HPA1

Related Reading

Background

The extracellular matrix (ECM) is essential for maintaining homeostasis and tissue integrity. Heparan sulfate (HS) is an important component of ECM, which maintains its regulatory function and structural integrity in the form of heparan sulphate proteoglycans (HSPGs). HSPGs exist in ECM and basement membrane (as well as on the cell surface and intracellularly) in many forms. 

Heparanase (HPSE, also known as HPA1) is only expressed in a few cell and tissue types, such as platelets and immune cells, and is the only mammalian enzyme that cleaves heparan sulfate. The enzymatic activity of HPSE leads to ECM remodeling and the increased bioavailability of HSBP. This in turn affects physiological and pathological processes such as angiogenesis, immune cell migration, wound healing, inflammation, and metastasis. Dysregulation of gene expression is a key sign of cancer. It can lead to overexpression of HPSE in the tumor microenvironment (TME), leading to pathological ECM remodeling and promoting the release of cancer-promoting HSBPs. Basically, all cancers have been reported to overexpression of heparanase, which leads to tumor growth and metastasis, and concomitant poor patient survival. In addition, heparanase also exhibits a variety of non-enzymatic functions in the process of cell signal transduction and regulation of gene expression, such as promoting cell adhesion and procoagulant activity. Due to the multiple roles of this enzyme in the tumor microenvironment, it has been shown to regulate these landmark characteristics and advance the research of heparanase-targeted therapy.

The role of heparanase in the hallmarks of cancer

Cell proliferation is no longer a meticulously choreographed process in cancer. HS binds to and isolates a variety of HSBP that regulates cell proliferation, thereby limiting its bioavailability and controlling downstream signal transduction. HPSE-mediated HS cleavage remodels ECM and then releases these HSBPs, thereby up-regulating cell proliferation. A key regulator in the growth of cancer cells is the p53 tumor suppressor encoded by TP53. The expression of HPSE is related to the binding of wild-type p53 to the HPSE promoter. Mutations in the TP53 gene lead to up-regulation of HPSE expression, which promotes many HPSE-mediated growth suppressor-evasion mechanisms. By definition, cancer cells are immortal. Telomeres at the end of chromosomes are the key to regulating cell replication. Cancer expressing telomerase can achieve immortal replication, and there may be a cooperative relationship between telomerase and HPSE. Many immune cells have been shown to be closely related to TME and promote tumor progression. Because of the similarity between the tumor stroma and the wound inflammation, tumors are described as " wounds that do not heal." In addition, infection is believed to be responsible for more than 15% of malignant tumors, and inflammation plays a major role in the development of infection-mediated cancer.

HPSE can promote the migration of white blood cells, and has been shown to affect many types of innate immune cells, such as macrophages, neutrophils, DCs and mast cells, which are all involved in mediating acute and chronic inflammatory responses. Although some infiltrating immune cells play a role in eliminating tumors, certain other immune cells promote tumor growth, leading to a poor clinical outcome.

Figure 1. HPSE regulates all hallmarks and enabling characteristics of cancer (Jayatilleke, K.M.; Hulett, M.D. 2020)

A dual role of HPSE within the TME?

Due to the important and multiple roles of HPSE in tumor development, HPSE has been attracting a large number of researchers as a potential therapeutic target. At present, some inhibitors have entered human clinical trials, and many inhibitors are in various stages of development. Recent studies on HPSE-mediated tumor immunity suggest that HPSE may play a dual role in both promoting and inhibiting tumor growth in TME. In view of these conflicting data, scientists have raised the question of whether targeting HPSE in TME is harmful or beneficial to patients. With more and more data on the role of HPSE in cancer, it is obvious that a one-size-fits-all approach may not be ideal. In fact, HPSE inhibitors cause more harm than good in some cancers, which may also explain why several human trials in the past have failed. The development of MMP inhibitors provides valuable insights into the complexity of targeting TME components, which have been shown to have conflicting effects, suggesting the risk of indiscriminately targeting ECM-modifying enzymes in TME. Therefore, it is important to clarify the exact role of HPSE in a specific tumor environment, and thoroughly understand its pro- and anti-tumor effects before using HPSE inhibitors.

Figure 2. Targeting HPSE within the TME may promote tumour growth (Jayatilleke, K.M.; Hulett, M.D. 2020)