Clinical Markers for Prostate Cancer
Dr Antonio Serafin
Title of the project
Clinical markers for prostate cancer.
Prostate cancer (PCa) is the second most frequent cancer in males. Prostate cancer screening using prostate specific antigen (PSA) is controversial due to the risk of over-diagnosis and over-treatment as most cancers diagnosed would remain asymptomatic. Urokinase Plasminogen Activator (uPA) and its inhibitor, Plasminogen Activator Inhibitor type-1 (PAI-1), have been implicated in tumour aggressiveness and metastatic potential in breast cancer. In view of the relatedness of breast and prostate cancers, and similarities of the invasion process, it was decided to determine the abundance of urokinase plasminogen activator and its inhibitor in prostate tissue, using enzyme-linked immunosorbent assay (ELISA) methodology.
The project was aimed at developing a bioassay which would characterise the presence and severity of prostate disease in patients. Tissue of defined pathology was secured from the surgeons, homogenised, and proteins extracted. We then analysed the extract with specific antibodies using an enzyme-linked immunosorbent assay (ELISA) to determine the concentration of the proteins in question. We tested the correlation between stage of disease, age of patient, and PSA value, with the abundance of the marker protein under investigation.
The goal of the study reported here was to validate findings from an earlier cohort of prostate biopsy samples. Combined, the results confirmed our assertion that PAI-1 may be a candidate prostate biomarker, and further showed a significantly raised PAI-1 level in the absence of prostate disease for individuals older than 70 years of age. However, what was not clear about this phenomenon of raised PAI-1 level was whether it was a diagnostic grey zone or due to benign prostatic hyperplasia with prostatitis, or other pathologies. Because of the semi-random nature of sampling of the prostate during biopsy, urologists and pathologists report that initial prostate biopsy histopathology has a 20 to 30% chance of missing a tumour. To partly address this clinically relevant issue, we proposed a “malignancy index” derived from four parameters, namely, PSA (ng/mL), uPA and PAI-1 (ng/mg of total protein), and patient age (years). We show that this index displays robustness in distinguishing between BPH and PCa, and may potentially serve as a reliable tool for diagnosing prostate malignancies, especially in individuals above 60 years of age.
To test the robustness of the proposed index even further, data from TURP tissue, previously presented in the uPA/PAI-1 ratio studies, were used to derive indices. In addition to the clear distinction between the BPH and PCa patient groups, the index shows potential in separating benign from malignant tumours, regardless of age. This differs from the finding that it only appears to be capable of distinguishing between BPH and PCa in the elderly, suggesting that this approach may be more appropriate when evaluating TURP tissue than biopsy tissue. In our new study, we attempted to discriminate prostate cancer from non-cancer in a cohort of plasma samples, using ELISA methodology. PAI-1 levels were found to be higher in prostate cancer patients than in healthy donors; uPA levels were higher in healthy donors than in prostate cancer patients; and the uPA/PAI-1 ratio was higher in healthy donors than in prostate cancer patients. The malignancy index clearly distinguished prostate disease from non-disease in blood plasma samples, concurring with findings in core needle biopsies and transurethral resection tissue, reported earlier. On average, malignancy indices in TURP tissue, biopsy tissue, and plasma from PCa patients were ~39-, ~19-, and ~9-fold higher than those obtained from individuals with BPH, or healthy donors, respectively. This work has just been published (Discovery Medicine; ISSN: 1539-6509; Discov Med, Volume 25, Number 139, May 2018) “The Malignancy Index in Plasma Samples as a Prostate Cancer Biomarker” Serafin A, Fernandez P, Chinhengo A, Akudugu J