Anti-angiogenic properties of prostate‐specific antigen

Abstract

The prostate produces high levels of prostate‐specific antigen (PSA, also known as kallikrein‐related peptidase 3, KLK3), which is a potential target for tumor imaging and treatment. Although serum PSA levels are elevated in prostate cancer, PSA expression is lower in malignant than in normal prostatic epithelium and it is further reduced in poorly differentiated tumors. PSA has been shown to inhibit angiogenesis both in in vitro and in vivo models.

In this review we focus on our recent studies concerning the mechanism of the antiangiogenic function of PSA. We have recently shown that the antiangiogenic activity of PSA is related to its enzymatic activity. Inactive PSA isoforms do not have antiangiogenic activity as studied by a human umblical vein endothelial cell (HUVEC) tube formation model. Furthermore, inhibition of PSA, either by a monoclonal antibody or small molecule inhibitors abolishes the effect of PSA, while a peptide that stimulates the activity of PSA enhaces the antiangiogenic effect. We have analyzed changes in gene expression associated with the PSAinduced reduction of tube formation in the HUVEC model. Several small changes were observed and they were found to be opposite to those associated with tube formation.

Taken together, these studies suggest that PSA exerts antiantiogenic activity related to its enzymatic activity. Thus it might be associated with the slow growth of prostate cancer.

https://doi.org/10.1080/00365510903056031

Anti-metastatic role of the prostate-specific antigen

Highlights

• Prostate specific antigen is the standard circulating biomarker for prostate cancer.

• We provide novel evidence that collagen 1 is an additional substrate for PSA.

• PSA hampers first steps of cancer invasion.

• Tissue-related PSA content/activity is inversely correlated to tumor progression.

• Tissue-related PSA levels improve prediction of prostate cancer specific mortality.

Abstract

Aim: Since its discovery Prostate Specific Antigen (PSA), also referred to as kallikrein-3 (KLK3), has been used as standard circulating biomarker for prostate cancer (PCa). However, its specificity remains not adequate and its mechanism of action still elusive. Therefore, deciphering PSA role throughout PCa-pathobiology would be relevant in improving both cancer diagnosis and outcome prediction. We investigated the possible role played by PSA on/in the tumor microenvironment and over the first steps of cancer invasion.

Methods: Fresh PCa-specimens and cell lines were used for ex-vivo/in-vitro invasion assays and assessment of prostate tissue-PSA (tPSA), type 1 collagen (COL1A1) and ß1-integrin expression. Tissue Cancer Genome Atlas (TCGA) and Decipher® datasets were considered to estimate tPSA clinical relevance.

Results: A more precise, inverse, correspondence between tPSA and clinical/pathological parameters was found than for circulating PSA. KLK3 combined with Gleason grade and pathologic stage, better predicted cancer-related mortality. Consistently, we demonstrated that PSA inhibits prostate extracellular-matrix (ECM) invasion by PCa cells. As for the mechanism of action, we provided novel information that PSA is able to cleave COL1A1, a main component of the ECM. Finally, ß1-integrin, a crucial COL1A1 transducing-receptor involved in tumor adhesion/invasion, resulted to be downregulated in PCa specimens with higher levels of tPSA.

Conclusions: By interfering with type 1 collagen and its downstream targets, PSA may hamper adhesion and path of the cancer cells through ECM and their migration ability, thus explaining the inverse correlation highlighted between prostate tPSA levels and clinically significant disease.

https://doi.org/10.1016/j.tranon.2021.101211

Prostate-specific antigen stimulation enhance its anti-angiogenic activity

Abstract

BACKGROUND: Proteolytically active prostate-specific antigen (PSA or kallikrein-related peptidase 3, KLK3) has been shown to exert antiangiogenic properties. High levels of PSA in prostatic tumors may thus slow down cancer progression by inhibiting angiogenesis. We hypothesize that factors stimulating the activity of PSA could be used to reduce prostate tumor growth. Using phage display, we have developed peptides C4 and B2 that stimulate the enzymatic activity of PSA. Our aim was to study whether these peptides enhance the antiangiogenic activity of PSA.

METHODS: We used an in vitro angiogenesis assay where human umbilical vein endothelial cells (HUVECs) form tubular networks when they are grown on Matrigel. Proteolytically active PSA and peptides that stimulate the activity of PSA were added to the cells. Endothelial cell tube formation was quantified and expressed as an angiogenesis index.

RESULTS: PSA reduced the angiogenesis index to ∼50% of controls both in serum-containing and serum-free medium. The addition of peptide C4 or B2 together with PSA caused a significant further decrease in angiogenesis index to ∼70% of that caused by PSA alone. A similar decrease in angiogenesis index was observed when PSA concentration was increased 2.4-fold of that used with peptides.

CONCLUSIONS: The inhibitory effect of PSA on tube formation can be enhanced by the addition of peptides that stimulate the activity of PSA. This supports our hypothesis that stimulation of PSA activity can be used to reduce angiogenesis and thereby inhibit prostate tumor growth.

https://doi.org/10.1002/pros.22512

Interestingly, I was talking to someone whose PSA was rising and he was not worried about it. His reasoning was that PSA rises to prevent cancer from spreading. So when he tried various things to combat his prostate cancer, if he saw an immediate rise in PSA, he thought it could actually be a good thing.