Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand in FGFR3-mutated Tumors.

BACKGROUND: Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. OBJECTIVE: To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and therapeutic outcomes. DESIGN, SETTING, AND PARTICIPANTS: Proteomic data were obtained for 40 MIBC and 23 NMIBC cases for which transcriptomic and genomic data were already available. Four BC-derived cell lines harboring FGFR3 alterations were tested with interventions. INTERVENTION: Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), second mitochondrial-derived activator of caspases mimetic (birinapant), pan-FGFR inhibitor (erdafitinib), and FGFR3 knockdown. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Proteomic groups from unsupervised analyses (uPGs) were characterized using clinicopathological, proteomic, genomic, transcriptomic, and pathway enrichment analyses. Additional enrichment analyses were performed for FGFR3-mutated tumors. Treatment effects on cell viability for FGFR3-altered cell lines were evaluated. Synergistic treatment effects were evaluated using the zero interaction potency model. RESULTS AND LIMITATIONS: Five uPGs, covering both NMIBC and MIBC, were identified and bore coarse-grained similarity to transcriptomic subtypes underlying common features of these different entities; uPG-E was associated with the Ta pathway and enriched in FGFR3 mutations. Our analyses also highlighted enrichment of proteins involved in apoptosis in FGFR3-mutated tumors, not captured through transcriptomics. Genetic and pharmacological inhibition demonstrated that FGFR3 activation regulates TRAIL receptor expression and sensitizes cells to TRAIL-mediated apoptosis, further increased by combination with birinapant. CONCLUSIONS: This proteogenomic study provides a comprehensive resource for investigating NMIBC and MIBC heterogeneity and highlights the potential of TRAIL-induced apoptosis as a treatment option for FGFR3-mutated bladder tumors, warranting a clinical investigation. PATIENT SUMMARY: We integrated proteomics, genomics, and transcriptomics to refine molecular classification of bladder cancer, which, combined with clinical and pathological classification, should lead to more appropriate management of patients. Moreover, we identified new biological processes altered in FGFR3-mutated tumors and showed that inducing apoptosis represents a new potential therapeutic option.

Synthesis of Multifunctional Polymersomes Prepared by Polymerization-Induced Self-Assembly.

Polymersomes are an exciting modality for drug delivery due to their structural similarity to biological cells and their ability to encapsulate both hydrophilic and hydrophobic drugs. In this regard, the current work aimed to develop multifunctional polymersomes, integrating dye (with hydrophobic Nile red and hydrophilic sulfo-cyanine5-NHS ester as model drugs) encapsulation, stimulus responsiveness, and surface-ligand modifications. Polymersomes constituting poly(N-2-hydroxypropylmethacrylamide)-b-poly(N-(2-(methylthio)ethyl)acrylamide) (PHPMAm-b-PMTEAM) are prepared by aqueous dispersion RAFT-mediated polymerization-induced self-assembly (PISA). The hydrophilic block lengths have an effect on the obtained morphologies, with short chain P(HPMAm)16 affording spheres and long chain P(HPMAm)43 yielding vesicles. This further induces different responses to H2O2, with spheres fragmenting and vesicles aggregating. Folic acid (FA) is successfully conjugated to the P(HPMAm)43, which self-assembles into FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes. The FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes entrap both hydrophobic Nile red (NR) and hydrophilic Cy5 dye. The NR-loaded FA-linked polymersomes exhibit a controlled release of the encapsulated NR dye when exposed to 10 mM H2O2. All the polymersomes formed are stable in human plasma and well-tolerated in MCF-7 breast cancer cells. These preliminary results demonstrate that, with simple and scalable chemistry, PISA offers access to different shapes and opens up the possibility of the one-pot synthesis of multicompartmental and responsive polymersomes.

Apalutamide Prevents SARS-CoV-2 Infection in Lung Epithelial Cells and in Human Nasal Epithelial Cells.

In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.

The Neuropilin-1/PKC axis promotes neuroendocrine differentiation and drug resistance of prostate cancer.

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is a multi-resistant variant of prostate cancer (PCa) that has become a major challenge in clinics. Understanding the neuroendocrine differentiation (NED) process at the molecular level is therefore critical to define therapeutic strategies that can prevent multi-drug resistance. METHODS: Using RNA expression profiling and immunohistochemistry, we have identified and characterised a gene expression signature associated with the emergence of NED in a large PCa cohort, including 169 hormone-naïve PCa (HNPC) and 48 castration-resistance PCa (CRPC) patients. In vitro and preclinical in vivo NED models were used to explore the cellular mechanism and to characterise the effects of castration on PCa progression. RESULTS: We show for the first time that Neuropilin-1 (NRP1) is a key component of NED in PCa cells. NRP1 is upregulated in response to androgen deprivation therapies (ADT) and elicits cell survival through induction of the PKC pathway. Downmodulation of either NRP1 protein expression or PKC activation suppresses NED, prevents tumour evolution toward castration resistance and increases the efficacy of docetaxel-based chemotherapy in preclinical models in vivo. CONCLUSIONS: This study reveals the NRP1/PKC axis as a promising therapeutic target for the prevention of neuroendocrine castration-resistant variants of PCa and indicates NRP1 as an early transitional biomarker.

Proviral role of human respiratory epithelial cell-derived small extracellular vesicles in SARS-CoV-2 infection.

Small Extracellular Vesicles (sEVs) are 50-200 nm in diameter vesicles delimited by a lipid bilayer, formed within the endosomal network or derived from the plasma membrane. They are secreted in various biological fluids, including airway nasal mucus. The goal of this work was to understand the role of sEVs present in the mucus (mu-sEVs) produced by human nasal epithelial cells (HNECs) in SARS-CoV-2 infection. We show that uninfected HNECs produce mu-sEVs containing SARS-CoV-2 receptor ACE2 and activated protease TMPRSS2. mu-sEVs cleave prefusion viral Spike proteins at the S1/S2 boundary, resulting in higher proportions of prefusion S proteins exposing their receptor binding domain in an 'open' conformation, thereby facilitating receptor binding at the cell surface. We show that the role of nasal mu-sEVs is to complete prefusion Spike priming performed by intracellular furin during viral egress from infected cells. This effect is mediated by vesicular TMPRSS2 activity, rendering SARS-CoV-2 virions prone to entry into target cells using the 'early', TMPRSS2-dependent pathway instead of the 'late', cathepsin-dependent route. These results indicate that prefusion Spike priming by mu-sEVs in the nasal cavity plays a role in viral tropism. They also show that nasal mucus does not protect from SARS-CoV-2 infection, but instead facilitates it.

Overexpression of Nucleolin and Associated Genes in Prostate Cancer.

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer death in men worldwide. If local PCa presents a favorable prognosis, available treatments for advanced PCa display limiting benefits due to therapeutic resistances. Nucleolin (NCL) is a ubiquitous protein involved in numerous cell processes, such as ribosome biogenesis, cell cycles, or angiogenesis. NCL is overexpressed in several tumor types in which it has been proposed as a diagnostic and prognostic biomarker. In PCa, NCL has mainly been studied as a target for new therapeutic agents. Nevertheless, little data are available concerning its expression in patient tissues. Here, we investigated the expression of NCL using a new cohort from Mondor Hospital and data from published cohorts. Results were then compared with NCL expression using in vitro models. NCL was overexpressed in PCa tissues compared to the normal tissues, but no prognostic values were demonstrated. Nine genes were highly co-expressed with NCL in patient tissues and tumor prostate cell lines. Our data demonstrate that NCL is an interesting diagnostic biomarker and propose a signature of genes co-expressed with NCL.

Urinary extracellular vesicles contain mature transcriptome enriched in circular and long noncoding RNAs with functional significance in prostate cancer.

Long noncoding (lnc)RNAs modulate gene expression alongside presenting unexpected source of neoantigens. Despite their immense interest, their ability to be transferred and control adjacent cells is unknown. Extracellular Vesicles (EVs) offer a protective environment for nucleic acids, with pro and antitumourigenic functions by controlling the immune response. In contrast to extracellular nonvesicular RNA, few studies have addressed the full RNA content within human fluids' EVs and have compared them with their tissue of origin. Here, we performed Total RNA-Sequencing on six Formalin-Fixed-Paraffin-Embedded (FFPE) prostate cancer (PCa) tumour tissues and their paired urinary (u)EVs to provide the first whole transcriptome comparison from the same patients. UEVs contain simplified transcriptome with intron-free cytoplasmic transcripts and enriched lnc/circular (circ)RNAs, strikingly common to an independent 20 patients' urinary cohort. Our full cellular and EVs transcriptome comparison within three PCa cell lines identified a set of overlapping 14 uEV-circRNAs characterized as essential for prostate cell proliferation in vitro and 28 uEV-lncRNAs belonging to the cancer-related lncRNA census (CLC2). In addition, we found 15 uEV-lncRNAs, predicted to encode 768 high-affinity neoantigens, and for which three of the encoded-ORF produced detectable unmodified peptides by mass spectrometry. Our dual analysis of EVs-lnc/circRNAs both in urines' and in vitro's EVs provides a fundamental resource for future uEV-lnc/circRNAs phenotypic characterization involved in PCa.

Extracellular Vesicles in Advanced Prostate Cancer: Tools to Predict and Thwart Therapeutic Resistance.

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. At first, advanced PCa is treated by androgen deprivation therapy with a good initial response. Nevertheless, recurrences occur, leading to Castrate-Resistance Prostate Cancer (CRPC). During the last decade, new therapies based on inhibition of the androgen receptor pathway or taxane chemotherapies have been used to treat CRPC patients leading to an increase in overall survival, but the occurrence of resistances limits their benefits. Numerous studies have demonstrated the implication of extracellular vesicles (EVs) in different cancer cellular mechanisms. Thus, the possibility to isolate and explore EVs produced by tumor cells in plasma/sera represents an important opportunity for the deciphering of those mechanisms and the discovery of biomarkers. Herein, we summarized the role of EVs in therapeutic resistance of advanced prostate cancer and their use to find biomarkers able to predict these resistances.

Men1 disruption in Nkx3.1-deficient mice results in ARlow/CD44+ microinvasive carcinoma development with the dysregulated AR pathway.

Dysregulated androgen receptor (AR) plays a crucial role in prostate cancer (PCa) development, though further factors involved in its regulation remain to be identified. Recently, paradoxical results were reported on the implication of the MEN1 gene in PCa. To dissect its role in prostate luminal cells, we generated a mouse model with inducible Men1 disruption in Nkx3.1-deficient mice in which mouse prostatic intraepithelial neoplasia (mPIN) occur. Prostate glands from mutant and control mice were analyzed pathologically and molecularly; cellular and molecular analyses were carried out in PCa cell lines after MEN1 knockdown (KD) by siRNA. Double-mutant mice developed accelerated mPIN and later displayed microinvasive adenocarcinoma. Markedly, early-stage lesions exhibited a decreased expression of AR and its target genes, accompanied by reduced CK18 and E-cadherin expression, suggesting a shift from a luminal to a dedifferentiated epithelial phenotype. Intriguingly, over 60% of menin-deficient cells expressed CD44 at a later stage. Furthermore, MEN1 KD led to the increase in CD44 expression in PC3 cells re-expressing AR. Menin bound to the proximal AR promoter and regulated AR transcription via the H3K4me3 histone mark. Interestingly, the cell proliferation of AR-dependent cells (LNCaP, 22Rv1, and VCaP), but not of AR-independent cells (DU145, PC3), responded strongly to MEN1 silencing. Finally, menin expression was found reduced in some human PCa. These findings highlight the regulation of the AR promoter by menin and the crosstalk between menin and the AR pathway. Our data could be useful for better understanding the increasingly reported AR-negative/NE-negative subtype of PCa and the mechanisms underlying its development.

Erratum: CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities.

[This corrects the article DOI: 10.18632/oncotarget.2740.].

Extracellular vesicles released by mesenchymal-like prostate carcinoma cells modulate EMT state of recipient epithelial-like carcinoma cells through regulation of AR signaling.

Extracellular vesicles released from cancer cells may play an important role in cancer progression by shuttling oncogenic information into recipient cells. However, our knowledge is still fragmentary and there remain numerous questions regarding the mechanisms at play and the functional consequences of these interactions. We have recently established a mesenchymal-like prostate cancer cell line (22Rv1/CR-1; Mes-PCa). In this study, we assessed the effects of the extracellular vesicles released by these cells on recipient androgen-dependent epithelial VCaP prostate cancer cells. Mes-PCa derived vesicles were found to promote mesenchymal features in the recipient epithelial-like prostate cancer cells. This transformation was accompanied by a modulation of androgen receptor signaling and activation of TGFß signaling pathway. Moreover, recipient cells acquiring mesenchymal traits displayed enhanced migratory and invasive features as well as increased resistance to the androgen receptor antagonist, enzalutamide. Our results suggest a previously unappreciated role for Mes-PCa secreted vesicles in cancer promotion by transferring cell-mediated signals and promoting phenotypic changes in recipient prostate cancer cells.

Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer.

Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.

Evidence of estrone-sulfate uptake modification in young and middle-aged rat prostate.

High plasma exposure to estrogens is often associated with prostate cancer. Reducing this phenomenon may present therapeutic benefits. The involvement of estrone sulphate (E1S), the most abundant circulating estrogen in men, has been partially studied in this age-related pathology. To investigate the consequences of plasma E1S overload on blood and prostate sex steroid levels and inflammatory tissue responses, young and middle-aged male rats were treated with E1S with or without steroid sulfatase (STS) inhibitor STX64 for 21 consecutive days. A plasma and prostate tissue steroid profile was determined. STS activity, mRNA expression of E1S organic anion transporting polypeptides (slco1a2, slco2b1, slco4a1) and pro-inflammatory cytokines (Il1-beta, Il6, TNF-alpha) were evaluated in prostate tissue according to age and treatment group. A significant correlation between plasma and prostate steroid levels related to hormone treatment was observed in all rat age groups. However, while the E1S level in prostate tissue increased in middle-aged treated rats (p<0.0001), no significant variation was observed in young treated rats. The protective effect of STX64 during E1S infusion was observed by the maintenance of low free estrogen concentrations in both plasma and tissue. However, this protection was not associated with mRNA expression stability of pro-inflammatory cytokines in older rat prostate. These results suggest that E1S uptake in rat prostate cells increases during aging. Therefore, if a similar phenomenon existed in men, preventively reducing the STS activity could be of interest to limit uptake of estrogens in prostate when high E1S plasma level is assayed.

Clinical value of ERG, TFF3, and SPINK1 for molecular subtyping of prostate cancer.

BACKGROUND: In view of the marked molecular heterogeneity of prostate cancer (PCa), clinical and pathologic parameters alone may be unreliable for predicting disease outcomes after surgical intervention. The development of biomarkers may be helpful to estimate tumor heterogeneity and stratify patients in terms of their risk of progression. Levels of v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), trefoil factor 3 (TFF3), and serine peptidase inhibitor, Kazal type 1 (SPINK1) are commonly elevated in PCa, but it is unclear whether the evaluation of these 3 markers can help to discriminate patients who will have different clinical outcomes. The authors investigated whether assessment of ERG, TFF3, and SPINK1 expression could help to define clinically relevant, distinct subsets of patients with PCa. METHODS: The cohort consisted of 279 men with PCa who underwent radical prostatectomy at Henri Mondor Hospital. Expression levels of ERG, TFF3, and SPINK1 were evaluated immunohistochemically in the prostatectomy specimens. Potential associations of ERG, TFF3, and SPINK1 with age, prostate-specific antigen (PSA), tumor stage, Gleason score, and biochemical recurrence, defined by PSA failure, were investigated. RESULTS: Although prognostic significance was not observed for ERG or TFF3, an exclusive pattern of expression was demonstrated for TFF3 and ERG. SPINK1 expression was observed exclusively in a subgroup of cancers that expressed TFF3 (41 of 175 tumors). Moreover, SPINK1 positivity was identified as predictive of biochemical recurrence in univariate (P = .0009) and multivariate (P = .0003) analyses. CONCLUSIONS: The current results suggest that ERG and TFF3 characterize 2 distinct subsets of PCa, with a more aggressive subgroup of TFF3-expressing tumors that express SPINK1. Together, these findings support a rationale of screening for these biomarkers for prognostic purposes and molecular subtyping of the disease.

CRIPTO overexpression promotes mesenchymal differentiation in prostate carcinoma cells through parallel regulation of AKT and FGFR activities.

Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors.

Prospective evaluation of an extended 21-core biopsy scheme as initial prostate cancer diagnostic strategy.

BACKGROUND: The debate on the optimal number of prostate biopsy core samples that should be taken as an initial strategy is open. OBJECTIVE: To prospectively evaluate the diagnostic yield of a 21-core biopsy protocol as an initial strategy for prostate cancer (PCa) detection. DESIGN, SETTING, AND PARTICIPANTS: During 10 yr, 2753 consecutive patients underwent a 21-core biopsy scheme for their first set of biopsy specimens. INTERVENTION: All patients underwent a standardized 21-core protocol with cores mapped for location. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The PCa detection rate of each biopsy scheme (6, 12, or 21 cores) was compared using a McNemar test. Predictive factors of the diagnostic yield achieved by a 21-core scheme were studied using logistic regression analyses. RESULTS AND LIMITATIONS: PCa detection rates using 6 sextant biopsies, 12 cores, and 21 cores were 32.5%, 40.4%, and 43.3%, respectively. The 12-core procedure improved the cancer detection rate by 19.4% (p=0.004), and the 21-biopsy scheme improved the rate by 6.7% overall (p<0.001). The six far lateral cores were the most efficient in terms of detection rate. The diagnostic yield of the 21-core protocol was >10% in prostates with volume >70 ml, in men with a prostate-specific antigen level<4 ng/ml, with a prostate-specific antigen density (PSAD) <0.20 ng/ml per gram. A PSAD <0.20 ng/ml per gram was the strongest independent predictive factor of the diagnostic yield offered by the 21-core scheme (p<0.001). The 21-core protocol significantly increased the rate of PCa eligible for active surveillance (62.5% vs 48.4%; p=0.036) than those detected by a 12-core scheme without statistically increasing the rate of insignificant PCa (p=0.503). CONCLUSIONS: A 21-core biopsy scheme improves significantly the PCa detection rate compared with a 12-core protocol. We identified a cut-off PSAD (0.20 ng/ml per gram) below which an extended 21-core scheme might be systematically proposed to significantly improve the overall detection rate without increasing the rate of detected insignificant PCa.

Lipidosterolic extract of serenoa repens modulates the expression of inflammation related-genes in benign prostatic hyperplasia epithelial and stromal cells.

Despite the high prevalence of histological Benign Prostatic Hypeplasia (BPH) in elderly men, little is known regarding the molecular mechanisms and networks underlying the development and progression of the disease. Here, we explored the effects of a phytotherapeutic agent, Lipidosterolic extract of the dwarf palm plant Serenoa repens (LSESr), on the mRNA gene expression profiles of two representative models of BPH, BPH1 cell line and primary stromal cells derived from BPH. Treatment of these cells with LSESr significantly altered gene expression patterns as assessed by comparative gene expression profiling on gene chip arrays. The expression changes were manifested three hours following in vitro administration of LSESr, suggesting a rapid action for this compound. Among the genes most consistently affected by LSESr treatment, we found numerous genes that were categorized as part of proliferative, apoptotic, and inflammatory pathways. Validation studies using quantitative real-time PCR confirmed the deregulation of genes known to exhibit key roles in these biological processes including IL1B, IL1A, CXCL6, IL1R1, PTGS2, ALOX5, GAS1, PHLDA1, IL6, IL8, NFkBIZ, NFKB1, TFRC, JUN, CDKN1B, and ERBB3. Subsequent analyses also indicated that LSESr treatment can impede the stimulatory effects of certain proinflammatory cytokines such as IL6, IL17, and IL15 in these cells. These results suggest that LSESr may be useful to treat BPH that manifest inflammation characteristics. This also supports a role for inflammation in BPH presumably by mediating the balance between apoptosis and proliferation.

Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer.

Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance.

Risk of repeat biopsy and prostate cancer detection after an initial extended negative biopsy: longitudinal follow-up from a prospective trial.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Even after a negative set of prostate biopsies, the risk of undetected prostate cancer remains clinically significant. Predictive markers of such a risk are undefined. In addition to PSA and PSAD, low prostate volume and %fPSA are interesting time-varying risk factors and are relevant in biopsy decision-making. OBJECTIVE: To assess prospectively the time-varying risk of rebiopsy and of prostate cancer (PCa) detection after an initial negative biopsy protocol. PATIENTS AND METHODS: Over a period of 10 years, 1995 consecutive patients with initially negative biopsies were followed. Rebiopsies were performed in patients who had a persistent suspicion of PCa. Predictive factors for rebiopsy and for PCa detection were tested using univariate, multivariate and time-dependent models. RESULTS: A total of 617 men (31%) underwent at least one rebiopsy after a mean follow-up of 19 months. PCa detection rates during second, third, and fourth sets of biopsies were 16.7, 16.9 and 12.5%, respectively. The overall rate of detected PCa was 7.0%. The 5-year rebiopsy-free and PCa-free survival rates were 65.9 and 92.5%, respectively. Indications for rebiopsy were more frequently reported in patients having a high prostate-specific antigen (PSA) level (P = 0.006) or a high PSA density (PSAD; P < 0.001) and in younger patients (P = 0.008). The risk of PCa on rebiopsies was not correlated with age, but significantly increased more than twofold in cases of PSA >6 ng/mL, PSAD >0.15 ng/mL/g, free-to-total PSA ratio (%fPSA) <15, and/or prostate volume <50 mL. Time-dependent analyses were in line with these findings. The main study limitation was the lack of control of the absence of PCa and PSA kinetics in men not rebiopsied. CONCLUSIONS: The overall risk of detected PCa after an initial negative biopsy was low. In addition to PSA and PSAD, which are well-used in rebiopsy indications, low prostate volume and %fPSA are interesting time-varying risk factors for PCa on rebiopsy and could be relevant in biopsy decision-making.