Low Inorganic Phosphate Stress Inhibits Liver Cancer Progression: from In Vivo to In Vitro

Metabolic stress (for example, low pO(2), low pH) stimulates cancer progression in a complex and largely unresolved manner. Excessive inorganic phosphate burden is being considered as another stimulator, until now there is no well-designed study to examine the potential benefits of reducing phosphate burden on cancer progression. Sevelamer microspheres, a polymeric phosphate binder, are introduced as embolic material for interventional treatment of rabbit VX2 liver cancer model. This technique is named as "transarterial sevelamer embolization (TASE)." The microspheres prove to be highly biocompatible, and TASE is found to be a safe local-regional technique. Compared with conventional transarterial chemoembolization (TACE), TASE is found to not only occlude the tumor-feeding vessel, but simultaneously deplete intratumoral inorganic phosphate (Pi), thereby inducing severe necrosis as well reducing metastasis and recurrence. Reduced Pi stress inhibits tumor vascularity, invasion, and metastasis by downregulating the angiogenic factors and oncoprotein expression. Energy metabolomics indicate that Pi stress also suppresses tumor anaerobic glycolysis and glutaminolysis. This systemic anti-cancer effect indicates a promising new application for sevelamer and TASE as a potential alternative to conventional TACE for liver cancer treatment.