Summary
Invasion of glioma cells involves the attachment of invading tumor cells to extracellular matrix (ECM), disruption of ECM components, and subsequent cell penetration into adjacent brain structures. Discoidin domain receptor 1 (DDR1) tyrosine kinases constitute a novel family of receptors characterized by a unique structure in the ectodomain (discoidin-I domain). These cell surface receptors bind to several collagens and facilitate cell adhesion. Little is known about DDR1 expression and function in glioblastoma multiforme. In this study we demonstrate that DDR1 is overexpressed in glioma tissues using cDNA arrays, immunohistochemistry and Western blot analysis. Functional comparison of two splice variants of DDR1 (DDR1a and DDR1b) reveal novel differences in cell based glioma models. Overexpression of either DDR1a or DDR1b caused increased cell attachment. However, glioma cells overexpressing DDR1a display enhanced invasion and migration. We also detect increased levels of matrix metalloproteinase-2 in DDR1a overexpressing cells as measured by zymography. Inhibition of MMP activity using MMP inhibitor suppressed DDR1a stimulated cell-invasion. Similarly, an antibody against DDR1 reduced DDR1a mediated invasion as well as the enhanced adhesion of DDR1a and DDR1b overexpressing cells. These results suggest that DDR1a plays a critical role in inducing tumor cell adhesion and invasion, and this invasive phenotype is caused by activation of matrix metalloproteinase-2.
Similar content being viewed by others
References
PJ Jukich BJ McCarthy TS Surawicz S Freels FG Davis (2001) ArticleTitleTrends in incidence of primary brain tumors in the United States, 1985–1994 Neuro-Oncology 3 141–151 Occurrence Handle10.1215/15228517-3-3-141 Occurrence Handle1:STN:280:DC%2BD38%2Fit1GhtA%3D%3D Occurrence Handle11465394
JF Reavey-Cantwell RI Haroun M Zahurak RE Clatterbuck RJ Parker R Mehta JP Fruehauf H Brem (2001) ArticleTitleThe prognostic value of tumor markers in patients with glioma multiforme: analysis of 32 patients and review of the literature J Neuro-Oncol 55 195–204 Occurrence Handle10.1023/A:1013845004294 Occurrence Handle1:STN:280:DC%2BD387isFGhsg%3D%3D
AN Shelling R Butler T Jones S Laval JM Boyle TS Ganesan (1995) ArticleTitleLocalization of an epithelial-specific receptor kinase (EDDR1) to chromosome 6q16 Genomics 25 584–587 Occurrence Handle10.1016/0888-7543(95)80065-T Occurrence Handle1:CAS:528:DyaK2MXjvV2hsLg%3D Occurrence Handle7789998
W Vogel GD Gish F Alves T Pawson (1997) ArticleTitleThe discoidin domain receptor tyrosine kinases are activated by collagen Mol Cell 1 13–23 Occurrence Handle10.1016/S1097-2765(00)80003-9 Occurrence Handle1:CAS:528:DyaK1cXlt1KjsA%3D%3D Occurrence Handle9659899
G Hou W Vogel MP Bendeck (2001) ArticleTitleThe discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair J Clin Invest 107 727–735 Occurrence Handle1:CAS:528:DC%2BD3MXitVGns7c%3D Occurrence Handle11254672
CA Curat WF Vogel (2002) ArticleTitleDiscoidin domain receptor 1 controls growth and adhesion of mesangial cells J Am Soc Nephrol 13 2648–2656 Occurrence Handle10.1097/01.ASN.0000032419.13208.0C Occurrence Handle1:CAS:528:DC%2BD38XnvF2lsro%3D Occurrence Handle12397034
J Dejmek K Dib M Jonsson T Andersson (2003) ArticleTitleWnt-5a and G-protein signaling are required for collagen-induced DDR1 receptor activation and normal mammary cell adhesion Int J Cancer 103 344–351 Occurrence Handle10.1002/ijc.10752 Occurrence Handle1:CAS:528:DC%2BD3sXht1yjug%3D%3D Occurrence Handle12471617
CA Curat M Eck X Dervillez WF Vogel (2001) ArticleTitleMapping of epitopes in discoidin domain receptor 1 critical for collagen binding J Biol Chem 276 45952–45958 Occurrence Handle10.1074/jbc.M104360200 Occurrence Handle1:CAS:528:DC%2BD3MXptVymsLw%3D Occurrence Handle11598108
W Vogel (1999) ArticleTitleDiscoidin domain receptors: structural relations and functional implications FASEB J 13 S77–S82 Occurrence Handle1:CAS:528:DyaK1MXjtFGku7g%3D Occurrence Handle10352148
F Alves S Saupe M Ledwon F Schaub W Hiddemann WF Vogel (2001) ArticleTitleIdentification of two novel, kinase-deficient variants of discoidin domain receptor 1: differential expression in human colon cancer cell lines FASEB J 15 1321–1321 Occurrence Handle1:CAS:528:DC%2BD3MXlvVOqsb0%3D Occurrence Handle11344127
F Alves W Vogel K Mossie B Millauer H Hofler A Ullrich (1995) ArticleTitleDistinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer Oncogene 10 609–618 Occurrence Handle1:CAS:528:DyaK2MXjsl2mtbY%3D Occurrence Handle7845687
MP Sanchez P Tapley SS Saini B He D Pulido M Barbacid (1994) ArticleTitleMultiple tyrosine protein kinases in rat hippocampal neurons: isolation of Ptk-3, a receptor expressed in proliferative zones of the developing brain Proc Natl Acad Sci 91 1819–1823 Occurrence Handle1:CAS:528:DyaK2cXis1aksbk%3D Occurrence Handle8127887
JD Johnson JC Edman WJ Rutter (1993) ArticleTitleA receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain Proc Nat Acad Sci 90 5677–5681 Occurrence Handle1:CAS:528:DyaK3sXltlChtbc%3D Occurrence Handle8390675
S Laval R Butler AN Shelling AM Hanby R Poulsom TS Ganesan (1994) ArticleTitleIsolation and characterization of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line Cell Growth Differ 11 1173–1183
WF Vogel A Aszodi F Alves T Pawson (2001) ArticleTitleDiscoidin domain receptor 1 tyrosine kinase has an essential role in mammary gland development Mol Cell Biol 21 2906–2917 Occurrence Handle10.1128/MCB.21.8.2906-2917.2001 Occurrence Handle1:CAS:528:DC%2BD3MXisVyhtrk%3D Occurrence Handle11283268
HL Weiner H Huang D Zagzag H Boyce R Lichtenbaum EB Zif (2000) ArticleTitleConsistent and selective expression of the discoidin domain receptor-1 tyrosine kinase in human brain tumors Neurosurgery 47 1400–1409 Occurrence Handle1:STN:280:DC%2BD3M7gtl2nug%3D%3D Occurrence Handle11126911
W Vogel F Grunebach CA Messam L Kanz W Brigger HJ Buhring (2003) ArticleTitleHeterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitor cells Haemotologica/J Hematol 88 126–133
S Muller P Kunkel K Lamszus U Ulbricht G Lorente AM Nelson D Schack Particlevon DJ Chin SC Lohr M Westphal T Melcher (2003) ArticleTitleA role for receptor tyrosine phosphatase zeta in glioma cell migration Oncogene 22 6661–6668 Occurrence Handle14555979
CE Brinckerhoff LM Matrisian (2002) ArticleTitleMatrix metalloproteinases: a tail of a frog that became a prince Nat Rev Mol Cell Biol 3 207–214 Occurrence Handle10.1038/nrm763 Occurrence Handle1:CAS:528:DC%2BD38XitFShsLs%3D Occurrence Handle11994741
JH Uhm NP Dooley JG Villemure VW Yong (1996) ArticleTitleGlioma invasion in vitro: regulation by matrix metalloprotease-2 and protein kinase C Clin Exp Metastasis 14 421–433 Occurrence Handle10.1007/BF00128958 Occurrence Handle1:CAS:528:DyaK28XntVGjsLs%3D Occurrence Handle8871536
H Kamohara S Yamashiro C Galligan T Yoshimura (2001) ArticleTitleDiscoidin domain receptor 1 isoform-a (DDR1a) promotes migration of leukocytes in three-dimensional collagen lattices FASEB J 15 2724–2726 Occurrence Handle1:CAS:528:DC%2BD3MXptFags7g%3D Occurrence Handle11606478
E Olaso K Ikeda FJ Eng L Xu LH Wang H Lin S Friedman (2001) ArticleTitleDDR2 receptor promotes MMP-2 mediated proliferation and invasion by hepatic stellate cells J Clin Invest 108 1369–1378 Occurrence Handle10.1172/JCI200112373 Occurrence Handle1:CAS:528:DC%2BD3MXot12ktb8%3D Occurrence Handle11696582
E Olaso P Labrador L Wang K Ikeda FJ Eng R Klein DH Lovett HC Lin SL Friedman (2002) ArticleTitleDDR2 receptor regulates fibroblast proliferation and migration through extracellular matrix by transcriptional activation of MMP-2 J Biol Chem 277 3606–3613 Occurrence Handle10.1074/jbc.M107571200 Occurrence Handle1:CAS:528:DC%2BD38XhtVaktLc%3D Occurrence Handle11723120
M Jonsson T Andersson (2001) ArticleTitleRepression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells J Cell Sci 114 2043–2053 Occurrence Handle1:CAS:528:DC%2BD3MXkslWktLY%3D Occurrence Handle11493640
W Vogel C Brakebusch R Fassler F Alves F Ruggerio T Pawson (2000) ArticleTitleDiscoidin domain receptor 1 is activated independently of ß1 integrin J Biol Chem 275 5779–5784 Occurrence Handle1:CAS:528:DC%2BD3cXhsFKktb0%3D Occurrence Handle10681566
RS Bhatt T Tomada Y Fang ME Hatten (2000) ArticleTitleDiscoidin domain receptor 1 functions in axon extension of cerebellar granule neurons Genes Dev 14 2216–2228 Occurrence Handle10.1101/gad.821600 Occurrence Handle1:CAS:528:DC%2BD3cXmtlensr0%3D Occurrence Handle10970885
WG Stetler-Stevenson S Aznavoorian LA Liotta (1993) ArticleTitleTumor cell interactions with the extracellular matrix during invasion and metastasis Annu Rev Cell Biol 9 541–573 Occurrence Handle10.1146/annurev.cb.09.110193.002545 Occurrence Handle1:CAS:528:DyaK2cXltFamsw%3D%3D Occurrence Handle8280471
H Nomura H Sato M Seiki M Mai Y Okada (1995) ArticleTitleExpression of membrane-type matrix metalloproteinase in human gastric carcinomas Cancer Res 55 3263–3266 Occurrence Handle1:CAS:528:DyaK2MXnt1ansLw%3D Occurrence Handle7614460
SK Chintala JC Tonn JS Rao (1999) ArticleTitleMatrix metalloproteinases and their biological function in human gliomas Int J Dev Neurosci 17 495–502 Occurrence Handle1:CAS:528:DC%2BD3cXhtlyqug%3D%3D Occurrence Handle10571411
T Nakagawa T Kubota M Kabuto N Fujimoto Y Okada (1996) ArticleTitleSecretion of matrix metalloproteinase-2 (72 kD gelatinase/type IV collagenase = gelatinase A) by malignant glioma cell lines: implications for the growth and cellular invasion of the extracellular matrix J Neuro-Oncol 28 13–24 Occurrence Handle10.1007/BF00300442 Occurrence Handle1:STN:280:BymA3crmvV0%3D
M Yamamoto S Mohanam R Sawaya GN Fuller M Seiki H Sato ZL Gokaslan LA Liotta GL Nicolson JS Rao (1996) ArticleTitleDifferential expression of membrane-type matrix metalloproteinase and its correlation with gelatinase A activation in human malignant brain tumors in vivo and in vitro Cancer Res 56 384–392 Occurrence Handle1:CAS:528:DyaK28XmtVGmuw%3D%3D Occurrence Handle8542596
D Koul R Parthasarathy R Shen MA Davies SA Jasser SK Chintala JS Rao Y Sun EN Benvenisite TJ Liu (2001) ArticleTitleSuppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN Oncogene 20 6669–6678 Occurrence Handle10.1038/sj.onc.1204799 Occurrence Handle1:CAS:528:DC%2BD3MXotFahsbk%3D Occurrence Handle11709701
A Price Q Shi D Morris ME Wilcox PM Brasher NB Rewcastle D Shalinsky H Zou K Appelt RN Johnston (1999) ArticleTitleMarked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340 Clin Cancer Res 5 845–854 Occurrence Handle1:CAS:528:DyaK1MXislOnsb4%3D Occurrence Handle10213221
CL Gladson (1999) ArticleTitleThe extracellular matrix of gliomas: modulation of cell function J Neuropathol Exp Neurol 58 1029–1040 Occurrence Handle1:CAS:528:DyaK1MXmsl2gurc%3D Occurrence Handle10515226
A Giese M Wertphal (1996) ArticleTitleGlioma invasion in the central nervous system Neurosurgery 39 235–252 Occurrence Handle10.1097/00006123-199608000-00001 Occurrence Handle1:STN:280:BymH38blsF0%3D Occurrence Handle8832660
PP Ongusaha JI Kim L Fang TW Wong GD Yancopoulos SA Aaronson SW Lee (2003) ArticleTitlep53 induction and activation of DDR1 kinase counteract p53-mediated apoptosis and influence p53 regulation through a positive feedback loop EMBO J 22 1289–1301 Occurrence Handle10.1093/emboj/cdg129 Occurrence Handle1:CAS:528:DC%2BD3sXit1yrsb4%3D Occurrence Handle12628922
CG L’hote PH Thomas TS Ganesan (2002) ArticleTitleFunctional analysis of discoidin domain receptor 1: effect of adhesion on DDR1 phosphorylation FASEB J 16 234–236 Occurrence Handle1:CAS:528:DC%2BD38XhsVequ7g%3D Occurrence Handle11772944
ED Foehr A Tatavos E Tanabe S Raffioni S Goetz E Dimarco M DeLuca RA Bradshaw (2000) ArticleTitleDiscoidin domain receptor 1 (DDR1) signaling in PC12 cells: Activation of juxtamembrane domains in PDGFR/DDR1/TrkA chimeric receptors FASEB J 7 973–981
W Matsuyama H Kamohara C Galligan M Faure T Yoshimura (2003) ArticleTitleInteraction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages FASEB J 17 1286–1288 Occurrence Handle1:CAS:528:DC%2BD3sXltFersL0%3D Occurrence Handle12738814
P Kleihues WK Cavenee (2000) Pathology and Genetics of Tumor of the Nervous System EditionNumber2 IARC Press Lyon France 9–54
Kleihues P, Burger PC and Scheithauer BW: Histological Typing of Tumours of the Central Nervous System. In: Sobin LH (ed) Berlin, Springer-Verlag, 1993, pp. 11–20.
Q Yu I Stamenkovic (2000) ArticleTitleCell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis Genes Dev. 14 163–176 Occurrence Handle10652271
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ram, R., Lorente, G., Nikolich, K. et al. Discoidin Domain Receptor-1a (DDR1a) Promotes Glioma Cell Invasion and Adhesion in Association with Matrix Metalloproteinase-2. J Neurooncol 76, 239–248 (2006). https://doi.org/10.1007/s11060-005-6874-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-005-6874-1