Differences in the expression of telomerase and prostate-specific membrane antigen in non-advanced prostatic cancer

Abstract

Early recognition of prostate cancer (PC) based on biological markers could be helpful in identification of differences in benign and malignant lesions and facilitate further precise indication for more aggressive treatment. Therefore, the aim of our study was to assess expression of hTERT (human telomerase reverse transcriptase, a catalytic subunit of telomerase) and prostate-specific membrane antigen (PSMA), both considered to be markers of tumor aggressiveness. 140 low advanced PC specimens from patients who underwent radical prostatectomy were studied. Protein expression was assessed immunohistochemically on tumor sections and expressed as labeling index (LI), i.e. the percentage of positively stained cells. In case of telomerase, only nuclear staining and in case of PSMA, membrane and cytoplasmic staining, were considered as positive. The mean age of the patients was 62.9 ± 6.2 years. There were 75 (53.6%) well differentiated tumors (Gleason score 6), 52 (37.1%) moderately differentiated tumors (Gleason score of 7) and 13 (9.3%) poorly differentiated tumors (Gleason score 8-10). The mean pre-operative serum PSA was 9.9 ± SE 5.5 ng/mL, and the mean LI were 18.0 ± 1.5% and 44.1 ± 1.9%, for hTERT and PSMA, respectively. With increase of pathological tumor stage and tumor grade statistically significant increase of PSA serum concentration (P < 0.011) and PSMA (P < 0.004) expression was noticed, however, for expression of telomerase the relation was opposite one. The observed in higher pTNM stages and tumor grades decrease in nuclear expression of hTERT was caused by translocation of the subunit to the cytoplasm, what may indicate extranuclear telomerase activity independent of telomere lengthening, hence, it cannot be considered as a marker of malignancy. Higher PSMA expression in higher pTNM stages and tumor grades suggest that PSMA may be a good marker of biological aggressiveness suitable for patients' selection for more aggressive treatment.

Prognostic Significance of Serum PSA Level and Telomerase, VEGF and GLUT-1 Protein Expression for the Biochemical Recurrence in Prostate Cancer Patients after Radical Prostatectomy

“…This may be true, as we observed it in our patients with anaplastic tumours, the highest PSA levels and the lowest nuclear hTERT expression [15]. Earlier we showed that higher PSMA expression in higher pTNM stages and tumour grades may indicate PSMA as a good marker of biological aggressiveness suitable for patients' selection for more aggressive treatment [15]. However, now we are unable to show utility of PSMA for predicting patients' prognosis for BRFS which is in agreement with some studies [22].…”

“…Another explanation for our results is a hypothesis that telomerase activity is regulated by androgens and the wild-type human androgen receptor inhibits the expression of hTERT in the presence of androgen receptor agonists [30]. This may be true, as we observed it in our patients with anaplastic tumours, the highest PSA levels and the lowest nuclear hTERT expression [15]. Earlier we showed that higher PSMA expression in higher pTNM stages and tumour grades may indicate PSMA as a good marker of biological aggressiveness suitable for patients' selection for more aggressive treatment [15].…”

“…For Ki-67 visualization we used a mouse-antiKi-67 monoclonal antibody (clone MIB-1, DAKO, 1:75), for GLUT-1 a rabbit monoclonal antibody (Millipore, 1:300), for CD34 a mouse anti-human monoclonal antibody (DAKO, 1:200), for VEGF a mouse anti-VEGF monoclonal antibody (DAKO, 1:25), for hTERT a rabbit polyclonal antibody to human telomerase (Novus Lab. Biologicals, Littleton, USA), (1:300) and for PSMA a mouse anti-human prostate specific membrane antigen (Novocastra, Newcastle, United Kingdom)(1:200), diluted in TRIS-buffered saline (pH = 7.4), as described earlier [14][15][16]. Proteins expression was presented as the number of positively staining cells (labelling index, LI) of nuclear (Ki-67, hTERT), membrane (PSMA, CD34), membrane/ cytoplasmic (GLUT-1) and cytoplasmic (VEGF) staining and MVD (CD34 immunoreactivity) as a mean vessel count per 1 mm 2 of tumour volume.…”

“…Earlier, we checked, based of pretreatment PSA level and immunohistochemical analysis of 6 proteins, if it is possible to select, before RP, more aggressive tumours for more aggressive treatment. We showed that increase of pathological tumour volume and tumour grade was associated with statistically significant increase in serum PSA, Ki-67 [14] and prostate specific membrane antigen (PSMA) expression [15], however, for telomerase enzyme activity (human telomerase reverse transcriptase, a catalytic subunit of telomerase, hTERT) the relation was opposite, indicating extranuclear telomere activity independent of telomere lengthening, and suggesting that it cannot be considered as a marker of malignancy [15]. However, significantly higher vascular endothelial growth factor (VEGF) was observed in pT3 and pT4 than in pT1 stage [16] indicating induction of angiogenesis and endothelial cell growth, as it is considered to be hypoxiainducible pro-angiogenic protein [17].…”

Telomerase in differentiated thyroid cancer: Promoter mutations, expression and localization

“…The relevance of the present study relies on the combination of genetic data with expression and localization studies. In particular, WB data have been obtained for the first time in human thyroid tumor tissues, whereas IHC analyses for TERT have been previously performed in several normal and neoplastic human tissues, with discordant results concerning the immunolocalization of hTERT, reported to be exclusively nuclear (Ito et al, 2005;Lantuejoul et al, 2004;Preto et al, 2004) or both cytoplasmic and nuclear (Gasinska et al, 2013;Kyo et al, 2003;Mavrommatis et al, 2005). The discrepancies are likely to be mainly due to the different antibodies (Ab) used, since around 15 different monoclonal and polyclonal Ab are available (Fabricius et al, 2009), which are directed against different portions of the protein.…”