Abstract
The cadherin switch has profound consequences on cancer invasion and metastasis. The endothelial-specific vascular endothelial cadherin (VE-cadherin) has been demonstrated in diverse cancer types including breast cancer and is supposed to modulate tumor progression and metastasis, but underlying mechanisms need to be better understood. First, we evaluated VE-cadherin expression by tissue microarray in 392 cases of breast cancer tumors and found a diverse expression and distribution of VE-cadherin. Experimental expression of fluorescence-tagged VE-cadherin (VE-EGFP) in undifferentiated, fibroblastoid and E-cadherin-negative MDA-231 (MDA-VE-EGFP) as well as in differentiated E-cadherin-positive MCF-7 human breast cancer cell lines (MCF-VE-EGFP), respectively, displayed differentiation-dependent functional differences. VE-EGFP expression reversed the fibroblastoid MDA-231 cells to an epithelial-like phenotype accompanied by increased β-catenin expression, actin and vimentin remodeling, increased cell spreading and barrier function and a reduced migration ability due to formation of VE-cadherin-mediated cell junctions. The effects were largely absent in both MDA-VE-EGFP and in control MCF-EGFP cell lines. However, MCF-7 cells displayed a VE-cadherin-independent planar cell polarity and directed cell migration that both developed in MDA-231 only after VE-EGFP expression. Furthermore, VE-cadherin expression had no effect on tumor cell proliferation in monocultures while co-culturing with endothelial cells enhanced tumor cell proliferation due to integration of the tumor cells into monolayer where they form VE-cadherin-mediated cell contacts with the endothelium. We propose an interactive VE-cadherin-based crosstalk that might activate proliferation-promoting signals. Together, our study shows a VE-cadherin-mediated cell dynamics and an endothelial-dependent proliferation in a differentiation-dependent manner.
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Acknowledgements
The authors are grateful for highly sufficient assistance by Annelie Ahle, Vesna Bojovic and Christine Schimp. We thank Martin Muermann for MS editing and to the “Biobank” of University Cancer Center Dresden (UCC) for supporting the preparation of tissue microarray. We also thank Anke Klawitter and Thomas Brock for sharing unpublished results. This work was supported by grants from the German Research Council to H.S. (DFG INST 2105/24-1 and SCHN 430/6-2). The Excellence Cluster Cells In Motion (CIM) of the WWU-Münster, flexible fund to H.S (FF-2014-15).
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Rezaei, M., Cao, J., Friedrich, K. et al. The expression of VE-cadherin in breast cancer cells modulates cell dynamics as a function of tumor differentiation and promotes tumor–endothelial cell interactions. Histochem Cell Biol 149, 15–30 (2018). https://doi.org/10.1007/s00418-017-1619-8
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DOI: https://doi.org/10.1007/s00418-017-1619-8