Search

The main advantage of urinary biomarkers is their noninvasive character and the ability to detect multifocal prostate cancer (CaP). We have previously implemented a quadruplex assay of urinary markers into clinical practice (PCA3, AMACR, TRPM8 and MSMB with KLK3 normalization). In this study, we aimed to validate it in a larger cohort with serum PSA 2.5&ndash, 10 ng/mL and test other selected transcripts and clinical parameters, including the percentage of free prostate-specific antigen (PSA) (% free PSA) and inflammation. In the main cohort of 299 men, we tested the quadruplex transcripts. In a subset of 146 men, we analyzed additional transcripts (CD45, EPCAM, EZH2, Ki67, PA2G4, PSGR, RHOA and TBP). After a prostate massage, the urine was collected, RNA isolated from a cell sediment and qRT-PCR performed. Ct values of KLK3 (i.e., PSA) were strongly correlated with Ct values of other genes which play a role in CaP (i.e., PCA3, AMACR, TRPM8, MSMB and PSGR). AMACR, PCA3, TRPM8 and EZH2 mRNA expression, as well as % free PSA, were significantly different for BPH and CaP. The best combined model (% free PSA plus PCA3 and AMACR) achieved an AUC of 0.728 in the main cohort. In the subset of patients, the best AUC 0.753 was achieved for the combination of PCA3, % free PSA, EPCAM and PSGR. PCA3 mRNA was increased in patients with inflammation, however, this did not affect the stratification of patients indicated for prostate biopsy. In conclusion, the percentage of free PSA and urinary markers contribute to a more accurate indication for prostate biopsy.

The molecular basis for the transition of carcinoma of the prostate from androgen-dependent to androgen-independent growth is largely unknown. Currently for example, it is not clear whether the androgen-independent phenotype is a result of selection of a subgroup of genetically distinct prostate tumour cells which are already hormone-resistant or a genetic adaptation of prostate tumour cells to the hormone therapy itself. It has also been established that prostate tumour transformation is a result of homeostatic control defects, a line of thinking directed toward elucidating the apoptotic profile of prostate tumour cells that may be important in determining prognosis, response to therapy and illness progression. Main consideration in this part of rewiev is given to the role of tumour suppressor genes pRb and PTEN and also the natural inhibitors of cyclin dependent kinases - proteins p21(Waf1/Cip1) and p27(Kip1). Attention is also given to the role of FAS-mediated pathways in apoptosis induction.

Phosphatase and tension homology deleted on chromosome ten (PTEN) is a tumor suppressor gene with protein and lipid phosphatase activity frequently altered in several types of human cancers. Herein, we demonstrate the effect of transfected wild type (wt) PTEN and its mutants (mt) L57W, H123Y, G129R that have lost lipid and protein phosphatase activity; and G129E characterized by loss of only lipid phosphatase activity, during the cell cycle and on apoptosis. We characterized the expression of important proteins regulating the cell cycle and the PI3-K/PKB/Akt pathway, analyzed PTEN cellular localization, and performed PTEN mutation analysis in DU-145 and PC-3 cells. The transfection of wt PTEN and its mt with defective lipid phosphatase activity (G129E) inhibited S-phase entry of DU-145 and PC-3 cells. In DU-145 cells, transfection of wt PTEN induced apoptosis. An inverse expression of PTEN and phosphorylated PKB/Akt was observed. We did not find any mutations of the PTEN gene in either cell line. PTEN influenced the cell cycle of tested cells in a p53 and pRb independent manner, and the effect was cell type specific.

Intracellular levels of phosphorylation are regulated by the coordinated action of protein kinases and phosphatases. Disregulation of this balance can lead to cellular transformation. Here we review knowledge of the mechanisms of one protein phosphatase, the tumour suppressor PTEN/MMAC/TEP 1 apropos its role in tumorigenesis and signal transduction. PTEN plays an important role in the phosphatidyl-inositol-3-kinase (PI3-K) pathway by catalyzing degradation of phosphatidylinositol-(3,4,5)-triphosphate generated by PI3-K. This inhibits downstream targets mainly protein kinase B (PKB/Akt), cell survival and proliferation. PTEN contributes to cell cycle regulation by blockade of cells entering the S phase of the cell cycle, and by upregulation of p27(Kip1) which is recruited into the cyclin E/cdk2 complex. PTEN also modulates cell migration and motility by regulation of the extracellular signal-related kinase - mitogen activated protein kinase (ERK-MAPK) pathway and by dephosphorylation of focal adhesion kinase (FAK). We also emphasize the increasingly important role that PTEN has from an evolutionary point of view. A number of PTEN functions have been elucidated but more information is needed for utilization in clinical application and potential cancer therapy.

The molecular basis for the transition of carcinoma of the prostate from androgen-dependent to androgen-independent growth is largely unknown. Currently for example, it is not clear whether the androgen-independent phenotype is a result of selection of a subgroup of genetically distinct prostate tumour cells which are already hormone-resistant or a genetic adaptation of prostate tumour cells to the hormone therapy itself. It has also been established that prostate tumour transformation is a result of homeostatic control defects, a line of thinking directed toward elucidating the apoptotic profile of prostate tumour cells that may be important in determining prognosis, response to therapy and illness progression. Main consideration in this part of rewiev is given to the role of Bcl-2 and members of the Bcl-2 family, and tumour suppressor gene p53.