The roles of proteases in prostate cancer

Abstract

Since the proposition of the pro-invasive activity of proteolytic enzymes over 70 years ago, several roles for proteases in cancer progression have been established. About half of the 473 active human proteases are expressed in the prostate and many of the most well-characterized members of this enzyme family are regulated by androgens, hormones essential for development of prostate cancer. Most notably, several kallikrein-related peptidases, including KLK3 (prostate-specific antigen, PSA), the most well-known prostate cancer marker, and type II transmembrane serine proteases, such as TMPRSS2 and matriptase, have been extensively studied and found to promote prostate cancer progression. Recent findings also suggest a critical role for proteases in the development of advanced and aggressive castration-resistant prostate cancer (CRPC). Perhaps the most intriguing evidence for this role comes from studies showing that the protease-activated transmembrane proteins, Notch and CDCP1, are associated with the development of CRPC. Here, we review the roles of proteases in prostate cancer, with a special focus on their regulation by androgens.

Keywords: AR; CDCP1; CUB domain-containing protein 1; FAP; KLK; MMP; Notch; PAR; TMPRSS2; androgen; androgen receptor; fibroblast activation protein; hepsin; kallikrein-related peptidases; matriptase; matrix metalloproteinase; peptidases; prostate cancer; protease-activated receptor; proteases; trypsin; uPA; urokinase-type plasminogen activator.

Figure 1.. Examples of the roles of proteases in prostate cancer development and progression.

A simplified scheme of the roles of the major proteases discussed in this review is illustrated. The schematic representation of tumor growth and early steps of metastatic dissemination, shown in the center panel, include: 1) Proliferative and EMT signaling (interaction of cancer and stromal cells and inflammatory responses); 2) Cancer cell migration and invasion, involving ECM remodeling and signaling; 3) Stimulation of (lymph)angiogenesis and intravasation of invasive cancer cells, involving ECM remodeling, degradation of anti-angiogenic factors, production of angiogenic peptides and growth-factor activation; 4) Stromal cells, including cancer-associated fibroblasts (CAFs), are also involved in tumorigenic processes; 5) A small fraction of circulating tumor cells (CTCs) survive and eventually form distant metastases. These processes often involve autocrine-paracrine loops in the prostate cancer microenvironment, which due to simplicity have been omitted here.