CXCR4/CXCL12 Participate in Extravasation of Metastasizing Breast Cancer Cells within the Liver in a Rat Model

Abstract

IntroductionOrgan-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.MethodsTime 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.ResultsIn 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.

Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

“…Chemokine signalling through CXCL12/CXCR4 is a common mechanism controlling the migration of several cell types along the body axis, such as hematopoietic progenitor cells 40 , vascular endothelial cells 41 , melanocytes 42 and tumour cells 43,44 . In addition to the present results, it has been reported that in the CNS, in addition to CR cells, the migration of cerebellar granule precursors 34 , cortical interneurons 23 , microglia 45 , neural precursor cells 46 , and certain brain tumour cells 33 is also dependent on CXCL12/CXCR4…”

Aqp1 Enhances Migration of Bone Marrow Mesenchymal Stem Cells Through Regulation of FAK and β-Catenin

“…Multiple factors have been identified as regulating MSC migration, such as CCR1, mi335, HIF-1a, and SDF/ CXCR4 [34][35][36][37]. Among these factors, SDF/CXCR4 was an indispensable universal pathway to regulate the migration of many cell types, as has been studied and reported previously in MSCs [38][39][40]. In this study, we demonstrated that Aqp1 could regulate MSC migration independently of the SDF-1/ CXCR4 pathway, indicating that Aqp1 may be a new and previously unknown factor controlling the MSC migration capacity.…”

Inflammatory chemokines and metastasis—tracing the accessory

“…Later, the same chemokine axis was identified in melanoma cells (15). CXCL12 is the sole ligand for CXCR4 that is also expressed in the bone marrow (BM) and liver (16,17). Accordingly, breast cancer cells metastasize to these organs in a CXCR4-dependent manner.…”