title: Anti-angiogenesis therapy and gap junction inhibition reduce MDA-MB-231 breast cancer cell invasion and metastasis in vitro and in vivo.
abstract: Cancer cells secrete VEGF, which plays a key role in their growth, invasion, extravasation and metastasis. Direct cancer cell-endothelial cell interaction, mediated by gap junctions, is of critical importance in the extravasation process. In this study, we evaluated avastin (Av), an anti-VEGF antibody; and oleamide (OL), a gap junction inhibitor, using MDA-MB-231 human breast cancer cells in vitro and a xenograft murine model in vivo. Results showed that Av/OL significantly decreased proliferation, induced cell cycle arrest and decreased migration and invasion of MDA-MB-231 cells in vitro. In addition, Av/OL significantly decreased homo and hetero-cellular communication interaction between MDA-MDA and MDA-endothelial cells, respectively. The expression levels of several factors including VEGF, HIF1α, CXCR4, Cx26, Cx43, and MMP9 were attenuated upon Av/OL treatment in vitro. On the other hand, avastin, but not oleamide, reduced tumor size of NSG mice injected subdermally (s.d.) with MDA-MB-231 cells, which was also associated with increased survival. Furthermore, Av but also OL, separately, significantly increased the survival rate, and reduced pulmonary and hepatic metastatic foci, of intravenously (i.v.) injected mice. Finally, OL reduced MMP9 protein expression levels, better than Av and in comparisons to control, in the lungs of MDA-MB-231 i.v. injected NSG mice. In conclusion, while avastin has anti-angiogenic, anti-tumor and anti-metastatic activities, oleamide has anti-metastatic activity, presumably at the extravasation level, providing further evidence for the role of gap junction intercellular communication (GJIC) in cancer cell extravasation.
authors.affiliation: ER045 - Laboratory of Stem Cells, PRASE, Biology Department, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
authors.forename: Kazem
authors.initials: K
authors.lastname: Zibara
authors.affiliation: ER045 - Laboratory of Stem Cells, PRASE, Biology Department, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
authors.forename: Zahraa
authors.initials: Z
authors.lastname: Awada
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Leila
authors.initials: L
authors.lastname: Dib
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Jamal
authors.initials: J
authors.lastname: El-Saghir
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Sara
authors.initials: S
authors.lastname: Al-Ghadban
authors.affiliation: ER045 - Laboratory of Stem Cells, PRASE, Biology Department, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
authors.forename: Aida
authors.initials: A
authors.lastname: Ibrik
authors.affiliation: ER045 - Laboratory of Stem Cells, PRASE, Biology Department, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
authors.forename: Nabil
authors.initials: N
authors.lastname: El-Zein
authors.affiliation: Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Marwan
authors.initials: M
authors.lastname: El-Sabban
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000072259:Connexin 26; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C527276:CXCR4 protein, human; D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; D000072259:Connexin 26; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9