[en] Astrocytic tumours are associated with dismal prognoses due to their pronounced ability to diffusely invade the brain parenchyma. Various neuropeptides, including gastrin, are able to modulate tumour astrocyte migration. While neurotensin has been shown to influence the proliferation of glioma cells and the migratory ability of a large set of other cell types, its role in glioma cell migration has never been investigated. Neurotensin-induced modifications to the motility features of human U373 glioblastoma cells therefore constitute the topic of the present study. We evidenced that three subtypes of neurotensin receptors (NTR1, NTR2 and NTR3) are expressed in U373 glioblastoma cells, at least as far as their mRNAs are concerned. Treating U373 tumour cells with 10 nM neurotensin markedly modified the morphological patterns of these cells and also profoundly altered the organization of their actin cytoskeletons. Pull-down assays revealed that neurotensin induced the activation in U373 cells of both Rac1 and Cdc42 but not RhoA. Scratch wound assays evidenced that neurotensin (0.1 and 10 nM) very significantly inhibited wound colonization by U373 cells cultured in the absence of serum. In addition, quantitative phase-contrast videomicroscopy analyses showed that neurotensin decreases the motility levels of U373 glioblastoma cells when these cells are cultured on plastic. In sharp contrast, neurotensin stimulates the motility of U373 cells when they are cultured on laminin, which is a pro-adhesive extracellular matrix component ubiquitously secreted by glioma cells. Our data thus strongly suggest that, in addition to gastrin, neurotensin is a neuropeptide capable of modulating tumour astrocyte migration into the brain parenchyma.
Disciplines :
Neurosciences & behavior Neurology
Author, co-author :
Servotte, S.; Université de Liège - ULiège > Département des Sciences Biomédicales et Précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Camby, I.; Université Libre de Bruxelles - ULB > Institut de Pharmacie > Laboratoire de Toxicologie
Debeir, O.; Université Libre de Bruxelles - ULB > Department of Logical and Numerical Systems > Faculty of Applied Science
Deroanne, Christophe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Lambert, C.; Université de Liège - ULiège > Département des Sciences biomédicales et précliniques > Laboratoire de Biologie des Tissus Conjonctifs
Lapiere, C. M.; Université de Liège - ULiège
Kiss, R.; Université Libre de Bruxelles - ULB > Institut de Pharmacie > Laboratoire de Toxicologie
Nusgens, Betty ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Decaestecker, C.; Université Libre de Bruxelles - ULB > Institut de Pharmacie > Laboratoire de Toxicologie
Language :
English
Title :
The in vitro influences of neurotensin on the motility characteristics of human U373 glioblastoma cells
Kleihues P, Cavenee WK (eds). Pathology and Genetics of Tumours of the Nervous System. World Health Organization Classification of Tumours. Lyon: IARC Press, 2000; 10-39
Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 2005; 23: 2411-22
Rozengurt E. Neuropeptides as growth factors for normal and cancerous cells. Trends Endocrinol Metab 2002; 13: 128-33
Camby I, Salmon I, Danguy A, Pasteels JL, Brotchi J, Martinez J, Kiss R. Influence of gastrin on human astrocytic tumor cell proliferation. J Natl Cancer Inst 1996; 88: 594-600
Lefranc F, Sadeghi N, Metens T, Brotchi J, Salmon I, Kiss R. Characterization of gastrin-induced cytostatic effect on cell proliferation in experimental malignant gliomas. Neurosurgery 2003; 52: 881-91
De Hauwer C, Camby I, Darro F, Migeotte I, Decaestecker C, Verbeek C, Danguy A, Pasteels JL, Brotchi J, Salmon I, Van Ham P, Kiss R. Gastrin inhibits motility, decreases cell death levels and increases proliferation in human glioblastoma cell lines. J Neurobiol 1998; 37: 373-82
Kucharczak J, Pannequin J, Camby I, Decaestecker C, Kiss R, Martinez J. Gastrin induces over-expression of genes involved in human U373 glioblastoma cell migration. Oncogene 2001; 20: 7021-8
Lefranc F, Camby I, Belot N, Bruyneel E, Chaboteaux C, Brotchi J, Mareel M, Salmon I, Kiss R. Gastrin significantly modifies the migratory abilities of experimental glioma cells. Lab Invest 2002; 82: 1241-52
Reubi JC, Waser B, Schaer JC, Laissue JA. Neurotensin receptors in human neoplasms: high incidence in Ewing sarcomas. Int J Cancer 1999; 82: 213-18
Camby I, Salmon I, Bourdel E, Nagy N, Danguy A, Brotchi J, Pasteels JL, Martinez J, Kiss R. Neurotensin-mediated effects on astrocytic tumor cell proliferation. Neuropeptides 1996; 30: 133-9
Giese A, Rief MD, Loo MA, Berens ME. Determinants of human astrocytoma migration. Cancer Res 1994; 54: 3897-904
Gladson CL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol 1999; 58: 1029-40
Paulus W, Baur I, Huettner C, Schmausser B, Roggendorf W, Schlingensiepen KH, Brysch W. Effects of transforming growth factor-β1 on collagen synthesis, integrin expression, adhesion and invasion of glioma cells. J Neuropathol Exp Neurol 1995; 54: 236-44
Chintala SK, Rao JS. Invasion of human glioma: role of extracellular matrix proteins. Front Biosci 1996; 1: 324-39
Haugland HK, Tysnes BB, Tysnes OB. Adhesion and migration of human glioma cells are differently dependent on extracellular matrix molecules. Anticancer Res 1997; 17: 1035-42
Raftopoulou M, Hall A. Cell migration: rho GTPases lead the way. Dev Biol 2004; 265: 23-32
Rozengurt E. Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists. J Cell Physiol 1998; 177: 507-17
Rozengurt E, Walsh JH. Gastrin, CCK, signaling, and cancer. Annu Rev Physiol 2001; 63: 49-76
Hall A. Rho GTPases and the actin cytoskeleton. Science 1998; 279: 509-14
Nobes CD, Hall A. Rho, Rac and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 1995; 81: 53-62
Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesion and actin stress fibers in response to growth factors. Cell 1992; 70: 389-99
Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 1992; 70: 401-10
Belot N, Rorive S, Doyen I, Lefranc F, Bruyneel E, DeDecker R, Micik S, Brotchi J, Decaestecker C, Salmon I, Kiss R, Camby C. The molecular characterization of cell-substratum attachments in human glial tumors relates to prognostic features. Glia 2001; 36: 375-90
Branle F, Lefranc F, Camby I, Jeuken J, Geurts-Moespot A, Sprenger S, Sweep F, Kiss R, Salmon I. Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy. Cancer 2002; 95: 641-55
Rorive S, Belot N, Decaestecker C, Lefranc F, Gordower L, Micik S, Maurage CA, Kaltner H, Ruchoux MM, Danguy A, Gabius HJ, Salmon I, Kiss R, Camby I. Galectin-1 is highly expressed in human gliomas with relevance for modulation of invasion of tumor astrocytes into the brain parenchyma. Glia 2001; 33: 241-55
Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev 2003; 24: 389-427
Thomas RP, Hellmich MR, Townsend CM, Evers BM. Role of gastrointestinal hormones in the proliferation of normal and neoplastic tissues. Endocr Rev 2003; 24: 571-99
Vincent JP, Mazella J, Kitabgi P. Neurotensin and neurotensin receptors. Trends Pharmacol Sci 1999; 20: 302-9
Sarret P, Perron A, Stroh T, Beaudet A. Immunohistochemical distribution of NTS2 neurotensin receptors in the rat central nervous system. J Comp Neurol 2003; 461: 520-38
Sarret P, Krzywkowski P, Segal L, Nielsen MS, Petersen CM, Mazella J, Stroh T, Beaudet A. Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J Comp Neurol 2003; 461: 483-505
Alexander MJ, Leeman SE. Widespread expression in adult rat forebrain of mRNA encoding high-affinity neurotensin receptor. J Comp Neurol 1998; 402: 475-500
Ren XD, Kiosses WB, Schwartz MA. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J 1999; 18: 578-85
Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG. Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 1999; 147: 1009-22
Debeir O, Van Ham P, Kiss R, Decaestecker C. Tracking of migrating cells under phase-contrast video microscopy with combined mean-shift processes. IEEE Trans Med Imaging 2005; 24: 697-711
Senger DL, Tudan C, Guiot MC, Mazzoni IE, Molenkamp G, LeBlanc R, Antel J, Olivier A, Snipes GJ, Kaplan DR. Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. Cancer Res 2002; 62: 2131-40
Pettibone DJ, Hess JF, Hey PJ, Jacobson MA, Leviten M, Lis EV, Mallorga PJ, Pascarella DM, Snyder MA, Williams JB, Zeng Z. The effects of deleting the mouse neurotensin receptor NTR1 on central and peripheral responses to neurotensin. J Pharmacol Exp Ther 2002; 300: 305-13
Goldman R, Bar-Shavit Z, Romeo D. Neurotensin modulates human neutrophil locomotion and phagocytic capability. FEBS Lett 1983; 159: 63-7
Garrido JJ, Arahuetes RM, Hernanz A, De la Fuente M. Modulation by neurotensin and neuromedin N of adherence and chemotaxis capacity of murine lymphocytes. Regul Pept 1992; 41: 27-37
De la Fuente M, Garrido JJ, Arahuetes RM, Hernanz A. Stimulation of phagocytic function in mouse macrophages by neurotensin and neuromedin N. J Neuroimmunol 1993; 42: 97-104
Martin S, Vincent JP, Mazella J. Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of human microglia. J Neuroscience 2003; 23: 1198-205
Brun P, Mastrotto C, Beggiao E, Stefani A, Barzon L, Sturniolo GC, Palu G, Castagliuolo I. Neuropeptide neurotensin stimulates wound healing following chronic intestinal inflammation. Am J Physiol Gastrointest Liver Physiol 2005; 288: G621-9
Ushiro S, Mizoguchi K, Yoshida S, Jimi S, Fujiwara T, Yoshida M, Wei ET, Kitabgi P, Amagaya S, Ono M, Kuwano M. Stimulation of cell-surface urokinase-type plasminogen activator activity and cell migration in vascular endothelial cells by a novel hexapeptide analogue of neurotensin. FEBS Lett 1997; 418: 341-5
Magazin M, Poszepczynska-Guigne E, Bagot M, Boumsell L, Pruvost C, Chalon P, Culouscou JM, Ferrara P, Bensussan A. Sezary syndrome cells unlike normal circulating T lymphocytes fail to migrate following engagement of NTR1 receptor. J Invest Dermatol 2004; 122: 111-18
Kimura T, Honda T, Higashi T, Konishi J. High concentration of cholecystokinin octapeptide suppress protein kinase C activity in guinea pig pancreatic acini. Peptides 1996; 17: 917-25
Martin S, Navarro V, Vincent JP, Mazella J. Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT-29 cell line. Gastroenterology 2002; 123: 1135-43
Ding Q, Stewart J Jr, Olman MA, Klobe MR, Gladson CL. The pattern of enhancement of Src kinase activity on platelet-derived growth factor stimulation of glioblastoma cells is affected by the integrin-engaged. J Biol Chem 2003; 278: 39882-91
Yoshikawa M, Matsumoto K, Iida M, Akasawa A, Moriyama H, Saito H. Effect of extracellular matrix proteins on platelet-activating factor-induced eosinophil chemotaxis. Int Arch Allergy Immunol 2002; 128 (Suppl. 1): 3-11
Zhao D, Kuhnt-Moore S, Zeng H, Wu JS, Moyer MP, Pothoulakis C. Neurotensin stimulates IL-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF-kappa B pathways. Am J Physiol Cell Physiol 2003; 284: C1397-404
