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.

Prognostic impact of kallikrein‐related peptidase transcript levels in prostate cancer

“…However, it is speculative to draw conclusions of their potential roles solely based on the changes in expression levels as those may not correlate with the activity of KLKs, which are expressed as zymogens. Furthermore, the activity of proteases is regulated by several other mechanisms, like endogenous inhibitors, 52 which were not addressed in the present study. Such inhibitors are present also in prostate 52,53 and, for example, in ovarian cancer ascites fluid only a small portion of the immunodetectable KLK proteins have enzymatic activity, which is at least partially explained by the presence of proteinase inhibitors 54 .…”

“…Furthermore, the activity of proteases is regulated by several other mechanisms, like endogenous inhibitors, 52 which were not addressed in the present study. Such inhibitors are present also in prostate 52,53 and, for example, in ovarian cancer ascites fluid only a small portion of the immunodetectable KLK proteins have enzymatic activity, which is at least partially explained by the presence of proteinase inhibitors. 54 Thus, based only on expression levels, it is challenging to know the concentration of active proteases in a tumor microenvironment.…”

“…However, the same furin‐activable propeptide we used here has previously been successfully used for activation of KLK3 in PC‐3 cells, 36 suggesting that KLK12 and KLK15 should also be activated. Further, it is challenging to predict the clinical outcomes based on artificial and simplistic cellular models, lacking full tumor microenvironment, like stromal cells, and showing variable expression of protease inhibitors and substrates 52 . Additionally, individual cell lines, or prostate cancer cell lines in general, are not able to recapitulate intratumoral or intertumoral heterogeneity of multifocal prostate cancer 60 .…”

“…Further, it is challenging to predict the clinical outcomes based on artificial and simplistic cellular models, lacking full tumor microenvironment, like stromal cells, and showing variable expression of protease inhibitors and substrates. 52 Additionally, individual cell lines, or prostate cancer cell lines in general, are not able to recapitulate intratumoral or intertumoral heterogeneity of multifocal prostate cancer. 60 While PC-3 cells are useful for invasion studies, those do not express AR or most of the KLKs.…”

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer

“…Treatment of HUVEC cells with Wt PSA reduced their angiogenic potential, but these cellular effects were observed to a lesser degree with Thr 163 PSA expressing cells or recombinant forms. Wt PSA exerts antiangiogenic activity in endothelial cell models in-vitro 37,38 , however, recently it has been suggested to have a lymphangiogenic role as it activates VEGF-C and VEGF-D 10 . This supports previous observations of a dual role of PSA in tumour progression, promoting it by cleaving growth factors and ECM proteins or suppressing it by its antiangiogenic potential and bone remodelling 39,40 .…”