1:32 Q2t1:33 t1:34

D

t1:4

Table 1 Summary of GBM clinical studies administering drugs against integrins or proteases as well as particle irradiation. Abbreviations: MOS, mean overall survival; RT, radiotherapy; TMZ, temozolomide; MRM, Marimastat; CGT, Cilengitide; CRT, carbon ion therapy; PT, proton therapy; GyE, Gray equivalent dose.

E

t1:1 t1:2 t1:3

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546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591

A. Vehlow, N. Cordes / Biochimica et Biophysica Acta xxx (2013) xxx–xxx

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Please cite this article as: A. Vehlow, N. Cordes, Invasion as target for therapy of glioblastoma multiforme, Biochim. Biophys. Acta (2013), http:// dx.doi.org/10.1016/j.bbcan.2013.07.001

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