title: Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas.
abstract: BACKGROUND
  Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a non-destructive way that suggests cooperation between glioma cells and their environment. Recent studies using an engineered rodent C6 tumor cell line have pointed to mechanisms of invasion that involved gap junctional communication (GJC), with connexin 43 as a substrate. We explored whether this concept may have clinical relevance by analyzing the participation of GJC in human glioblastoma invasion.
  
  
  RESULTS
  Three complementary in vitro assays were used: (i) seeding on collagen IV, to analyze homocellular interactions between tumor cells (ii) co-cultures with astrocytes, to study glioblastoma/astrocytes relationships and (iii) implantation into organotypic brain slice cultures, that mimic the three-dimensional parenchymal environment. Carbenoxolone, a potent blocker of GJC, inhibited cell migration in the two latter models. It paradoxically increased it in the first one. These results showed that homocellular interaction between tumor cells supports intercellular adhesion, whereas heterocellular glioblastoma/astrocytes interactions through functional GJC conversely support tumor cell migration. As demonstrated for the rodent cell line, connexin 43 may be responsible for this heterocellular functional coupling. Its levels of expression, high in astrocytes, correlated positively with invasiveness in biopsied tumors.
  
  
  CONCLUSIONS
  our results underscore the potential clinical relevance of the concept put forward by other authors based on experiments with a rodent cell line, that glioblastoma cells use astrocytes as a substrate for their migration by subverting communication through connexin 43-dependent gap junctions.
authors.affiliation: INSERM/UPVM 421, Plasticité cellulaire et thérapeutique, Faculté de Médecine, 94010 Créteil cedex France. oliveira@im3.inserm.fr
authors.forename: Roxane
authors.initials: R
authors.lastname: Oliveira
authors.forename: Christo
authors.initials: C
authors.lastname: Christov
authors.forename: Jean Sébastien
authors.initials: JS
authors.lastname: Guillamo
authors.forename: Sophie
authors.initials: S
authors.lastname: de Boüard
authors.forename: Stéphane
authors.initials: S
authors.lastname: Palfi
authors.forename: Laurent
authors.initials: L
authors.lastname: Venance
authors.forename: Marcienne
authors.initials: M
authors.lastname: Tardy
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
mesh_terms: D001253:Astrocytes / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D018920:Coculture Techniques; D018031:Connexin 43 / Q000502:physiology; D017629:Gap Junctions / Q000473:pathology*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D018031:Connexin 43
references.citation: J Cell Sci. 2000 May;113 ( Pt 9):1535-42
references.pmid: 10751145
references.citation: Biochem Biophys Res Commun. 1986 Jan 14;134(1):29-36
references.pmid: 3947327
references.citation: J Neurosci Res. 2000 Aug 15;61(4):357-63
references.pmid: 10931521
references.citation: Nat Cell Biol. 1999 Nov;1(7):457-9
references.pmid: 10559992
references.citation: Glia. 2001 Feb;33(2):107-17
references.pmid: 11180508
references.citation: Exp Cell Res. 1987 Feb;168(2):422-30
references.pmid: 2433137
references.citation: Science. 1988 Jul 8;241(4862):170-6
references.pmid: 3291116
references.citation: J Pharmacol Exp Ther. 1988 Sep;246(3):1104-7
references.pmid: 3418512
references.citation: Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1883-7
references.pmid: 1848013
references.citation: Curr Opin Cell Biol. 1990 Oct;2(5):875-80
references.pmid: 1964569
references.citation: Science. 1991 Apr 26;252(5005):563-6
references.pmid: 1850552
references.citation: Cell Tissue Res. 1991 Jul;265(1):73-81
references.pmid: 1655272
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10218-21
references.pmid: 1332037
references.citation: Trends Neurosci. 1993 May;16(5):186-92
references.pmid: 7685944
references.citation: Biotechniques. 1995 Mar;18(3):490-7
references.pmid: 7779401
references.citation: Exp Cell Res. 1996 Jan 10;222(1):48-53
references.pmid: 8549672
references.citation: J Neurosurg. 1996 May;84(5):839-45; discussion 846
references.pmid: 8622159
references.citation: Neurosurgery. 1996 Apr;38(4):755-64
references.pmid: 8692396
references.citation: Neurosurgery. 1996 Aug;39(2):235-50; discussion 250-2
references.pmid: 8832660
references.citation: Neuropathol Appl Neurobiol. 1996 Oct;22(5):421-4
references.pmid: 8930952
references.citation: J Neurosci. 1997 Mar 15;17(6):1981-92
references.pmid: 9045727
references.citation: J Neurosci. 1997 May 1;17(9):3096-111
references.pmid: 9096144
references.citation: Dev Genet. 1997;20(2):119-32
references.pmid: 9144923
references.citation: J Neurosci Res. 1997 Sep 1;49(5):528-40
references.pmid: 9302074
references.citation: Neoplasma. 1998;45(1):25-9
references.pmid: 9604998
references.citation: J Natl Cancer Inst. 1998 Sep 16;90(18):1400-6
references.pmid: 9747871
references.citation: Eur J Neurosci. 1998 Jul;10(7):2444-63
references.pmid: 9749772
references.citation: Cancer Res. 1998 Nov 15;58(22):5089-96
references.pmid: 9823317
references.citation: J Surg Oncol. 1999 Jan;70(1):21-4
references.pmid: 9989416
references.citation: Exp Neurol. 1999 Mar;156(1):16-32
references.pmid: 10192774
references.citation: Mol Biol Cell. 2000 May;11(5):1815-27
references.pmid: 10793154
references.citation: Acta Neuropathol. 2001 May;101(5):449-59
references.pmid: 11484816
references.citation: J Neurooncol. 2001 May;52(3):205-15
references.pmid: 11519850
references.citation: J Neurosci. 2002 Feb 1;22(3):644-53
references.pmid: 11826094
references.citation: J Neurooncol. 2001 Dec;55(3):195-204
references.pmid: 11859975
references.citation: J Neurosci. 2002 Jun 1;22(11):4302-11
references.pmid: 12040035
references.citation: J Neurosurg. 2002 Jul;97(1):169-76
references.pmid: 12134908
references.citation: Glia. 2003 Apr 15;42(2):109-17
references.pmid: 12655595
references.citation: J Clin Oncol. 2003 Apr 15;21(8):1624-36
references.pmid: 12697889
references.citation: J Neurosurg. 2003 Dec;99(6):1039-46
references.pmid: 14705732
references.citation: Eur J Neurosci. 2004 Feb;19(4):1005-15
references.pmid: 15009148
references.citation: Biochim Biophys Acta. 2004 Mar 23;1662(1-2):81-95
references.pmid: 15033580
references.citation: Int J Biochem Cell Biol. 2004 Jul;36(7):1171-86
references.pmid: 15109565
references.citation: Front Biosci. 1998 Feb 15;3:d208-36
references.pmid: 9458335
references.citation: Br J Cancer. 2004 Aug 16;91(4):745-52
references.pmid: 15292940
references.citation: J Biol Chem. 2004 Aug 27;279(35):36943-50
references.pmid: 15213231
references.citation: Nature. 1970 Aug 15;227(5259):680-5
references.pmid: 5432063
references.citation: J Cell Biol. 1980 Jun;85(3):890-902
references.pmid: 6248568
references.citation: Cancer Res. 1999 Apr 15;59(8):1994-2003
references.pmid: 10213512