Heparanase—A single protein with multiple enzymatic and nonenzymatic functions

作者：Israël Vlodavsky, Yasmin Kayal, Maram Hilwi, Soaad Soboh, Ralph D. Sanderson, Neta Ilan · 发表于：Proteoglycan Research · 年份：2023 · DOI：10.1002/pgr2.6 · 被引用次数：30 · 研究领域：Proteoglycans and glycosaminoglycans research、Glycosylation and Glycoproteins Research、Protease and Inhibitor Mechanisms

Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase-based therapy has not been implemented in the clinic. Unlike heparanase, heparanase-2 (Hpa...