Prostate Specific Antigen

This is an infographic from pathologyreport.org showing 5 common things that should be known about the Prostate Specific Antigen Assay.

Prostate specific antigen (PSA), was first discovered and purified in 1979 by the Wang et al. group. This discovery made a small splash in the scientific community until the work was expanded upon. The foundation laid down by the Wang et al. group proved to be fundamental and changed the history of prostate cancer. Quickly, groups started to investigate the protein and see if there is a correlation to prostate cancer. In 1980, the first PSA assay to was developed.

Following this invention, groups around the world started to improve and use this assay to look at the underpinnings of prostate cancer. Through the 1980’s groups started to look into why the levels of PSA were raised when a patient had cancer. Through numerous studies it was found out that PSA was also a protease that cleaved seminal vesicle proteins. Through further analysis of PSA, it was found out that this protease had a similar primary structure to serine proteases and kallikreins. Additionally, the experimental data showed that the activity of PSA was similar to trypsin and chymotrypsin. Finally, it was determined in the late 1980’s that PSA was a serine protease with kallikrein like enzymatic activity that was especially selective towards hydrophobic molecules.  After the function of PSA was determined, the Peter et al. group proposed the accepted hypothesis that the PSA cleaves gel-forming proteins from the seminal vesicles. After the research was done in the labs explaining PSA, it made its way to clinicians and their patients (De Angelis et al.).

PSA was one of the diagnostic tools that physicians used that radically changed how to diagnose and treat prostate cancer. When the PSA assay was first used, it was thought to be an incredibly advantage towards treating and diagnosing prostate cancer. In the late 1980’s the assay was used and started to shift the paradigm concerning overall prostate cancer treatment and diagnosis. Many studies were carried out in the following decade demonstrating how useful PSA was as a diagnostic tool; especially when it was used in combination of other diagnostic tools such as ultrasound and digital rectal exams. Through these efforts, the FDA approved the PSA assay in 1994. Since its widespread use, the PSA assay has come under scrutiny since it was used for so many cases which resulted in false positives and overtreatment of patients (De Angelis et al.).

Even though PSA assay was viewed as an incredible success in the beginning, it quickly became apparent that the PSA assay was not as great as once thought. Through numerous recent studies, it appears PSA assays are not as accurate as once thought. Of those who have the PSA, only 40% of the time does the assay accurately predict a cancerous tumor. The other 60% of the time resulted in men receiving an unneeded biopsy. Since the PSA assay has it downfalls, researchers are starting to develop a replacement. Two current possibilities are looking at PCA3 gene expression and AMACR gene expression (De Angelis et al.).

2 Comments

  1. Hi Calvin – Nice work! The part about the inconsistencies with the PSA assay strikes me as an interesting bioanalytical problem. My understanding is that the assay is either a chemiluminescence or ELISA assay, and I would have expected the tissue specificity of PSA to make for a good diagnostic. Can you go into more detail on why the PSA assay is so unreliable and, if possible, how the gene expression strategies you mentioned seek to address these issues.

    Thanks,
    Zach Zimmerman (biochem ’15)

  2. Hey Zach, thank you for taking the time to ready my post and asking a great question! The PSA assay relies on using two different plates immunoenzymatic plates facing each other (almost like a sandwich). The PSA sample is then added to the middle of these two plates where they to the PSA in their respective locations. After washing the plates, a luminescent is added so the amount of PSA bound to the plates can be quantified by luminometer.

    The problem with the reliability of the PSA assay does not lie in the experimentation but the reasons why the PSA concentration is raised or lowered. Since many factors impact the levels of PSA, doctors never know whether the concentration of PSA is increased due to an enlarged prostate, prostate cancer, or simply because of age. Likewise, PSA concentration can also be lower in some people due to their medication, obesity, or urinary conditions. Since everyone has a different “normal” level of PSA floating in their blood, it is hard to decide if an elevation occurs.

    Lastly, the De Angelis group is investigating different ways to detect cancer while not relying on PSA concentration levels. Like previously stated, PSA is very variable from person to person making it tough to fully rely on for cancer diagnosis – hence why multiple approaches are used now. With this being said, the De Angelis group is developing a way to diagnose prostate cancer that has to deal with prostate cancer directly. PSA does not necessarily increase in concentration due to prostate cancer, but often it does. Alternatively, PCA3 and AMACR is overexpresssed up to 95% the time when a patient has prostate cancer. This increased expression rates allows more a much more accurate test than PSA – almost as accurate as a biopsy.

    I hope this cleared up some questions you had! Below are two references I found helpful. The first one is a link to a medical laboratory’s approach to testing PSA and the other has some reasons why PSA levels may be increased or decreased. Thanks!

    (https://www.cdc.gov/nchs/data/nhanes/nhanes_03_04/l11psa_c_met_total_psa.pdf)
    (https://www.mayoclinic.org/tests-procedures/psa-test/about/pac-20384731)

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