Top

Published in:

Open Access 01-12-2011 | Research

Targeting α_νβ₃ and α_νβ₅ inhibits photon-induced hypermigration of malignant glioma cells

Authors: Stefan Rieken, Daniel Habermehl, Angela Mohr, Lena Wuerth, Katja Lindel, Klaus Weber, Jürgen Debus, Stephanie E Combs

Published in: Radiation Oncology | Issue 1/2011

Abstract

Background

Sublethal photon irradiation was recently suspected to increase tumor cell motility and promote locoregional recurrence of disease. This study was set up to describe mechanisms underlying increased glioma cell migration through photon irradiation and to analyse the modifiability of photon-altered glioma cell motility by integrin inhibition.

Methods

Eight μm pore size membranes were coated with vitronectin (VN), collagen I and collagen IV. U87 and Ln229 glioma cells were analysed in migration experiments with and without radiotherapy (RT), serum stimulation and addition of monoclonal antibodies directed to human integrins α_νβ₃ and α_νβ₅. Quantitative FACS analysis of integrins was performed in U87 and Ln229 glioma cells following RT. Statistical analysis was performed using Student's t- test.

Results

Glioma cell migration is serum-dependent and can be increased by photon RT which leads to enhanced expression of Vn receptor integrins. Blocking of either α_νβ₃ or α_νβ₅ integrins by antibodies inhibits Vn-based migration of both untreated and photon-irradiated glioma cells.

Conclusions

Peripheral glioma cells are at risk of attraction into the adjacent healthy brain by serum components leaking through the blood brain barrier (BBB). Radiation therapy is associated with upregulation of Vn receptor integrins and enhanced glioma cell migration at sublethal doses. This effect can be inhibited by specific integrin blockade. Future therapeutical benefit may be derived from pharmacological integrin inhibition in combination with photon irradiation.

Available only for authorised users

Stupp R, Roila F: Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009,20(Suppl 4):126-128.PubMed

Beckner ME, Zhang Z, Agostino NR, Day BW, Pollack IF: Albumin marks pseudopodia of astrocytoma cells responding to hepatocyte growth factor or serum. Lab Invest 2006,86(11):1103-1114.PubMed

Hartmann M, Jansen O, Egelhof T, Forsting M, Albert FK, Sartor K: Effect of brain edema on the recurrence pattern of malignant gliomas. Radiologe 1998,38(11):948-953. 10.1007/s001170050447CrossRefPubMed

Manning TJ Jr, Parker JC, Sontheimer H: Role of lysophosphatidic acid and rho in glioma cell motility. Cell Motil Cytoskeleton 2000,45(3):185-199. 10.1002/(SICI)1097-0169(200003)45:3<185::AID-CM2>3.0.CO;2-GCrossRefPubMed

Yang SX, Chen JH, Jiang XF, Wang QL, Chen ZQ, Zhao W, Feng YH, Xin R, Shi JQ, Bian XW: Activation of chemokine receptor CXCR4 in malignant glioma cells promotes the production of vascular endothelial growth factor. Biochem Biophys Res Commun 2005,335(2):523-528. 10.1016/j.bbrc.2005.07.113CrossRefPubMed

Sasaki H, Yoshida K: Inhibition of cellular adhesion and invasion in gliomas. Nippon Rinsho 2005,63(Suppl 9):68-73.PubMed

Ogata T, Teshima T, Kagawa K, Hishikawa Y, Takahashi Y, Kawaguchi A, Suzumoto Y, Nojima K, Furusawa Y, Matsuura N: Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res 2005,65(1):113-120.PubMed

Wild-Bode C, Weller M, Rimner A, Dichgans J, Wick W: Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. Cancer Res 2001,61(6):2744-2750.PubMed

Giannopoulou E, Katsoris P, Hatziapostolou M, Kardamakis D, Kotsaki E, Polytarchou C, Parthymou A, Papaioannou S, Papadimitriou E: X-rays modulate extracellular matrix in vivo. Int J Cancer 2001,94(5):690-698. 10.1002/ijc.1535CrossRefPubMed

10.

Chintala SK, Gokaslan ZL, Go Y, Sawaya R, Nicolson GL, Rao JS: Role of extracellular matrix proteins in regulation of human glioma cell invasion in vitro. Clin Exp Metastasis 1996,14(4):358-366. 10.1007/BF00123395CrossRefPubMed

11.

Senner V, Ratzinger S, Mertsch S, Grassel S, Paulus W: Collagen XVI expression is upregulated in glioblastomas and promotes tumor cell adhesion. FEBS Lett 2008,582(23-24):3293-3300. 10.1016/j.febslet.2008.09.017CrossRefPubMed

12.

Combs SE, Heeger S, Haselmann R, Edler L, Debus J, Schulz-Ertner D: Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)--phase I/II trial: study protocol. BMC Cancer 2006, 6: 133. 10.1186/1471-2407-6-133PubMedCentralCrossRefPubMed

13.

Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, et al.: Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009,27(28):4733-4740. 10.1200/JCO.2008.19.8721CrossRefPubMed

14.

Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, et al.: Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol 28(16):2712-2718.

15.

Tabatabai G, Weller M, Nabors B, Picard M, Reardon D, Mikkelsen T, Ruegg C, Stupp R: Targeting integrins in malignant glioma. Target Oncol 5(3):175-181.

16.

Seitz RJ, Wechsler W: Immunohistochemical demonstration of serum proteins in human cerebral gliomas. Acta Neuropathol 1987,73(2):145-152. 10.1007/BF00693780CrossRefPubMed

17.

Wolff M, Boker DK: Immunohistochemical demonstration of immunoglobulins and albumin in human brain tumors. Clin Neuropathol 1989,8(2):72-78.PubMed

18.

Geer CP, Grossman SA: Interstitial fluid flow along white matter tracts: a potentially important mechanism for the dissemination of primary brain tumors. J Neurooncol 1997,32(3):193-201. 10.1023/A:1005761031077CrossRefPubMed

19.

Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, et al.: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980,303(23):1323-1329. 10.1056/NEJM198012043032303CrossRefPubMed

20.

Goetze K, Scholz M, Taucher-Scholz G, Mueller-Klieser W: The impact of conventional and heavy ion irradiation on tumor cell migration in vitro. Int J Radiat Biol 2007,83(11-12):889-896. 10.1080/09553000701753826CrossRefPubMed

21.

Goldbrunner RH, Bernstein JJ, Tonn JC: ECM-mediated glioma cell invasion. Microsc Res Tech 1998,43(3):250-257. 10.1002/(SICI)1097-0029(19981101)43:3<250::AID-JEMT7>3.0.CO;2-CCrossRefPubMed

22.

Tysnes BB, Mahesparan R: Biological mechanisms of glioma invasion and potential therapeutic targets. J Neurooncol 2001,53(2):129-147. 10.1023/A:1012249216117CrossRefPubMed

23.

Huang S, Vader D, Wang Z, Stemmer-Rachamimov A, Weitz DA, Dai G, Rosen BR, Deisboeck TS: Using magnetic resonance microscopy to study the growth dynamics of a glioma spheroid in collagen I: A case study. BMC Med Imaging 2008, 8: 3. 10.1186/1471-2342-8-3PubMedCentralCrossRefPubMed

24.

McCall-Culbreath KD, Zutter MM: Collagen receptor integrins: rising to the challenge. Curr Drug Targets 2008,9(2):139-149. 10.2174/138945008783502494CrossRefPubMed

25.

Gladson CL, Wilcox JN, Sanders L, Gillespie GY, Cheresh DA: Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors. J Cell Sci 1995,108(Pt 3):947-956.PubMed

26.

Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC, Strasser JF, Villani R, Cheresh DA, Black PM: Alpha(v)beta3 and alpha(v)beta5 integrin expression in glioma periphery. Neurosurgery 2001,49(2):380-389. discussion 390PubMed

27.

Paulus W, Tonn JC: Interactions of glioma cells and extracellular matrix. J Neurooncol 1995,24(1):87-91. 10.1007/BF01052664CrossRefPubMed

28.

Fukushima Y, Tamura M, Nakagawa H, Itoh K: Induction of glioma cell migration by vitronectin in human serum and cerebrospinal fluid. J Neurosurg 2007,107(3):578-585. 10.3171/JNS-07/09/0578CrossRefPubMed

29.

Monferran S, Skuli N, Delmas C, Favre G, Bonnet J, Cohen-Jonathan-Moyal E, Toulas C: Alphavbeta3 and alphavbeta5 integrins control glioma cell response to ionising radiation through ILK and RhoB. Int J Cancer 2008,123(2):357-364. 10.1002/ijc.23498CrossRefPubMed

30.

Albert JM, Cao C, Geng L, Leavitt L, Hallahan DE, Lu B: Integrin alpha v beta 3 antagonist Cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models. Int J Radiat Oncol Biol Phys 2006,65(5):1536-1543. 10.1016/j.ijrobp.2006.04.036CrossRefPubMed

31.

Cordes N, Blaese MA, Meineke V, Van Beuningen D: Ionizing radiation induces up-regulation of functional beta1-integrin in human lung tumour cell lines in vitro. Int J Radiat Biol 2002,78(5):347-357. 10.1080/09553000110117340CrossRefPubMed

32.

Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC: Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. J Cell Biol 2008,183(1):143-155. 10.1083/jcb.200804140PubMedCentralCrossRefPubMed

33.

Roca-Cusachs P, Gauthier NC, Del Rio A, Sheetz MP: Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction. Proc Natl Acad Sci USA 2009,106(38):16245-16250. 10.1073/pnas.0902818106PubMedCentralCrossRefPubMed

34.

White DP, Caswell PT, Norman JC: alpha v beta3 and alpha5beta1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration. J Cell Biol 2007,177(3):515-525. 10.1083/jcb.200609004PubMedCentralCrossRefPubMed

Title: Targeting ανβ3 and ανβ5 inhibits photon-induced hypermigration of malignant glioma cells
Authors: Stefan Rieken
Daniel Habermehl
Angela Mohr
Lena Wuerth
Katja Lindel
Klaus Weber
Jürgen Debus
Stephanie E Combs
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Radiation Oncology / Issue 1/2011
Electronic ISSN: 1748-717X
DOI: https://doi.org/10.1186/1748-717X-6-132

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Targeting α_νβ₃ and α_νβ₅ inhibits photon-induced hypermigration of malignant glioma cells

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2011

Phospho-ERK and AKT status, but not KRAS mutation status, are associated with outcomes in rectal cancer treated with chemoradiotherapy

Comparison of outcomes in patients with stage III versus limited stage IV non-small cell lung cancer

Current measures of metabolic heterogeneity within cervical cancer do not predict disease outcome

Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

Validation of an elastic registration technique to estimate anatomical lung modification in Non-Small-Cell Lung Cancer Tomotherapy

Theoretical analysis of the dose dependence of the oxygen enhancement ratio and its relevance for clinical applications