title: CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model.
abstract: BACKGROUND
  Organ-specific composition of extracellular matrix proteins (ECM) is a determinant of metastatic host organ involvement. The chemokine CXCL12 and its receptor CXCR4 play important roles in the colonization of human breast cancer cells to their metastatic target organs. In this study, we investigated the effects of chemokine stimulation on adhesion and migration of different human breast cancer cell lines in vivo and in vitro with particular focus on the liver as a major metastatic site in breast cancer.
  
  
  METHODS
  Time lapse microscopy, in vitro adhesion and migration assays were performed under CXCL12 stimulation. Activation of small GTPases showed chemokine receptor signalling dependence from ECM components. The initial events of hepatic colonisation of MDA-MB-231 and MDA-MB-468 cells were investigated by intravital microscopy of the liver in a rat model and under shRNA inhibition of CXCR4.
  
  
  RESULTS
  In vitro, stimulation with CXCL12 induced increased chemotactic cell motility (p<0.05). This effect was dependent on adhesive substrates (type I collagen, fibronectin and laminin) and induced different responses in small GTPases, such as RhoA and Rac-1 activation, and changes in cell morphology. In addition, binding to various ECM components caused redistribution of chemokine receptors at tumour cell surfaces. In vivo, blocking CXCR4 decreased extravasation of highly metastatic MDA-MB-231 cells (p<0.05), but initial cell adhesion within the liver sinusoids was not affected. In contrast, the less metastatic MDA-MB-468 cells showed reduced cell adhesion but similar migration within the hepatic microcirculation.
  
  
  CONCLUSIONS
  Chemokine-induced extravasation of breast cancer cells along specific ECM components appears to be an important regulator but not a rate-limiting factor of their metastatic organ colonization.
authors.affiliation: Department of General and Visceral Surgery, University Hospital Muenster, Muenster, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wendel
authors.forename: André
authors.initials: A
authors.lastname: Hemping-Bovenkerk
authors.forename: Julia
authors.initials: J
authors.lastname: Krasnyanska
authors.forename: Sören Torge
authors.initials: ST
authors.lastname: Mees
authors.forename: Marina
authors.initials: M
authors.lastname: Kochetkova
authors.forename: Sandra
authors.initials: S
authors.lastname: Stoeppeler
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007700:Kinetics; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000473:pathology*; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D016023:Integrins; D021122:Protein Subunits; D019718:Receptors, CXCR4; D020741:rho GTP-Binding Proteins