Heparinase III cleaved HS promotes vasculogenic mimicry in Triple Negative Breast Cancer via VEGFA signaling

Anti-angiogenic therapy sometimes triggers alternative vasculogenic mimicry, which is a predictor of poor prognosis. Researches on angiogenesis and vasculogenic mimicry double-related targets and the mechanism behind them could help with this dilemma. The interaction between HS and growth factors in the extracellular matrix can affect various biological behaviors of cells, including tumor cells. Heparinase III from Flavobacterium heparin is an enzyme primarily degrading heparan sulfate (HS). Using heparinase III and HS degeneration inhibitor OGT2115 as regulators, we found that HS-cleaved triple-negative breast cancer cells were more capable of obtaining blood supply by enhanced angiogenesis and vasculogenic mimicry formation. Further studies showed that this effect was achieved by affecting the affinity between HS and VEGFA because HS functions as a co-receptor of VEGFA and induces a stronger signal response by heparinase III exposed neo-epitope. Our work shows for the first time that cleaved heparan sulfate is able to promote VM formation and comes up with a combination of heparinase inhibitors or HS mimetics with anti-angiogenic agents or VEGFR2 inhibitors will be a promising tumor treatment strategy.