Table 1.

Summary of tumor-related proteases and their characteristics.

Protease	Classification	Property	Function
MMPs	Gelatinases Matrilysins Archetypal MMPs Furin-activatable MMPs	The enzymatic potency of MMPs undergoes three processes: the synthesis of inactive pre-proenzymes, the removal of signal peptides to produce proenzymes, and the cleavage of the bridge structure leading to enzyme activation	Physiological activities: angiogenesis, wound healing, embryonic development, and tissue remodeling Pathological features: tumorigenesis, migration, invasion and metastasis
Serine proteases	uPA	uPA is secreted in a non-activated pro-uPA form and activated by binding to uPAR, and then it cleaves plasminogen into plasmin that exerts serine protease activity directly or reciprocally activates pro-uPA to uPA in a positive feedback loop	Induce ECM degradation and tissue remodeling Promote tumor growth, progression, and migration
	PSA	Active PSA is only localized near the prostate cells. It specifically recognizes and rapidly cleaves heptapeptide sequence based on semenogelin	Induce ECM degradation and tissue remodeling Promote tumor development
	Thrombin	It converts soluble fibrinogen into insoluble fibrin and increases malignant cell adhesion	Promote tumorigenesis, progression, and metastasis
Cysteine proteases	Cathepsins	They are lysosomal proteases sharing a common papain-like fold containing three α-helix domains and a β-barrel domain except for cathepsin C, as well as they show a tissue-specific distribution	Participate in antigen presentation, thyroid hormone liberation, epidermal homeostasis, precursor activation, keratinocyte differentiation, cell apoptosis, and bone remodelling Promote ECM degradation and tumor progression and metastasis
	Legumain	Legumain is synthesized as an inactive zymogen and then be catalytically activated in an acidic lysosome	Stimulate angiogenesis, enhance tumor progression and metastasis
Threonine proteases	Testes-specific protease 50	Its catalytic triplet is located near the opening of the pocket consisting of two sets of β sheets, which facilitates the substrate peptides to approach the threonine catalytic site	Participate in multiple cellular physiological processes Promote cell proliferation, stimulate tumor formation and progression
	Threonine aspartase 1	It is a “non-oncogene addiction” protease to crack the main regulator of mixed leukemic proteins and other human regulatory proteins	Be involved in head morphogenesis, segment recognition, spermatogenesis, and proliferation Affect cell proliferation, transformation, cycle progression, and tumor development
Aspartic proteases	Cathepsin D Cathepsin E Memapsin	They are synthesized as inactive zymogen progenitors and convert to mature active proteases under acidic pH without the assistance of other catalytic molecules.	Perform a series of physiological functions Promote cancer initiation and progression

MMPs, matrix metalloproteinases; uPA, urokinase plasminogen activator; uPAR, uPA receptor; ECM, extracellular matrix; PSA, prostate specific antigen.