Complex Formation Between PSA Isoenzymes and Protease Inhibitors

Leinonen, Jari; Zhang, Wanming; Stenman, Ulf‐Hǎkan

doi:10.1016/s0022-5347(01)66399-7

Cited by 100 publications

(44 citation statements)

References 20 publications

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“…Moreover, the fact that PSA is found bound to ACT in MLL-PSA-2 cells in vitro and in serum from mice injected with MLL-PSA cells (Figures 1b and 3b) suggests that PSA is secreted in an active form, the form of PSA that ACT predominantly binds to and inhibits. 38 PSA has several biological properties important in invasion and metastasis of prostate cancer. Our in vitro data suggest that PSA may inhibit or increase invasive properties of prostate cancer cells dependent on the specific form of PSA secreted.…”

Section: Discussionmentioning

confidence: 99%

PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

Cumming

Hopmans

Vukmirović-Popović

et al. 2011

Prostate Cancer Prostatic Dis

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BACKGROUND:Patients with advanced prostate cancer frequently have a poor prognosis as a result of metastasis and present with high serum PSA levels. There is evidence suggesting that the serine protease activity of PSA could be involved in the invasion and metastasis of prostate cancer. In this study, we determined the effects of PSA and its precursor, pro-PSA, on invasion and the type of bone metastasis. METHODS:We stably transfected prostate adenocarcinoma cells, human DU-145 and rat MatLyLu, with either the fulllength prepro-PSA sequence or pre-PSA DNA, to generate subclones of cells that secrete pro-PSA or free PSA, respectively. Secretion of PSA was measured by western blot analysis and enzyme-linked immunosorbent assay (ELISA). The invasive and migratory properties of the cells were determined using a basement membrane extract and were compared with corresponding empty vector control cells. Twelve days after injection of PSA-secreting MatLyLu cells into the femora of nude mice, bone tumor burden and histomorphometry were determined using a stereological technique. RESULTS:The transfected cells secreted 0.15-2.23 ng PSA/10 6 cells/day. Pro-PSA-secreting subclones increased invasion and migration by 24-263%. Conversely, the PSA-secreting subclones significantly reduced both invasion and migration by 59-70%. The divergent effects on invasion and migration observed in pro-PSA-and PSA-secreting subclones indicate that different forms of PSA may have different functions. Intrafemoral injections with PSA-secreting MatLyLu cells resulted in an increase in osteoblastic parameters when compared with non-PSA-secreting subclones as measured by bone histomorphometry. Concomitantly, a decrease in osteoclasts and eroded surface was observed.CONCLUSIONS: Our in vitro data suggest that PSA, dependent on the predominant form secreted, may decrease or increase invasive properties of prostate cancer cells. The in vivo results indicate that PSA in the bone microenvironment may contribute to the osteoblastic phenotype of bone metastasis frequently observed in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

Cumming

Hopmans

Vukmirović-Popović

et al. 2011

Prostate Cancer Prostatic Dis

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“…When added to serum in vitro. 60%-70% of PSA forms complexes with AMG, 15%-20% forms complexes with ACT and most of the rest remains free [13,21]. although a minor fraction reacts with API [21].…”

Section: Release Of Psa Into the Circulationmentioning

confidence: 99%

“…The complex formation with AMG is much more rapid than that with ACT and API. and the latter complex forms very slowly [21,22].…”

Section: Release Of Psa Into the Circulationmentioning

confidence: 99%

“…this transfer is slow: hence, PSA is retained for a long time in the extracellular space, where it is susceptible to proteolytic degradation [14]. Such PSA reacts poorly or not at all with ACT [21]. Interestingly, PSA occurring in Quid from hyperplastic pro tatic tissue is actually extensively 'nicked' [30].…”

Section: Why Is the Degree Of Psa Complexation Higher In Prostate Canmentioning

confidence: 99%

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Prostate‐specific antigen, clinical use and staging: an overview

Stenman

1997

British Journal of Urology

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“…The corresponding positive predictive value has been 29-33% (Labrie et al, 1992;Brawer et al, 1993;Catalona et al, 1993;Mettlin et al, 1993b (Leinonen et al, 1996).…”

mentioning

confidence: 99%

Screening for prostate cancer using serum prostate-specific antigen: a randomised, population-based pilot study in Finland

Auvinen

Tammela²,

Stenman³

et al. 1996

Br J Cancer

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Summary The possibility of screening the general population for prostate cancer using serum prostate-specific antigen (PSA) level (alone or in combination with other tests) as screening test has recently been discussed. A number of studies are on the way, but the published reports have almost exclusively been based on men volunteering for screening. We assessed the feasibility of a screening study based on men identified from a central population registry. A random sample of 600 men in the age groups 55, 60 and 65 years was identified from the Finnish Population Registry as the study population. Half of them were randomised to the intervention group and an invitation to participate was sent to them. The participation rate was 77% (230 out of 300). Twenty-five men had a serum PSA concentration of 4.0 pg I-or above and were invited for further examination including digital rectal examination, transrectal ultrasound and transrectal Tru-cut biopsies (directed and/or random). Six cases of cancer were detected among the 230 participating men, which corresponds to a detection rate of 2.6% and a positive predictive value of 24%. The number of cases detected is equivalent to the expected number of prostate cancer cases during a 10 year follow-up in this population. The ratio of free to total PSA was also measured and a cut-off level of 0.20 was chosen. Its use as an additional criterion of the screening test would have decreased the prevalence of falsepositive screening tests from 8% (19 of 230) to 3% (7 of 230) at a cost of missing one of the six cancers compared with serum total PSA concentration alone. Of the six cancers, five were clinically regarded as localised and locally confined disease was confirmed pathologically in four of them. In conclusion, a population-based study in Finland seems feasible and the properties of the PSA test can be regarded as suitable for a randomised screening study. Thus, all prerequisites for a multicentre study, which is planned, seem to exist.

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Complex Formation Between PSA Isoenzymes and Protease Inhibitors

Abstract: alpha 2-macroglobulin is the major inhibitor of PSA when it reached the circulation. Contrary to earlier assumptions, nicked PSA can bind to A2M rendering it inaccessible to antibodies.

Cited by 100 publications

References 20 publications

PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo

Prostate‐specific antigen, clinical use and staging: an overview

Screening for prostate cancer using serum prostate-specific antigen: a randomised, population-based pilot study in Finland

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