Endothelial cell-derived nidogen-1 inhibits migration of SK-BR-3 breast cancer cells

BMC Cancer

Nicola Aceto¹  Cinzia Donato¹  Martin Buess²  Maren Diepenbruck³  Gerhard Christofori³  Daniela A. Ferraro³  Sara Zanivan⁴  Francesca Patella⁴  Monica Giannotta⁵  Elisabetta Dejana⁵ 

[1] Cancer Metastasis, Department of Biomedicine, University of Basel;Department of Oncology, St. Claraspital;Tumor Biology, Department of Biomedicine, University of Basel;Tumour Microenvironment and Proteomics, Cancer Research UK Beatson Institute;Vascular Biology Unit, FIRC Institute of Molecular Oncology;

关键词: Tumor stroma;    Endothelial cells;    Breast cancer;   

DOI  :  10.1186/s12885-019-5521-8

来源: DOAJ

【 摘 要 】

Abstract Background The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood. Methods We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro. Results Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression. Conclusion The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.

【 授权许可】

Unknown