Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy

Abstract

Because of its impact on multiple biological pathways, heparanase has emerged as a major regulator of cancer, inflammation and other disease processes. Heparanase accomplishes this by degrading heparan sulfate which regulates the abundance and location of heparin-binding growth factors thereby influencing multiple signaling pathways that control gene expression, syndecan shedding and cell behavior. In addition, heparanase can act via non-enzymatic mechanisms that directly activate signaling at the cell surface. Clinical trials testing heparanase inhibitors as anti-cancer therapeutics are showing early signs of efficacy in patients further emphasizing the biological importance of this enzyme. This review focuses on recent developments in the field of heparanase regulation of cancer and inflammation, including the impact of heparanase on exosomes and autophagy, and novel mechanisms whereby heparanase regulates tumor metastasis, angiogenesis and chemoresistance. In addition, the ongoing development of heparanase inhibitors and their potential for treating cancer and inflammation are discussed.

NK cell heparanase controls tumor invasion and immune surveillance

“…LWT1 (60) and RMA-S-RAE-1β (25) cell lines were cultured in complete RPMI 1640 (cRPMI) media containing 10% FBS, 100 U/ml penicillin, 100 μg/ml streptomycin, 2 mM glutamax, 55 μM 2-mercaptoethanol, HEPES, and sodium pyruvate. sis, and various rare diseases (10,(46)(47)(48). We have explored the importance of heparanase production by NK cells in their infiltration into Matrigel and tumors, but it might be interesting to assess the impact of heparanase loss in other NK cell-dependent conditions such as Herpes virus infections or recruitment into inflammatory sites caused by TLR agonists or similar danger signals, in which NK cells are known to be critical in host defense (49,50).…”

“…We have explored the importance of heparanase production by NK cells in their infiltration into Matrigel and tumors, but it might be interesting to assess the impact of heparanase loss in other NK cell-dependent conditions such as Herpes virus infections or recruitment into inflammatory sites caused by TLR agonists or similar danger signals, in which NK cells are known to be critical in host defense (49,50). However, heparanase is best known for its involvement in tumor growth and angiogenesis, metastasis, and chemoresistance (10,46), indicating that heparanase is a promising therapeutic target for cancer therapy. Preclinical studies in mice clearly showed that inhibition of heparanase reduces the growth and metastasis of solid tumors (51) and hematological malignancies (52,53).…”

“…Heparanase is secreted as an enzymatically inactive pro-heparanase and requires reuptake into the cell and processing by cathepsin-L in lysosomes (7) or α granules (8) in order to give rise to the enzymatically active heparanase protein. In recent years, it has become evident that heparanase is a complex protein with both enzymatic and nonenzymatic activities, depending on its location and cleavage (9)(10)(11)(12)(13). The degradation of HSPGs and remodeling of the ECM require the enzymatically active heparanase protein to be secreted into the extracellular space.…”

Forty Years of Basic and Translational Heparanase Research

“…In fact, heparanase research markedly reinforced the significance of the ECM in the control of cell proliferation and differentiation [149][150][151][152]. It led to important and often unexpected observations in diverse normal and pathological processes including, wound healing, angiogenesis [63], autophagy [98], signal transduction [107,156,161], protein trafficking [162], lysosomal secretion [144,163], blood coagulation [92,164], epithelial-mesenchymal transition [165], activation of immune cells [21,[121][122][123], exosome formation [99,100,102], drug resistance [34,166], gene transcription [35,104] and others. While most studies emphasize the involvement of heparanase in cancer progression, other pathologies were investigated.…”

Ultrasensitive small molecule fluorogenic probe for human heparanase

“…Heparanase has been considered a drug target for cancer and inflammation [39][40][41][42][43][44] . Nonetheless, only four saccharide-based inhibitors have been assessed in clinical trials 1,45 .…”