Heparanase regulates EMT and cancer stem cell properties in prostate tumors

Abstract

Prostate cancer displays a certain phenotypic plasticity that allows for the transition of cells from the epithelial to the mesenchymal state. This process, known as epithelial–mesenchymal transition (EMT), is one of the factors that give the tumor cells greater invasive and migratory capacity with subsequent formation of metastases. In addition, many cancers, including prostate cancer, are derived from a cell population that shows the properties of stem cells. These cells, called cancer stem cells (CSCs) or tumor-initiating cells, not only initiate the tumor process and growth but are also able to mediate metastasis and drug resistance. However, the impact of EMT and CSCs in prostate cancer progression and patient survival is still far from fully understood. Heparanase (HPSE), the sole mammalian endoglycosidase capable of degrading heparan sulfate (HS), is also involved in prostate cancer progression. We had previously proved that HPSE regulates EMT in non-cancerous pathologies. Two prostate cancer cell lines (DU145 and PC3) were silenced and overexpressed for HPSE. Expression of EMT and stemness markers was evaluated. Results showed that the expression of several EMT markers are modified by HPSE expression in both the prostate cancer cell lines analyzed. In the same way, the stemness markers and features are also modulated by HPSE expression. Taken together, the present findings seem to prove a new mechanism of action of HPSE in sustaining prostate cancer growth and diffusion. As for other tumors, these results highlight the importance of HPSE as a potential pharmacological target in prostate cancer treatment.

Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

“…Among other aspects, heparanase research reinforced the significance of the ECM in the control of cell proliferation and differentiation. 174 , 175 It led to important and often unexpected observations in diverse normal and pathological processes including, wound healing, 176 angiogenesis, 31 autophagy, 99 signal transduction, 72 , 97 , 128 , 153 protein trafficking, 177 lysosomal secretion, 129 , 178 blood coagulation, 67 , 151 EMT, 173 , 179 glycocalyx remodeling, 116 , 180 activation of immune cells, 24 , 59 , 89 , 90 exosome formation, 82 , 83 , 84 drug resistance, 13 , 181 gene transcription, 73 , 74 and other key biological features. 11 , 12 , 97 While most studies emphasize the involvement of heparanase in cancer and inflammation, other pathologies were investigated.…”

“…Heparanase and Hpa2 not only exhibit opposite functions in terms of tumor growth but also in terms of the underlying mechanism. For example, while heparanase induces VEGF‐A and VEGF‐C 142 expression and promotes angiogenesis, Hpa2 attenuates the expression of VEGF‐A and VEGF‐C and decreases tumor vascularity 106 ; whereas heparanase attenuates cell differentiation and promotes epithelial‐to‐mesenchymal transition (EMT), 172 , 173 Hpa2 increases cell differentiation. 106 , 111 This mirrored functionality suggests that Hpa2 exerts these properties in part by modulating heparanase, as demonstrated by a significant decrease in heparanase activity in sarcoma cells overexpressing Hpa2.…”

A biological guide to glycosaminoglycans: current perspectives and pending questions

“…Reduced expression of syndecan‐1 during development and in breast cancer cells correlates with a reduction in the membrane expression of the epithelial marker and cell–cell adhesion molecule E‐cadherin and acquisition of a migratory phenotype [198]. Treatment of prostate cancer cells with heparanase results in a downregulation of syndecan‐1, E‐cadherin, and multiple mesenchymal markers, demonstrating an impact of HS on the process of EMT [199]. The upregulation of the HS 6‐ O ‐sulfate editing enzyme Sulf‐2 in hepatocellular carcinoma cells results in the activation of the TGFβ pathway and induces EMT in cocultured cancer‐associated fibroblasts [200].…”