Date Published: January 7, 2013
Publisher: Public Library of Science
Author(s): Hifzur Rahman Siddique, Aijaz Parray, Weixiong Zhong, R. Jeffery Karnes, Eric J. Bergstralh, Shahriar Koochekpour, Johng S. Rhim, Badrinath R. Konety, Mohammad Saleem, Natasha Kyprianou. http://doi.org/10.1371/journal.pone.0052993
Lack of reliable predictive biomarkers is a stumbling block in the management of prostate cancer (CaP). Prostate-specific antigen (PSA) widely used in clinics has several caveats as a CaP biomarker. African-American CaP patients have poor prognosis than Caucasians, and notably the serum-PSA does not perform well in this group. Further, some men with low serum-PSA remain unnoticed for CaP until they develop disease. Thus, there is a need to identify a reliable diagnostic and predictive biomarker of CaP. Here, we show that BMI1 stem-cell protein is secretory and could be explored for biomarker use in CaP patients.
Semi-quantitative analysis of BMI1 was performed in prostatic tissues of TRAMP (autochthonous transgenic mouse model), human CaP patients, and in cell-based models representing normal and different CaP phenotypes in African-American and Caucasian men, by employing immunohistochemistry, immunoblotting and Slot-blotting. Quantitative analysis of BMI1 and PSA were performed in blood and culture-media of siRNA-transfected and non-transfected cells by employing ELISA. BMI1 protein is (i) secreted by CaP cells, (ii) increased in the apical region of epithelial cells and stromal region in prostatic tumors, and (iii) detected in human blood. BMI1 is detectable in blood of CaP patients in an order of increasing tumor stage, exhibit a positive correlation with serum-PSA and importantly is detectable in patients which exhibit low serum-PSA. The clinical significance of BMI1 as a biomarker could be ascertained from observation that CaP cells secrete this protein in higher levels than cells representative of benign prostatic hyperplasia (BPH).
BMI1 could be developed as a dual bio-marker (serum and biopsy) for the diagnosis and prognosis of CaP in Caucasian and African-American men. Though compelling these data warrant further investigation in a cohort of African-American patients.
According to American Cancer Society, 241,740 will be diagnosed with prostate cancer (CaP) and 28,170 CaP patients were projected to die in the year 2012 in USA alone . The unsatisfactory outcome of overall management (treatment strategies and prognosis monitoring) for CaP disease could be associated to the lack of a reliable prognostic serum-biomarker. Although widely used, several important caveats have been reported in serum-PSA as a prognostic biomarker . For example, in some CaP cases, serum-PSA is (a) detected little if any, (b) lacks adequate sensitivity, and (c) fails to discriminate potentially significant cancers from insignificant ones –. PSA does not reflect cancer biology and a high risk of mistaken results –. Further, discrepancies in PSA as a diagnostic marker among different racial groups such as Caucasians and African-American have confounded the management of this cancer –. Therefore a great need persists for the development of improved serologic biomarkers in CaP, which is reliable for prognosis and diagnosis in Caucasian and African-American patients.
A prognostic biomarker provides evidence about a patient’s eventual outcomes from a disease independent of a given therapy, whereas a predictive-biomarker estimates the likelihood of response/benefit to a specific therapy in a specific context . PSA still remains the marker of choice for CaP diagnosis, prognosis, and active surveillance. However, PSA has several limitations –. For example, sipuleucel-T is known to improve survival without having an impact on early PSA levels . PSA progression during CRPC therapy is reported to be prognostic for overall survival but likewise is not a surrogate for overall survival . Some CaP types such as neuroendocrine tumors, produce little if any PSA and decreased secretion of PSA in patients suffering from ductal CaP has also been reported , . In these cases, PSA alterations do not correlate well with clinical benefit , . There is an unmet need to identify a robust and reliable biomarker which can detect disease progression in patients in whom PSA is not a reliable indicator. Thus, the development of biomarker(s) that can correlate with disease stage along the course of tumor progression is important for intervention and treatment of disease, especially chemoresistant CaP.