Heparanase Loosens E-Cadherin-Mediated Cell-Cell Contact via Activation of Src

Abstract

Activity of heparanase, responsible for cleavage of heparan sulfate (HS), is strongly implicated in tumor metastasis. This is due primarily to remodeling of the extracellular matrix (ECM) that becomes more prone to invasion by metastatic tumor cells. In addition, heparanase promotes the development of blood and lymph vessels that mobilize disseminated cells to distant organs. Here, we provide evidence for an additional mechanism by which heparanase affects cell motility, namely the destruction of E-cadherin based adherent junctions (AJ). We found that overexpression of heparanase or its exogenous addition results in reduced E-cadherin levels in the cell membrane. This was associated with a substantial increase in the phosphorylation levels of E-cadherin, β-catenin, and p120-catenin, the latter recognized as a substrate of Src. Indeed, we found that Src phosphorylation is increased in heparanase overexpressing cells, associating with a marked decrease in the interaction of E-cadherin with β-catenin, which is instrumental for AJ integrity and cell-cell adhesion. Notably, the association of E-cadherin with β-catenin in heparanase overexpressing cells was restored by Src inhibitor, along with reduced cell migration. These results imply that heparanase promotes tumor metastasis by virtue of its enzymatic activity responsible for remodeling of the ECM, and by signaling aspects that result in Src-mediated phosphorylation of E-cadherin/catenins and loosening of cell-cell contacts that are required for maintaining the integrity of epithelial sheets.

MRI-derived radiomics model for baseline prediction of prostate cancer progression on active surveillance

“…Patients were divided into two groups depending on disease progression status. Cases were represented by patients who demonstrated disease progression, which was defined as a switch to radical treatment triggered by either confirmed histopathological progression on repeat targeted biopsy, or definitive radiological stage progression of the target lesion (MRI-derived PRECISE 23 score 5). The control group included patients in whom the disease was regarded stable over the same follow-up period, with no signs of radiological progression recorded on all prospective MRI scans (PRECISE score 3) and no histopathological progression noted on all repeat targeted biopsies, with both criteria being compulsory.…”

Elucidating the Consequences of Heparan Sulfate Binding by Heparanase 2

“…In addition, cleavage of the HS side chains of syndecan-1 augments the shedding of this proteoglycan from the surface of myeloma cells, leading to a more aggressive disease (4,5). This, and many other mechanisms utilized by heparanase to promote tumorigenesis (3,(5)(6)(7)(8)(9), have turned this enzyme into a promising drug target and heparanase inhibitors are currently being evaluated in clinical trials as anti-cancer (10,11) and antiviral (12) drugs.…”

Egg White Photocrosslinkable Hydrogels as Versatile Bioinks for Advanced Tissue Engineering Applications

“…VE-cadherin/DAPI immunostaining was performed to observe the endothelial cell-to-cell junctions on the surface of the EWMA 7.5% hydrogel following protocol. [42] Briefly, the hydrogels were removed from the incubator on day 7 of culture, washed with DPBS, and fixed with 4% v/v paraformaldehyde for 20 min at room temperature. Paraformaldehyde was washed with DPBS, and samples were kept at 4 ○ C overnight.…”