Abstract
The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.


Similar content being viewed by others
References
Penas-Prado M, Gilbert MR (2007) Molecularly targeted therapies for malignant gliomas: advances and challenges. Expert Rev Anticancer Ther 7:641–661
Bello L, Giussani C, Carrabba G, Pluderi M, Costa F, Bikfalvi A (2004) Angiogenesis and invasion in gliomas. Cancer Treat Res 117:263–284
Onishi M, Kurozumi K, Ichikawa T, Date I (2013) Mechanisms of tumor development and anti-angiogenic therapy in glioblastoma multiforme. Neurol Med Chir (Tokyo) 53:755–763
Kurozumi K, Onishi M, Ichikawa T et al (2013) III. Molecular targeting therapy for glioma-bevacizumab and cilengitide. Gan To Kagaku Ryoho 40:718–722
Varner JA, Cheresh DA (1996) Integrins and cancer. Curr Opin Cell Biol 8:724–730
Varner JA, Cheresh DA (1996) Tumor angiogenesis and the role of vascular cell integrin alphavbeta3. Important Adv Oncol 69–87
Wong ML, Prawira A, Kaye AH, Hovens CM (2009) Tumour angiogenesis: its mechanism and therapeutic implications in malignant gliomas. J Clin Neurosci 16:1119–1130
Onishi M, Ichikawa T, Kurozumi K, Date I (2011) Angiogenesis and invasion in glioma. Brain Tumor Pathol 28:13–24
Onishi M, Ichikawa T, Kurozumi K et al (2015) Annexin A2 regulates angiogenesis and invasion phenotypes of malignant glioma. Brain Tumor Pathol 32:184–194
Rooprai HK, McCormick D (1997) Proteases and their inhibitors in human brain tumours: a review. Anticancer Res 17:4151–4162
Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6:622–634
Nakada M, Nakada S, Demuth T, Tran N, Hoelzinger D, Berens M (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64:458–478
Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4:118–132
Huang Z-Y, Wu Y, Hedrick N, Gutmann DH (2003) T-cadherin-mediated cell growth regulation involves G2 phase arrest and requires p21CIP1/WAF1 expression. Mol Cell Biol 23:566–578
Osborn L, Hession C, Tizard R et al (1989) Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59:1203–1211
Couldwell WT, de Tribolet N, Antel JP, Gauthier T, Kuppner MC (1992) Adhesion molecules and malignant gliomas: implications for tumorigenesis. J Neurosurg 76:782–791
Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte function associated LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev Immunol 5:223–252
Stoolman LM (1989) Adhesion molecules controlling lymphocyte migration. Cell 56:907–910
Sasaki H, Yoshida K, Ikeda E et al (1998) Expression of the neural cell adhesion molecule in astrocytic tumors. Cancer 82:1921–1931
Owens GC, Orr EA, DeMasters BKK, Muschel RJ, Berens ME, Kruse CA (1998) Overexpression of a transmembrane isoform of neural cell adhesion molecule alters the invasiveness of rat CNS-1 glioma. Cancer Res 58:2020–2028
Prag S, Lepekhin EA, Kolkova K et al (2002) NCAM regulates cell motility. J Cell Sci 115:283–292
Edvardsen K, Chen W, Rucklidge G, Walsh FS, Obrink B, Bock E (1993) Transmembrane neural cell-adhesion molecule (NCAM), but not glycosyl-phosphatidylinositol-anchored NCAM, down-regulates secretion of matrix metalloproteinases. Proc Natl Acad Sci 90:11463–11467
Woodfin A, Voisin M-B, Nourshargh S (2007) PECAM-1: a multi-functional molecule in inflammation and vascular biology. Arterioscler Thromb Vasc Biol 27:2514–2523
Takada Y, Ye X, Simon S (2007) The integrins. Genome Biol 8:215
Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2:91–100
Bello L, Francolini M, Marthyn P et al (2001) Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 49:380–389 (discussion 390)
Schnell O, Krebs B, Wagner E et al (2008) Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol 18:378–386
Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571
Kim S, Bell K, Mousa SA, Varner JA (2000) Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain of fibronectin. Am J Pathol 156:1345–1362
Kurozumi K, Ichikawa T, Onishi M, Fujii K, Date I (2012) Cilengitide treatment for malignant glioma: current status and future direction. Neurol Med Chir (Tokyo) 52:539–547
Novak U, Kaye AH (2000) Extracellular matrix and the brain: components and function. J Clin Neurosci 7:280–290
Timpl R, Brown JC (1994) The laminins. Matrix biology 14:275–281
Pankov R, Yamada KM (2002) Fibronectin at a glance. J Cell Sci 115:3861–3863
Uhm JH, Gladson CL, Rao JS (1999) The role of integrins in the malignant phenotype of gliomas. Front Biosci 4:188–199
Sweeney SM, Orgel JP, Fertala A et al (2008) Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J Biol Chem 283:21187–21197
Canty EG, Kadler KE (2005) Procollagen trafficking, processing and fibrillogenesis. J Cell Sci 118:1341–1353
Leitinger B (2011) Transmembrane collagen receptors. Annu Rev Cell Dev Biol 27:265–290
Khoshnoodi J, Pedchenko V, Hudson BG (2008) Mammalian collagen IV. Microsc Res Tech 71:357–370
Ogawa K, Oguchi M, Nakashima Y, Yamabe H (1989) Distribution of collagen type IV in brain tumors: an immunohistochemical study. J Neurooncol 7:357–366
Senner V, Ratzinger S, Mertsch S, Grässel S, Paulus W (2008) Collagen XVI expression is upregulated in glioblastomas and promotes tumor cell adhesion. FEBS Lett 582:3293–3300
Bauer R, Ratzinger S, Wales L et al (2011) Inhibition of collagen XVI expression reduces glioma cell invasiveness. Cell Physiol Biochem 27:217–226
Rutka JT, Apodaca G, Stern R, Rosenblum M (1988) The extracellular matrix of the central and peripheral nervous systems: structure and function. J Neurosurg 69:155–170
Giese A, Rief MD, Loo MA, Berens ME (1994) Determinants of human astrocytoma migration. Cancer Res 54:3897–3904
Deryugina EI, Bourdon MA (1996) Tenascin mediates human glioma cell migration and modulates cell migration on fibronectin. J Cell Sci 109:643–652
Zagzag D, Friedlander DR, Dosik J et al (1996) Tenascin-C expression by angiogenic vessels in human astrocytomas and by human brain endothelial cells in vitro. Cancer Res 56:182–189
Zagzag D, Shiff B, Jallo GI et al (2002) Tenascin-C promotes microvascular cell migration and phosphorylation of focal adhesion kinase. Cancer Res 62:2660–2668
Mahesparan R, Read T-A, Lund-Johansen M, Skaftnesmo K, Bjerkvig R, Engebraaten O (2003) Expression of extracellular matrix components in a highly infiltrative in vivo glioma model. Acta Neuropathol 105:49–57
Gatson NN, Chiocca EA, Kaur B (2012) Anti-angiogenic gene therapy in the treatment of malignant gliomas. Neurosci Lett 527:62–70
Nishimori H, Shiratsuchi T, Urano T et al (1997) A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1 repeats inhibits experimental angiogenesis. Oncogene 15:2145–2150
Nakada M, Nakamura H, Ikeda E et al (1999) Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol 154:417–428
Duda D, Sunamura M, Lozonschi L et al (2002) Overexpression of the p53-inducible brain-specific angiogenesis inhibitor 1 suppresses efficiently tumour angiogenesis. Br J Cancer 86:490–496
Kudo S, Konda R, Obara W et al (2007) Inhibition of tumor growth through suppression of angiogenesis by brain-specific angiogenesis inhibitor 1 gene transfer in murine renal cell carcinoma. Oncol Rep 18:785–791
Kaur B, Brat DJ, Devi NS, Van Meir EG (2005) Vasculostatin, a proteolytic fragment of brain angiogenesis inhibitor 1, is an antiangiogenic and antitumorigenic factor. Oncogene 24:3632–3642
Kaur B, Cork SM, Sandberg EM et al (2009) Vasculostatin inhibits intracranial glioma growth and negatively regulates in vivo angiogenesis through a CD36-dependent mechanism. Cancer Res 69:1212–1220
Hardcastle J, Kurozumi K, Dmitrieva N et al (2010) Enhanced antitumor efficacy of vasculostatin (Vstat120) expressing oncolytic HSV-1. Mol Ther 18:285–294
Yoo JY, Haseley A, Bratasz A et al (2012) Antitumor efficacy of 34.5 ENVE: a transcriptionally retargeted and “Vstat120”-expressing oncolytic virus. Mol Ther 20:287–297
Kurozumi K, Hardcastle J, Thakur R et al (2008) Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61. Mol Ther 16:1382–1391
Kurozumi K, Hardcastle J, Thakur R et al (2007) Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy. J Natl Cancer Inst 99:1768–1781
Fujii K, Kurozumi K, Ichikawa T et al (2013) The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus. Cancer Gene Ther 20:437–444
Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803–4810
Li J, Ye L, Owen S, Weeks HP, Zhang Z, Jiang WG (2015) Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review). Int J Mol Med 36:1451–1463
Ishida J, Kurozumi K, Ichikawa T et al (2015) Evaluation of extracellular matrix protein CCN1 as a prognostic factor for glioblastoma. Brain Tumor Pathol 32:245–252
Haseley A, Boone S, Wojton J et al (2012) Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma. Cancer Res 72:1353–1362
Kireeva ML, Lam SC, Lau LF (1998) Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin alphavbeta3. J Biol Chem 273:3090–3096
Iozzo RV, Schaefer L (2015) Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol 42:11–55
Wu YJ, La Pierre DP, Jin W, Albert JY, Burton BY (2005) The interaction of versican with its binding partners. Cell research 15:483–494
Silver DJ, Siebzehnrubl FA, Schildts MJ et al (2013) Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. J Neurosci 33:15603–15617
Hu F, a Dzaye OD, Hahn A et al (2015) Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling. Neuro Oncol 17:200–210
Heckmann D, Kessler H (2007) Design and chemical synthesis of integrin ligands. Methods Enzymol 426:463–503
Meyer A, Auernheimer J, Modlinger A, Kessler H (2006) Targeting RGD recognizing integrins: drug development, biomaterial research, tumor imaging and targeting. Curr Pharm Des 12:2723–2747
Tabatabai G, Weller M, Nabors B et al (2010) Targeting integrins in malignant glioma. Target Oncol 5:175–181
Leavesley DI, Ferguson GD, Wayner EA, Cheresh DA (1992) Requirement of the integrin beta 3 subunit for carcinoma cell spreading or migration on vitronectin and fibrinogen. J Cell Biol 117:1101–1107
MacDonald TJ, Stewart CF, Kocak M et al (2008) Phase I clinical trial of cilengitide in children with refractory brain tumors: pediatric Brain Tumor Consortium Study PBTC-012. J Clin Oncol 26:919–924
MacDonald TJ, Taga T, Shimada H et al (2001) Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 48:151–157
Onishi M, Kurozumi K, Ichikawa T et al (2013) Gene expression profiling of the anti-glioma effect of Cilengitide. Springerplus 2:160
Brooks PC, Montgomery AM, Rosenfeld M et al (1994) Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79:1157–1164
Onishi M, Ichikawa T, Kurozumi K et al (2013) Bimodal anti-glioma mechanisms of cilengitide demonstrated by novel invasive glioma models. Neuropathology 33:162–174
Tate MC, Aghi MK (2009) Biology of angiogenesis and invasion in glioma. Neurotherapeutics 6:447–457
Ishida J, Onishi M, Kurozumi K et al (2014) Integrin inhibitor suppresses bevacizumab-induced glioma invasion. Transl Oncol 7(292–302):e291
Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL (2002) Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res 62:4263–4272
Abdollahi A, Griggs DW, Zieher H et al (2005) Inhibition of alpha(v)beta3 integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res 11:6270–6279
Tentori L, Dorio AS, Muzi A et al (2008) The integrin antagonist cilengitide increases the antitumor activity of temozolomide against malignant melanoma. Oncol Rep 19:1039–1043
Reardon DA, Fink KL, Mikkelsen T et al (2008) Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 26:5610–5617
Mikkelsen T, Brodie C, Finniss S et al (2009) Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency. Int J Cancer 124:2719–2727
Shimazu Y, Kurozumi K, Ichikawa T et al (2015) Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. Gene Ther 22:146–154
Eskens FA, Dumez H, Hoekstra R et al (2003) Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of Cilengitide (EMD 121974), a novel inhibitor of the integrins alphavbeta3 and alphavbeta5 in patients with advanced solid tumours. Eur J Cancer 39:917–926
Stupp R, Van Den Bent M, Erridge S, et al. (2010) Cilengitide in newly diagnosed glioblastoma with MGMT promoter methylation: protocol of a multicenter, randomized, open-label, controlled phase III trial (CENTRIC). ASCO Annual Meeting Proceedings. p TPS152
Nabors LB, Fink KL, Mikkelsen T et al (2015) Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol 17:708–717
Weller M, Nabors L, Gorlia T et al (2016) Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome. Oncotarget. [Epub ahead of print]
Mason WP (2015) End of the road: confounding results of the CORE trial terminate the arduous journey of cilengitide for glioblastoma. Neuro Oncol 17:634–635
D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci 91:4082–4085
Hansen JM, Harris C (2004) A novel hypothesis for thalidomide-induced limb teratogenesis: redox misregulation of the NF-κB pathway. Antioxid Redox Signal 6:1–14
Fine HA, Figg WD, Jaeckle K et al. (2000) Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18:708–715
Giglio P, Dhamne M, Hess KR et al (2012) Phase 2 trial of irinotecan and thalidomide in adults with recurrent anaplastic glioma. Cancer 118:3599–3606
Bigner DD, Brown M, Coleman RE et al (1995) Phase I studies of treatment of malignant gliomas and neoplastic meningitis with131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab′) 2-a preliminary report. J Neurooncol 24:109–122
Reardon DA, Akabani G, Coleman RE et al (2002) Phase II trial of murine 131I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:1389–1397
Reulen H-J, Poepperl G, Goetz C et al (2015) Long-term outcome of patients with WHO Grade III and IV gliomas treated by fractionated intracavitary radioimmunotherapy. J Neurosurg 123:760–770
ClinicalTrials.gov: registry and results database of federally and privately supported clinical trials. http://clinicaltrials.gov/ct2/home. Accessed 24 Feb 2016
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
None of the authors have conflicts of interest to declare.
Rights and permissions
About this article
Cite this article
Shimizu, T., Kurozumi, K., Ishida, J. et al. Adhesion molecules and the extracellular matrix as drug targets for glioma. Brain Tumor Pathol 33, 97–106 (2016). https://doi.org/10.1007/s10014-016-0261-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10014-016-0261-9