Heparanase from triple‑negative breast cancer and platelets acts as an enhancer of metastasis

Abstract

Triple-negative breast cancer (TNBC), which is characterized by inherently aggressive behavior and lack of recognized molecular targets for therapy, poses a serious threat to women's health worldwide. However, targeted treatments have yet to be made available. A crosstalk between tumor cells and platelets (PLT) contributing to growth, angiogenesis and metastasis has been reported in numerous cancers. Heparanase (Hpa), the only mammalian endoglycosidase that cleaves heparan sulfate, has been demonstrated to contribute to the growth, angiogenesis and metastasis of numerous cancers. Hypoxia affects the growth, angiogenesis and metastasis of nearly all solid tumors, and the ability of Hpa to promote invasion is enhanced in hypoxia. However, whether Hpa can strengthen the crosstalk between tumor cells and PLT, and whether enhancing the biological function of Hpa in TNBC promotes malignant progression, have yet to be fully elucidated. The present study, based on bioinformatics analysis and experimental studies in vivo and in vitro, demonstrated that Hpa enhanced the crosstalk between TNBC cells and PLT to increase the supply of oxygen and nutrients, while also conferring tolerance of TNBC cells to oxygen and nutrient shortage, both of which are important for overcoming the stress of hypoxia and nutritional deprivation in the tumor microenvironment, thereby promoting malignant progression, including growth, angiogenesis and metastasis in TNBC. In addition, the hypoxia-inducible factor-1a (HIF-1a)/vascular endothelial growth factor-a (VEGF-a)/phosphorylated protein kinase B (p-)Akt axis may be the key pathway involved in the effects of Hpa on the biological processes mentioned above. Therefore, improving local hypoxia, anti-Hpa treatment and inhibiting PLT activation may improve the prognosis of TNBC.

Extracellular vesicles released during hypoxia transport heparanase and enhance macrophage migration, endothelial tube formation and cancer cell stemness

“…46 Numerous studies have revealed an upregulation of HPSE expression in cells growing in hypoxic conditions and some have linked that upregulation to an increase in cell invasion. [47][48][49] There is also evidence linking hypoxia, HPSE, and upregulation of VEGF and increased angiogenesis. This is consistent with our finding that hypoxic EVs from myeloma cells promote the formation of endothelial tubes (Figure 3).…”

Heparanase is a novel biomarker for immune infiltration and prognosis in breast cancer

“…Our previous bioinformatics and experimental studies demonstrated that HPSE promotes malignant progression, angiogenesis and metastasis in breast cancer by enhancing the crosstalk between tumor cells and platelet [ 65 ]. In this study, multi-database integration analysis indicated that high HPSE expression contributes to macrophage M2 polarization and T cell exhaustion, thus promoting tumor growth.…”

“…Human MDA-MB-231-HPSE and MDA-MB-231-mock cells, which represented breast cancer cell lines with high and low expression of HPSE, were handseled by Dr. Israel Vlodavsky, the GFP inserts were performed in Glyconovo Technologies Co., Ltd, and the HPSE expression have been detected between MDA-MB-231-HPSE and MDA-MB-231-mock cells by Western blot analysis, and the specific operation method were described previously [ 65 ].…”

“…Cell culture, animal care, and establishment of a nude mouse model were described previously [ 65 ].…”

Impact of Adjuvant Treatment on Heparanase Concentration in Invasive, Unilateral Breast Cancer Patients: Results of a Prospective Single-Centre Cohort Study

“…The study of Yang et al is in line with our findings that the expression of heparanase was significantly higher in the metastatic group with respect to their non-metastatic counterparts and a high expression of heparanase was also significantly linked with poor disease-free survival (DFS) and overall survival (OS) in triple-negative subjects. The authors have claimed that heparanase enhanced the blood and oxygen delivery of both the breast tumours and lung metastases through a new vessel network and vascular mimicry, thus leading to tumour growth and malignant progression [ 31 ].…”