Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium

Abstract

Tumor progression alters the composition and physical properties of the extracellular matrix. Particularly, increased matrix stiffness has profound effects on tumor growth and metastasis. While endothelial cells are key players in cancer progression, the influence of tumor stiffness on the endothelium and the impact on metastasis is unknown. Through quantitative mass spectrometry, we find that the matricellular protein CCN1/CYR61 is highly regulated by stiffness in endothelial cells. We show that stiffness‐induced CCN1 activates β‐catenin nuclear translocation and signaling and that this contributes to upregulate N‐cadherin levels on the surface of the endothelium, in vitro. This facilitates N‐cadherin‐dependent cancer cell–endothelium interaction. Using intravital imaging, we show that knockout of Ccn1 in endothelial cells inhibits melanoma cancer cell binding to the blood vessels, a critical step in cancer cell transit through the vasculature to metastasize. Targeting stiffness‐induced changes in the vasculature, such as CCN1, is therefore a potential yet unappreciated mechanism to impair metastasis.

Immune‐mediated ECM depletion improves tumour perfusion and payload delivery

“…For instance, stiff cancers can induce the expression of adhesion molecules which facilitate tumour cell adherence and transmigration through microvascular endothelia. Reducing these adhesive interactions by ECM degradation can thus be expected to prevent or reduce metastasis (Rath et al, 2017;Reid et al, 2017;Vennin et al, 2017). However, ECM degradation has also been shown to increase the release of tumour cells into the circulation, promoting metastasis (Sevenich & Joyce, 2014;Brown & Murray, 2015;Schmaus & Sleeman, 2015).…”

The CCN1 (CYR61) protein promotes skin growth by enhancing epithelial‐mesenchymal transition during skin expansion

“…40 The key of EMT is the transcriptional factors (EMT-TFs) Snail and Twist, 41,42 which modulate the whole process. [44][45][46] It has been reported that CCN1 expression can be induced by mechanical stretching in both vascular and bladder smooth muscle cells. CCN1 (CYR61) is an immediate-early response gene and a dynamically expressed matricellular protein that interacts with various integrins on cell membranes.…”

Integrated Transcriptomic and Proteomic Analysis of Primary Human Umbilical Vein Endothelial Cells

“…Endothelial dysfunction leads to hypertension, hypercholesterolemia, diabetes, septic shock, insulin resistance, chronic kidney failure, and Behcet's disease . Recent reports also demonstrate emerging role of endothelial cells in cancer invasion and spontaneous metastasis . For these reasons, the study of human endothelium is important to elucidate their molecular profile underlying the key role in vascular development and maintenance.…”

“…Early proteomics analysis of HUVECs were carried out by 2D gel electrophoresis and LC‐MS/MS methods which identified a few hundred proteins . Large‐scale analysis of HUVECs has been enabled by technological developments in mass spectrometry which led to the identification of thousands of proteins under various perturbations . The role of increased expression of cell adhesion molecules on HUVECs is well documented under the conditions of atherosclerosis and other pathological conditions .…”