CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model
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CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model. / Wendel, Claudia; Hemping-Bovenkerk, André; Krasnyanska, Julia; Mees, Sören Torge; Kochetkova, Marina; Stoeppeler, Sandra; Haier, Jörg.
in: PLOS ONE, Jahrgang 7, Nr. 1, 2012, S. e30046.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model
AU - Wendel, Claudia
AU - Hemping-Bovenkerk, André
AU - Krasnyanska, Julia
AU - Mees, Sören Torge
AU - Kochetkova, Marina
AU - Stoeppeler, Sandra
AU - Haier, Jörg
PY - 2012
Y1 - 2012
N2 - INTRODUCTION: 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.CONCLUSION: 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.
AB - INTRODUCTION: 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.CONCLUSION: 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.
KW - Animals
KW - Cell Adhesion
KW - Cell Line, Tumor
KW - Cell Membrane
KW - Cell Movement
KW - Chemokine CXCL12
KW - Cluster Analysis
KW - Disease Models, Animal
KW - Enzyme Activation
KW - Extracellular Matrix
KW - Female
KW - Flow Cytometry
KW - Humans
KW - Integrins
KW - Kinetics
KW - Liver Neoplasms
KW - Mammary Neoplasms, Animal
KW - Protein Subunits
KW - Rats
KW - Receptors, CXCR4
KW - Signal Transduction
KW - rho GTP-Binding Proteins
U2 - 10.1371/journal.pone.0030046
DO - 10.1371/journal.pone.0030046
M3 - SCORING: Journal article
C2 - 22253872
VL - 7
SP - e30046
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 1
ER -
