肝素酶（Hpa1）由肿瘤细胞和肿瘤微环境中的细胞表达，其功能是在细胞外重新塑造细胞外基质（ECM）并调节基质结合因子的生物可用性，增强基因转录、自噬、外泌体形成和肝素硫酸盐（HS）周转等多种效应。肝素酶对肿瘤进展的多数影响与其在调解肿瘤宿主相互作用方面的功能有关，通过使肿瘤微环境更好地支持肿瘤的生长、转移和化疗耐药性。该酶似乎具有一些正常功能，包括与囊泡运输、溶酶体分泌、自噬、HS周转和基因转录等相关联。它能够激活先天免疫系统的细胞，促进外泌体和自噬体的形成，并通过酶和非酶活性刺激信号转导途径。这些效应会动态影响多个调控通路，共同推动肿瘤生长、扩散、耐药性以及炎症反应。目前的观点是，肿瘤细胞、免疫细胞、内皮细胞和肿瘤微环境中的其他细胞表达的肝素酶是癌症具有侵袭性表型的关键调节剂，也是导致癌症患者预后不佳的重要因素和合理的治疗靶点。然而，迄今为止，尚未在临床上实施基于抗肝素酶的治疗。与肝素酶不同，肝素酶-2（Hpa2）是肝素酶（Hpa1）的近源同源物，不会经受蛋白水解处理，因此缺乏肝素酶特有的蛋白水解活性，即肝素酶的标志。Hpa2保留了与肝素/HS结合的能力，并且对HS的亲和力甚至比肝素酶更高，因此会竞争HS的结合并抑制肝素酶的酶活性。看起来Hpa2作为Hpa1的天然抑制剂，调节着维持组织稳态和正常功能的特定基因的表达，并在癌症和炎症方面发挥保护作用，这强调了维持Hpa1和Hpa2之间适当平衡的重要性。© 2023 The Authors. Proteoglycan Research published by Wiley Periodicals LLC.

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 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS-degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.© 2023 The Authors. Proteoglycan Research published by Wiley Periodicals LLC.