Heparanase: A Paramount Enzyme for Cancer Initiation, Progression, and Metastasis.

Consolidated data indicate that tumor bulk is not only made up of a heterogeneous set of neoplastic cells but also of a variety of resident and infiltrating host cells, soluble factors, and components of the extracellular matrix which as a whole is defined as the tumor microenvironment. In this context, the extracellular matrix plays a fundamental role in tumor progression as it acts as a repository for various biomolecules such as growth factors, cytokines, enzymes, and inhibitors which are mainly linked to heparan sulfate proteoglycans (HSPG) and whose release can regulate the response or not of cancer cells. Among the various enzymes involved in the degradation of the ECM, heparanase (HPSE) has been shown to be particularly involved in tumor progression and metastatic invasion. This enzyme, capable of cutting heparan sulfate (HS) chains, is overexpressed in practically all solid tumors, clearly demonstrating that it has pro-invasive and pro-angiogenic characteristics for neoplastic cells. Furthermore, considering that heparanase is released not only by tumor cells but also by platelets, endothelial cells, and immune cells, we can admit that its enzymatic activity has a strong impact on the tumor microenvironment. Here, we discuss the recent development in the study of heparanase in cancer progression as well as on novel mechanisms by which heparanase regulates the nature of the tumor microenvironment.