Importantly, heparanase mediates, through enzymatic and non-enzymatic activities, a vicious pro-inflammatory and pro-tumorigenic crosstalk in the tumor microenvironment by regulating gene expression, remodeling the ECM, and facilitating growth factor bioavailability and signaling [9], all highly relevant to mesothelioma tumorigenicity and chemoresistance [1–3]. This evidence concerns the gene HPSE and mesothelioma.