S. Terry

Prostate Cancer Antigen 3 Score Accurately Predicts Tumour Volume and Might Help in Selecting Prostate Cancer Patients for Active Surveillance

BACKGROUNDnThe optimal selection of prostate cancer (PCa) patients for active surveillance (AS) is currently being debated.nnnOBJECTIVEnTo assess the impact of urinary prostate cancer antigen 3 (PCA3) score as an AS criterion instead of and in addition to the current criteria.nnnDESIGN, SETTING, AND PARTICIPANTSnWe prospectively studied 106 consecutive low-risk PCa patients (prostate-specific antigen [PSA] ≤10 ng/ml, clinical stage T1c-T2a, and biopsy Gleason score 6) who underwent a PCA3 urine test before radical prostatectomy (RP).nnnMEASUREMENTSnPerformance of AS criteria (biopsy criteria, PCA3 score, PSA density, and magnetic resonance imaging [MRI] findings) was tested in predicting four prognostic pathologic findings in RP specimens: (1) pT3-4 disease; (2) overall unfavourable disease (OUD) defined by pT3-4 disease and/or pathologic primary Gleason pattern 4; (3) tumour volume <0.5 cm(3); and (4) insignificant PCa.nnnRESULTS AND LIMITATIONSnThe PCA3 score was strongly correlated with the tumour volume in a linear regression analysis (p<0.001, r=0.409). The risk of having a cancer ≥0.5 cm(3) and a significant PCa was increased three-fold in men with a PCA3 score of ≥25 compared with men with a PCA3 score of <25 with most AS biopsy criteria used. There was a trend towards higher PCA3 scores in patients with unfavourable and non-organ-confined disease and Gleason >6 cancers. In a multivariate analysis taking into account each AS criterion, a high PCA3 score (≥25) was an important predictive factor for tumour volume ≥0.5 cm(3) (odds ratio [OR]: 5.4; p=0.010) and significant PCa (OR: 12.7; p=0.003). Biopsy criteria and MRI findings were significantly associated with OUD (OR: 3.9 and 5.0, respectively; p=0.030 and p=0.025, respectively).nnnCONCLUSIONSnPCA3 score may be a useful marker to improve the selection for AS in addition to the current AS criteria. With a predictive cut-off of 25, PCA3 score is strongly indicative for tumour volume and insignificant PCa.

Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer.

Androgen action in prostate and prostate cancer cells is dependent upon the androgen receptor (AR) protein that transcriptionally regulates the expression of androgen‐dependent genes in the presence of a steroid ligand. Whereas the overall schema of androgen action mediated by this receptor protein appears to be relatively simple, androgen signaling is now known to be influenced by several other cell signal transduction pathways and here we review the evidence that the canonical Wnt signaling pathway also modulates androgen signaling at multiple levels. Wnt is a complex signaling pathway whose endpoint involves activation of transcription from LEF‐1/TCF transcription factors and it is known to be involved in the development and progression of numerous human epithelial tumors including prostate cancer. β‐catenin protein, a particularly critical molecular component of canonical Wnt signaling is now known to promote androgen signaling through its ability to bind to the AR protein in a ligand‐dependent fashion and to enhance the ability of liganded AR to activate transcription of androgen‐regulated genes. Under certain conditions, glycogen synthase kinase‐3β (GSK‐3β), a protein serine/threonine kinase that regulates β‐catenin degradation within the Wnt signaling pathway, can also phosphorylate AR and suppress its ability to activate transcription. Finally, it was recently found that the human AR gene itself is a target of LEF‐1/TCF‐mediated transcription and that AR mRNA is highly upregulated by activation of Wnt signaling in prostate cancer cells. Paradoxically, Wnt activation also appears to stimulate Akt activity promoting an MDM‐2‐mediated degradation process that reduces AR protein levels in Wnt‐stimulated prostate cancer cells. Collectively, this information indicates that the multifaceted nature of the interaction between the Wnt and the androgen signaling pathways likely has numerous consequences for the development, growth, and progression of prostate cancer. J. Cell. Biochem. 99: 402–410, 2006.

Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

β-Catenin, a component of the Wnt signaling pathway, is a coactivator of human androgen receptor (hAR) transcriptional activity. Here, we show that Wnt signaling also influences androgen-mediated signaling through its ability to regulate hAR mRNA and protein in prostate cancer (PCa) cells. Three functional LEF-1/TCF binding sites lie within the promoter of the hAR gene as shown by CHIP assays that captured β-catenin-bound chromatin from Wnt-activated LNCaP cells. Chimeric reporter vectors that use the hAR gene promoter to drive luciferase expression confirmed that these LEF-1/TCF binding elements are able to confer robust upregulation of luciferase expression when stimulated by Wnt-1 or by transfection with β-catenin and that dominant-negative TCF or mutations within the dominant TCF-binding element abrogated the response. Semi-quantitative and real time RT-PCR assays confirmed that Wnt activation upregulates hAR mRNA in PCa cells. In contrast, hAR protein expression was strongly suppressed by Wnt activation. The reduction of hAR protein is consistent with evidence that Wnt signaling increased phosphorylation of Akt and its downstream target, MDM2 that promotes degradation of hAR protein through a proteasomal pathway. These data indicate that the hAR gene is a direct target of LEF-1/TCF transcriptional regulation in PCa cells but also show that the expression of the hAR protein is suppressed by a degradation pathway regulated by cross-talk of Wnt to Akt that is likely mediated by Wnt-directed degradation of the B regulatory subunit of protein phosphatase, PP2A.

A Human- and Male-Specific Protocadherin that Acts through the Wnt Signaling Pathway to Induce Neuroendocrine Transdifferentiation of Prostate Cancer Cells

Protocadherin-PC (PCDH-PC) is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the beta-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear beta-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized beta-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against beta-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.

The NF-κB/IL-6 pathway in metastatic androgen-independent prostate cancer: new therapeutic approaches?

The nuclear factor of kappa beta (NF-κB) transcription factor regulates the transcription of numerous genes including that of interleukin 6 (IL-6). The IL-6 acts as an autocrine and paracrine growth factor of androgen-independent prostate cancer. An aberrant expression of the IL-6 gene and an increase in IL-6 expression are detected in bone metastatic and hormone-refractory prostate cancer. IL-6 has been suggested to have a crucial role in the resistance to chemotherapy or hormonal therapy involving apoptotic cell death. The NF-κB/IL-6 dependent pathways promote tumour-cell survival and in most situations protect cells against apoptotic stimuli. These data provide a rational framework for targeting NF-κB and IL-6 activity in novel biologically based therapies for aggressive and androgen independent prostate cancers.

Increased expression of class III β -tubulin in castration-resistant human prostate cancer

Background:Class III β-tubulin (βIII-tubulin) is expressed in tissues of neuronal lineage and also in several human malignancies, including non-small-cell lung carcinoma, breast and ovarian cancer. Overexpression of βIII-tubulin in these tumours is associated with an unfavourable outcome and resistance to taxane-based therapies. At present, βIII-tubulin expression remains largely uncharacterised in prostate cancer.Methods:In this report, we evaluated the expression of βIII-tubulin in 138 different human prostate tumour specimens by immunohistochemistry from patients with hormone-treated or hormone-untreated prostate cancer. βIII-tubulin expression was also examined in various prostatic cancer cell lines including in androgen-sensitive human prostate cancer cells, LNCaP, grown in androgen-depleted medium in 2D cultures or as tumour xenografts when the host mouse was castrated.Results:Whereas moderate-to-strong βIII-tubulin expression was detected in only 3 out of 74 (4%) hormone-naive tumour specimens obtained from patients who never received hormone therapy, 6 out of 24 tumour specimens (25%) from patients treated for 3 months with neoadjuvant hormone therapy and 24 out of 40 (60%) castration-resistant tumour specimens from chronic hormone-treated patients were found to express significant levels of βIII-tubulin. These findings were supported by in vitro and in vivo settings.Conclusion:Our data indicate that βIII-tubulin expression is augmented in prostate cancer by androgen ablation and that the expression of this β-tubulin isoform is associated with the progression of prostate cancer to the castration-resistant state, a stage largely responsible for mortality from prostate cancer.

Comparative expression of Hedgehog ligands at different stages of prostate carcinoma progression

Recent studies have revealed the potential involvement of Hedgehog (Hh) signalling in proliferation and invasive behaviour of prostate carcinoma (PCa). The aim of this study was to specify the role of Sonic Hh (Shh), Desert Hh (Dhh) and Indian Hh (Ihh) in the natural history of PCa. Hh ligands expression was compared in primary hormone‐naive PCa (HNPC), hormone‐treated PCa (HTPC) and hormone‐refractory PCa (HRPC), using immunohistochemistry. Shh and Dhh were expressed by both epithelial and stromal cells of prostate tissues. Ihh was only expressed by stromal cells. For the three ligands, mRNA and immunostaining were not correlated. In HNPC, Shh epithelial expression was significantly associated with high Gleason scores (p = 0.03), metastatic lymph nodes (p = 0.004) and Dhh epithelial staining was associated with high pT stages (p = 0.003), seminal vesicle invasion (p = 0.03) and bladder neck invasion (p = 0.0008). Negative Shh staining in stromal cells was associated with high Gleason scores (p = 0.015), high pT stages (p = 0.01) and bladder neck invasion (p = 0.04). Concomitant absence of Shh and Dhh expression in stromal cells was an independent prognostic parameter for biological recurrence on multivariate analysis (p = 0.01). Epithelial expression of Shh and Dhh was increased in HTPC compared to HNPC (p = 0.02 and p = 0.04). Interestingly, in vitro, transcript analysis also showed increased expression of these 2 Hh ligands when androgen‐sensitive LNCaP cells were maintained in androgen‐free medium mimicking hormonal therapy. Epithelial expression of Dhh was increased (p < 0.0001) in HRPC compared to HNPC, while stromal expression of Shh and Dhh was decreased (p < 0.0001). In conclusion, the Hh signalling pathway is associated with pejorative pathological parameters in HNPC and is up‐regulated in epithelial cells of HTPC and HRPC. Moreover, the lack of Hh molecules in stromal cells seems to be associated with invasive and hormone‐refractory behaviours and suggests specific changes in stromal–epithelial crosstalks during PCa progression. Copyright

Neuroendocrine differentiation in prostate cancer: From lab to bedside

Objectives: To discuss the current knowledge on induction, production, sustenance and promotion of neuroendocrine differentiation in human prostate cancer. Methods: Review of the literature using PubMed search and scientific journal publications. Results: Morphological evidence explains some functional relationship between neuroendocrine and neoplastic surrounding cells. Transdifferentiation phenomenon and new biochemical pathways could be included in the development of androgen independence and prostate cancer progression. Conclusion: Multiple evidence seems to confirm that a synergistic functional network between epithelial PSA secretory cells and neuroendocrine intraprostatic system is the main trigger for the induction and sustenance of neuroendocrine differentiation. The development of new antineoplastic molecules should consider the multiple interference of the intercellular network.

Left lobe of the prostate during clinical prostate cancer screening: the dark side of the gland for right-handed examiners

Background:The predictive value of the abnormality side during digital rectal examination (DRE) has never been studied, suggesting that physicians examined the left lobe of the gland as well as the right lobe. We aimed to assess the predictive value of the side of DRE abnormality for prostate cancer (PCa) detection and aggressiveness in right-handed urologists.Methods:An analysis of a prospective database was carried out that included all consecutive men undergoing prostate biopsies between 2001 and 2012. The main end point was the predictive value of the abnormality side during DRE for cancer detection in clinically suspicious unilateral T2 disease. The diagnostic performance of left- versus right-sided abnormality was also assessed in terms of sensitivity, specificity and negative/positive predictive values.Results:Overall, 308 patients had a suspicious unilateral clinical disease (detection rate 57.5%). The cancer detection rate was significantly higher in case of left-sided compared with right-sided clinical T2 stage (odds ratio 2.1). In case of left-sided disease, the number of positive cores, the rate of perineural invasion, the rate of primary grade 4 pattern and the percentage of cancer involvement per core were significantly higher compared with those reported for right-sided disease. The predictive value of abnormality laterality for cancer detection and aggressiveness remained statistically independent in multivariate models. The positive predictive value for cancer detection was 64.6 in case of suspicious left-sided disease versus 46.9 in case of right-sided disease.Conclusions:The risks of detecting PCa and aggressive disease on biopsy are significantly higher when DRE reveals a suspicious left-sided clinical disease as compared with right-sided disease. Right-handed physicians should be aware of this variance in diagnostic performance and potential underdetection of left-sided clinical disease, and should improve their examination of the left lobe of the gland by conducting longer exams or changing the patient’s position.