High-grade Prostate Carcinoma Research Articles

Efficacy of Magnetic Resonance Imaging/ Ultrasound-Guided Target Biopsy in Detecting Clinically Significant Prostate Cancer

Introduction: Prostate cancer remains a formidable health challenge, demanding diagnostic strategies that balance accuracy and invasiveness. To enhance early detection and accurate risk stratification, various diagnostic methods have been developed. Magnetic Resonance Imaging (MRI) is considered the standard imaging modality for the detection and localization of prostate cancer. Prostate Imaging Reporting and Data System (PI-RADS) is a standardized system that assigns scores to suspicious lesions based on MRI findings. This system helps distinguish the likelihood of clinically significant prostate cancer (CsPCa), guiding clinicians in decision-making. Magnetic Resonance Imaging/Ultrasound-Guided fusion target biopsy (MRI/US) has emerged as a promising technique in diagnosis of prostate cancer, fusing advanced imaging modalities with real-time ultrasound guidance. Material and methods: A retrospective study was carried out from January 2019 to June 2023. Patients included in the study had elevated tPSA levels and underwent MRI of the prostate. MRI findings were characterized on the basis of PIRADS grading. All patients with a score equal or higher than PI-RADS 3 underwent MRI/US-guided fusion target biopsy. The histopathological results were retrospectively analyzed. Results: 375 patients were included in the study. The mean age of the patients in our study was 67.8 ± 8.2 years. tPSA levels ranged 17.21 ± 31.36 ng/ml and mean prostate volume was 52.67 ± 19.6 cc. 87.5 % of the patients had a negative rectal digital exam and 12.5 % had a positive one. 29.4 % of the MRI exams had lesions scored as PI-RADS 3, 47.1 % – as PI-RADS 4 and 22.5 % as PI-RADS 5. 67.1 % of detected lesions were located in the peripheral zone, 26.5 % – in the transitional zone, 4.5 % in the anterior zone and 1.6% of the lesions were apical. 35.7 % patients had a negative for carcinoma histopathological result and were diagnosed with benign prostatic hyperplasia; 39.2 % of the histopathological results were classified as low grade prostate carcinoma and 29.5 % as high grade prostate carcinoma. All results were classified according to the Gleason score. 30.1 % were Gleason score 3+3=6, 25.1 % were Gleason 7 (13.1 % as Gleason 3+4 and 12 % as 4+3), 5.1 % were Gleason 8 and 5.6 % were Gleason 4+5 or 5+4. Conclusion: The integration of MRI/US fusion biopsy into the diagnostic pathway has significantly improved the detection and characterization of clinically significant prostate cancer. This approach enables more personalized and precise management strategies for patients with prostate cancer.

A high high-density lipoprotein level is associated with Gleason score upgrade in Chinese patients diagnosed with high-grade prostate carcinoma

BackgroundThe high incidence of Gleason score upgrading (GSU) made urologists underestimate the disease, leading to the inaccurate therapeutic decision. The study aimed to explore relevant laboratory examination evidence associated with GSU.MethodsPatients diagnosed with prostate carcinoma undergoing radical prostatectomy in our center between January 2015 and December 2019 were included in this retrospective study. Patients were divided into GSU and NGSU groups according to the occurrence of GSU. Medical records were reviewed and analyzed between groups.ResultsA total of 130 patients were enrolled, including 52 patients diagnosed with GS = 6 (20 NGSU and 32 GSU) and 78 patients with GS = 7 (36 NGSU and 42 GSU). No significant differences in demographic characteristics were found between groups. An increased neutrophil count (OR = 1.326, 95% CI = 1.005–1.748) and a decreased percentage of lymphocytes (OR = 0.951, 95% CI = 0.904–1) were associated with GSU in the GS = 6 group, whereas a high HDL level (OR = 7.735, 95% CI = 0.998–59.957) was associated with GSU in GS = 7 group. Preoperative high neutrophile count and low lymphocyte percentage were correlated with GSU in patients with low-grade prostate cancer. In contrast, high HDL level was associated with GSU in patients with high-grade prostate cancer.ConclusionsThese laboratory examination data could provide urologists with information before making a therapeutic protocol.

Correlation of multiparametric MRI with histopathological grade of peripheral zone prostate carcinoma.

Prostatic cancer is the second most common malignant tumor in men. Preoperative grading of prostate cancer is important for its management. Our objective is to compare individual and combined detection rates of T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI), and magnetic resonance spectroscopy (MRS) for prostate cancer with histopathological diagnosis as its golden standard. Forty-four patients with positive digital rectal examination (DRE) findings and elevated prostate specific antigen (PSA), underwent multiparametric MRI (Mp-MRI). T2WI, DWI, DCE-MRI and MRS were done in all the patients. Cognitive magnetic resonance-transrectal ultrasound (MR-TRUS) fusion biopsy was done in all the patients. Sensitivity and specificity of T2WI, DWI, DCE-MRI, and Prostate Imaging - Reporting and Data System PIRADS version 2 was obtained. Apparent diffusion coefficient (ADC) value and choline/citrate ratio were obtained for each lesion and correlated with histopathological grade. The mean age of the patients was 68.7 ± 10.1 years, and the mean serum PSA level was 58.1 ± 22.4 ng/dL. Of the 38 lesions in peripheral zone, 33 (87%) had histopathologically proven prostate cancer. T2WI had a sensitivity and specificity of 75.8% and 80% and DWI had a sensitivity and specificity of 90.9% and 80%, respectively, for detection of malignant prostatic lesion. The mean ADC values for prostate cancer, prostatitis, and normal prostatic parenchyma were 0.702 ± 0.094 × 10-3 mm2/sec, 0.959 ± 0.171 × 10-3 mm2/sec, and 1.31 ± 0.223 × 10-3 mm2/sec, respectively. Type 3 curve has lower sensitivity (45.5%) but high specificity (80%) for diagnosing prostate cancer. DWI can be useful to differentiate benign from malignant prostatic lesions, and low-grade from high-grade prostate carcinoma. ADC value has a positive correlation with histopathological grade of prostate cancer.

JAG1 Intracellular Domain Enhances AR Expression and Signaling and Promotes Stem-like Properties in Prostate Cancer Cells.

JAG1 expression is upregulated in high-grade metastatic prostate carcinomas and associated with poor disease-free survival of patients with prostate cancer. Intriguingly, all JAG1-positive prostate carcinomas express JICD although JICD function in prostate cancer (PC) cells is poorly understood. In this study, we found that JICD overexpression increased the expression levels of AR, especially AR-Vs, in PC cell lines and significantly enhanced androgen-independent and androgen-dependent function of ARs. Interestingly, JICD overexpression upregulated the expression of the PCSC marker CD133 in PC cells as the expression of self-renewal markers; namely, NANOG and OCT3/4 increased. In addition, JICD overexpression highly increased the expression of anti-apoptotic BCL-XL protein, while it little affected the expression of apoptotic BIM protein. In 3D cell culture assays, the spheres formed by JICD-overexpressing PC subline cells (C4-2 and CWR22Rv1) were larger than those formed by control (EV) subline cells with undifferentiated morphology. Although JICD overexpression caused quiescence in cell proliferation, it activated the expression of components in PCSC-related signaling pathways, increased PC cell mobility, and promoted in vivo xenograft mouse tumorigenesis. Therefore, JICD may play a crucial role in enhancing androgen independence and promoting stem-like properties in PC cells and should be considered a novel target for CRPC and PCSC diagnostic therapy.

Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series.

Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined. We reviewed institutional databases for in-house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post- androgen-deprivation therapy (ADT), and 33 post-RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small-cell/high-grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high-grade PCa and small-cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet-like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single-cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with 'Paneth cell-like' change: all primary. In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small-cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high-grade PCa + small-cell/HGNEC and 'Paneth cell-like' change occur in primary disease.

High eEF1A1 Protein Levels Mark Aggressive Prostate Cancers and the In Vitro Targeting of eEF1A1 Reveals the eEF1A1-actin Complex as a New Potential Target for Therapy.

Although the eukaryotic elongation factor eEF1A1 plays a role in various tumours, there is little information on its prognosis/therapeutic value in prostate carcinoma. In high-grade and castration-resistant prostate carcinoma (CRPC), the identification of novel therapeutic markers/targets remains a priority. The expression of eEF1A1 protein was determined in formalin-fixed, paraffin-embedded prostate cancer and hyperplasia tissue by IHC. The role of eEF1A1 was investigated in a cellular model using a DNA aptamer (GT75) we previously developed. We used the aggressive CRPC cancer PC-3 and non-tumourigenic PZHPV-7 lines. Cytotoxicity was measured by the MTS assay and eEF1A1 protein levels by in-cell Western assays. The mRNA levels of eEF1A1 were measured by qPCR and ddPCR. Higher expression of eEF1A1 was found in Gleason 7–8 compared with 4–6 tissues (Gleason ≥ 7, 87% versus Gleason ≤ 6, 54%; p = 0.033). Patients with a high expression of eEF1A1 had a worse clinical outcome. In PC-3, but not in PZHPV-7, GT75 decreased cell viability and increased autophagy and cell detachment. In PC-3 cells, but not in PZHPV-7, GT75 mainly co-localised with the fraction of eEF1A1 bound to actin. Overexpression of the eEF1A1 protein can identify aggressive forms of prostate cancer. The targeting of eEF1A1 by GT75 impaired cell viability in PC-3 cancer cells but not in PZHPV-7 non-tumourigenic cells, indicating a specific role for the protein in cancer survival. The eEF1A1–actin complexes appear to be critical for the viability of PC-3 cancer cells, suggesting that eEF1A1 may be an attractive target for therapeutic strategies in advanced forms of prostate cancer.

Clinicopathological Significance of Exosomal Proteins CD9 and CD63 and DNA Mismatch Repair Proteins in Prostate Adenocarcinoma and Benign Hyperplasia.

Introduction. Recently, it has been shown that exosomal biomarkers and DNA mismatch repair proteins (MMR) could play an important role in cancer risk stratification and prognosis assessment. The gold standard for prostate carcinoma (PCa) diagnosis is biopsy and histopathological examination. Thus, the complex evaluation of exosomal and MMR proteins could be beneficial for prostate cancer risk stratification and diagnostics. The aim of the current study was to evaluate and compare the expression of exosomal proteins CD9 and CD63 and MMR proteins in the tissue of patients with prostate benign hyperplasia (BPH) and PCa. Methods. The study was retrospective. Altogether, 92 patients with PCa and 20 patients with BPH (control group) were enrolled in the study. Exosomal and MMR protein expression was analyzed by immunohistochemistry (IHC). The follow-up for each PCa patient in our study lasted till disease progression and/or a maximum of 5 years. Results. Low-grade PCa was observed in 56 patients and high-grade PCa in 36 patients. CD63 expression was significantly higher in patients with high-grade PCa compared to those with low-grade PCa. CD9 expression was significantly downregulated in PCa patients compared to the control group. MMR protein expression deficiency was observed in 10 PCa patients. MMR proteins were maintained in all cases of BPH. The study found a negative correlation between MMR protein loss and PCa ISUP grade groups. Progression-free survival (PFS) in patients with MMR deficiency was significantly shorter than in patients with maintained MMR expression. Conclusions. CD9 protein expression was downregulated in PCa, compared to BPH, while CD63 protein expression was upregulated in high-grade PCa but downregulated in low-grade PCa. CD63 protein upregulation, CD9 downregulation, and loss of MMR protein characterized the shorter PFS of high-grade PCa patients. CD9, CD63, and MMR could be the routine immunohistochemical biomarkers for the diagnosis and risk stratification of PCa.

High Inter- and Intratumoral Variability of Ki67 Labeling Index in Newly Diagnosed Prostate Cancer with High Gleason Scores

Background: The majority of studies investigating the role of Ki67 labeling index (LI) in prostate carcinoma (PC) focused on localized PC treated radically, where Ki67 LI is regarded as a prognostic marker. The relevance of Ki67 in advanced PC remains largely unexplored. While Gleason score is still one of the best indicators of clinical outcomes in PC, differences in progression-free survival and overall survival in patients with high Gleason scores suggest that additional factors are involved in tumor progression. Understanding the underlying mechanisms could help to optimize treatment strategies for an individual patient. Here, we aimed to determine the inter- and intratumoral distribution of Ki67 LI in patients with PC with high Gleason scores and to correlate Ki67 LI with the status of ERG, PTEN, and Bcl-2. Methods: Immunohistochemistry for Ki67, ERG, PTEN, and Bcl-2 was performed on core needle biopsies from 112 patients with newly diagnosed PC Gleason score 8, 9, and 10. Results: Using a cutoff of ≥10%, 17/112 cases (15%) had a homogeneously low and 95/112 cases (85%) a high Ki67 LI. 41% of cases showed intratumoral heterogeneity containing areas with low and high proliferation. There was no association between Ki67 LI and ERG, PTEN, or Bcl-2 status. Conclusions: Our data demonstrate major inter- and intratumoral variability of Ki67 LI in high-grade PC with a surprisingly low Ki67 LI in a subset of cases. Further studies are necessary to explore the molecular basis and potential clinical implications of a paradoxically low proliferation rate in high-grade PC.

Prostatic Carcinoma With Aberrant Expression of p63: A Case Report and Review of the Literature

Abstract Prostatic carcinoma with aberrant expression of p63 is a rare variant of prostate cancer, which represents a potential diagnostic pitfall, as it may be easily confused with either benign prostatic glands or high-grade prostatic carcinoma. In studies of radical prostatectomies, these tumors appear to behave like low-grade carcinomas despite frequent poorly formed architecture. We report a case of prostatic carcinoma with aberrant expression of p63 with a review of the literature and helpful features in the differential diagnosis of this entity.

Intraductal carcinoma of the prostate in the absence of high-grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations.

Intraductal carcinoma of the prostate (IDC-P) most often appears associated with high-grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC-P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low-grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC-P (iIDC-P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC-P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC-P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC-P alterations were similar to those previously described in high-grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC-P (BRCA2, CHEK2, CDK12) and other known PCa-associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC-P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC-P and the low-grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC-P in four. Despite a CNA profile similar to conventional PCa, iIDC-P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC-P is not likely a precursor to the associated low-grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate.

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.

Morphological and Immunohistochemical Biomarkers in Distinguishing Prostate Carcinoma and Urothelial Carcinoma: A Comprehensive Review.

The differential diagnosis between high-grade prostate carcinoma and infiltrating urothelial carcinoma (UC) in transurethral resection prostate specimens as well as cystoprostatectomy specimens may often be challenging due to morphologic and clinical overlap of the 2 entities. Such distinction has critical therapeutic and staging consequences, yet it is hampered by both issues in morphology and by the low accuracy rates of single immunohistochemical markers, as reported in literature. This review aims to provide a comprehensive analysis of the available morphological and immunohistochemical parameters, which may allow to discriminate between prostate carcinoma and urothelial carcinoma in the proper clinical context and to discuss their diagnostic applications in daily practice.

Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin?

The current World Health Organization classification categorises high-grade neuroendocrine (NE) carcinomas of the prostate into small-cell and large-cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features. Five cases of high-grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate-specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small-cell or large-cell NE carcinoma were absent. As compared with conventional high-grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate-specific acid phosphatase, combined with diffuse or confluent/non-focal positivity for chromogranin-A and synaptophysin. Two hormone-naive cases showed a clinical response to androgen deprivation therapy. This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.

A specific spectral signature of serum and plasma-derived extracellular vesicles for cancer screening

In cancer, extracellular vesicles (EV) contribute to tumor progression by regulating local and systemic effects. Being released into body fluids, EV may be used in nanomedicine as a valuable source for diagnostic biomarkers. In this work, infrared and Raman spectroscopy were used for comprehensive comparative analysis of cancer versus non-cancer EV and patient screening. Two different EV fractions enriched in exosomes and microvesicles were isolated by differential centrifugation from serum and plasma of cancer and non-cancer patients and from serum and plasma of a healthy donor. The EV fractions were then subjected to drop-coating deposition and drying on calcium fluoride substrates. Reduction of alpha-helix-rich proteins and enhancement of beta-sheet-rich proteins as a cancer-specific blood EV signature was determined, and subsequently this feature was applied for a pilot study aiming to detect prostate cancer in a test cohort of patients with high-grade prostate carcinoma and benign hypoplasia.

Prostate-specific membrane antigen (PSMA) assembles a macromolecular complex regulating growth and survival of prostate cancer cells "in vitro" and correlating with progression "in vivo".

The expression of Prostate Specific-Membrane Antigen (PSMA) increases in high-grade prostate carcinoma envisaging a role in growth and progression. We show here that clustering PSMA at LNCaP or PC3-PSMA cell membrane activates AKT and MAPK pathways thus promoting proliferation and survival. PSMA activity was dependent on the assembly of a macromolecular complex including filamin A, beta1 integrin, p130CAS, c-Src and EGFR. Within this complex beta1 integrin became activated thereby inducing a c-Src-dependent EGFR phosphorylation at Y1086 and Y1173 EGF-independent residues. Silencing or blocking experiments with drugs demonstrated that all the complex components were required for full PSMA-dependent promotion of cell growth and/or survival in 3D culture, but that p130CAS and EGFR exerted a major role. All PSMA complex components were found assembled in multiple samples of two high-grade prostate carcinomas and associated with EGFR phosphorylation at Y1086. The expression of p130CAS and pEGFRY1086 was thus analysed by tissue micro array in 16 castration-resistant prostate carcinomas selected from 309 carcinomas and stratified from GS 3+4 to GS 5+5. Patients with Gleason Score ≤5 resulted negative whereas those with GS≥5 expressed p130CAS and pEGFRY1086 in 75% and 60% of the cases, respectively.Collectively, our results demonstrate for the first time that PSMA recruits a functionally active complex which is present in high-grade patients. In addition, two components of this complex, p130CAS and the novel pEGFRY1086, correlate with progression in castration-resistant patients and could be therefore useful in therapeutic or surveillance strategies of these patients.

Abstract 4577: Fibroblast growth factor receptor-4 (FGFR-4) as a novel therapeutic target for pancreatic cancer

Abstract The fibroblast growth factor receptor (FGFR) family plays crucial roles in development, tissue repair, and malignant tumors. FGFR-1, -2, and -3 each exist in two isoforms, IIIb and IIIc, due to alternative splicing of the extracellular domain, whereas FGFR-4 does not have these isoforms. FGFR-4 is reportedly over-expressed in various cancers such as breast, prostate, hepatocellular, ovarian, gastric, colorectal, and pancreatic cancers, wherein it contributes to tumor progression. Recent studies have shown that a decrease in FGFR-4 levels suppresses the aggressiveness of gastric, colorectal, and ovarian cancers. We found that pancreatic cancer cell lines expressed similar levels of the IIIb and IIIc isoforms of FGFR-1 to -3, but showed different FGFR-4 levels. These findings suggest that the cancer cells surviving after treatment with recently developed anti-FGFR drugs, which target FGFR-1 to -3, tend to express high levels of FGFR-4. Moreover, a single-nucleotide polymorphism (SNP) in exon 9 of the gene encoding FGFR-4 that results in the substitution of glycine with arginine at codon 388 (388 Gly/Arg) in the transmembrane domain is associated with poor outcomes of high-grade soft tissue sarcoma, prostate, lung, head and neck carcinoma, and advanced and treatment-resistant breast cancer. It has been reported that 40-50% of Caucasians carry at least one copy of the 388 Gly/Arg SNP of FGFR-4. In the present study, we examined the expression and roles of the 388 Gly/Arg SNP in pancreatic cancer and tried to clarify whether FGFR-4 may be a novel therapeutic target for cancer treatment. In human pancreatic tissues, FGFR-4 was weakly localized in the normal exocrine and endocrine pancreas, and was strongly expressed in 67 of 136 pancreatic ductal adenocarcinoma cases (49%). FGFR-4 expression positively correlated with larger primary tumors and more advanced stages of pancreatic cancer. FGFR-4 mRNA was expressed in 5 pancreatic cancer cell lines at various levels, and the mutation in codon 388 was detected in 3 of the cell lines, including PK-1 cells. A short hairpin RNA expression vector targeting FGFR-4 was stably transfected to these mutant-expressing PK-1 cells (388 Gly/Arg), which then showed lower growth rates and cell migration and invasion abilities compared to sham vector-transfected cells. DNA microarray analysis showed that decreased expression of FGFR-4 in PK-1 cells altered the expression levels of molecules related to cellular movement, cellular development, and cell-to-cell signaling and interactions. FGF-19—one of the major ligands for FGFR-4—was expressed in all 5 of the pancreatic cancer cell lines tested. These findings suggest that inhibition of the expression of FGFR-4 harboring the 388 Gly/Arg SNP may be a novel therapeutic strategy for pancreatic cancer, especially after treatment with the newly developed anti-FGFR-1 to -3-targeted drugs. Citation Format: Toshiyuki Ishiwata, Hisashi Yoshimura, Yoko Matsuda, Shunji Ishiwata. Fibroblast growth factor receptor-4 (FGFR-4) as a novel therapeutic target for pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4577.

Abstract 974: Characterization of the novel lncRNA, PCAT14, clinically associated with metastatic prostate cancer

Abstract Each year, over 180,000 men are diagnosed with prostate cancer in the United States. Advances in research have established a molecular stratification of prostate cancer disease improving screening and treatment options. However, some patients lack these genetic aberrations, indicating that prostate tumors may harbor disease-associated noncoding RNAs that further characterize molecular subtypes. Long non-coding RNAs (lncRNAs) are largely unexplored and are emerging as a new aspect of cancer biology through advances in sequencing technologies. To discover novel transcripts, and overcome the shortcomings of relying on incomplete or inaccurate annotations, we focused on an approach using a genome-wide annotation-independent method to identify regions of differential expression named SWORD (Sliding WindOw Region Discovery tool). We applied SWORD to recently generated data from aggressive prostate tumors and adjacent normal tissue. We discovered ten novel lncRNAs including the previously annotated Prostate Cancer Associated Transcript-14 (PCAT14). PCAT14 was consistently altered in an integrative analysis performed across three patient cohorts consisting of primary tumors with matched control transcriptome sequencing and Affymetrix gene expression including metastatic tumors. Utilizing the clinical data associated with the Affymetrix cohort, PCAT14 significantly associated with both high (9) and low (6) Gleason scores. Interestingly, PCAT14 is highly upregulated in primary tumors relative to control tissue and its expression is downregulated in metastatic tumors relative to primary tumors. These data suggest that PCAT14 expression promotes a metastatic phenotype. Therefore, we assessed PCAT14 expression within a cohort of 1008 radical prostatectomy specimens from three independent patient cohorts across institutes. We found that patients with high versus low PCAT14 expression showed significantly different rates of distant metastasis free survival, biochemical recurrence free survival, prostate cancer specific survival, and overall survival. Moreover, PCAT14 was implicated with protein-coding genes involved in biological processes promoting aggressive disease. In vitro experiments in prostate cancer cell lines further supported the clinical data associating PCAT14 with aggressive disease. Overall, we discovered that PCAT14 is broadly deregulated, promotes aggressive oncogenic phenotypes, and is significantly prognostic for multiple clinical endpoints supporting its significance for predicting metastatic disease. Due to its tissue-specific expression PCAT14 may serve as a valuable biomarker to define a subgroup of high-grade prostate carcinomas and improve disease management and patient prognosis. Citation Format: Nicole M. White, George Zhao, Jin Zhang, Elias Davicioni, Christopher A. Maher. Characterization of the novel lncRNA, PCAT14, clinically associated with metastatic prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 974.

MP62-18 CONVERSION OF ADENOCARCINOMA TO SMALL CELL CARCINOMA-LIKE BY REPROGRAMMING

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2016MP62-18 CONVERSION OF ADENOCARCINOMA TO SMALL CELL CARCINOMA-LIKE BY REPROGRAMMING Gisely Borges, Eneida Vencio, Sue-Ing Quek, Adeline Chen, Diego Salvanha, Ricardo Vencio, Holly Nguyen, Robert Vessella, Christopher Cavanaugh, Carol Ware, Pamela Troisch, and Alvin Liu Gisely BorgesGisely Borges More articles by this author , Eneida VencioEneida Vencio More articles by this author , Sue-Ing QuekSue-Ing Quek More articles by this author , Adeline ChenAdeline Chen More articles by this author , Diego SalvanhaDiego Salvanha More articles by this author , Ricardo VencioRicardo Vencio More articles by this author , Holly NguyenHolly Nguyen More articles by this author , Robert VessellaRobert Vessella More articles by this author , Christopher CavanaughChristopher Cavanaugh More articles by this author , Carol WareCarol Ware More articles by this author , Pamela TroischPamela Troisch More articles by this author , and Alvin LiuAlvin Liu More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.926AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Most prostate tumors are adenocarcinoma with glandular differentiation, and a small percentage, found most frequently in advanced diseases, are small cell neuroendocrine carcinoma without glandular differentiation. The LuCaP series is a family of prostate cancer xenografts propagated in male mice. LuCaP CR variants were obtained from passages in castrated hosts. Expression of stem cell transcription factor (TF) genes LIN28A, NANOG, POU5F1, SOX2 was examined in the LuCaP lines because some LuCaP lines were found to express stem cell markers. These four genes when forced expressed in somatic cells could induce reprogramming. METHODS The LuCaP cells were harvested and frozen by using a special protocol that preserved their viability. Gene expression was studied by RT-PCR. Adenocarcinoma LuCaP cells were plated on mouse embryonic fibroblast (MEF) feeder, which allowed them to grow in vitro. The cancer cells were transfected with lentiviral vectors containing the TF genes. Transfected cells on MEF were monitored over a period of 1 month. DNA microarrays were used to obtain cell type transcriptomes. RESULTS Most LuCaP lines expressed POU5F1, and LIN28A was upregulated in LuCaP 73CR vs. LuCaP 73. The small cell carcinoma LuCaP 145.1 expressed all four. Its expression of B2M (β-2 microglobulin) was also lower than that of other LuCaP lines. Low B2M expression is characteristic of stem cells. Many other LuCaP 145.1 genes (COTL1, ENO2, IGFBP2, ROBO1, chromogranin A) were also found in embryonic stem (ES) cells. TF transfection was carried out on five (AR+/PSA+) adenocarcinoma LuCaP lines: 70CR, 73CR, 86.2, 92, 105CR. All produced small dark cells as compared to large bright parental cells. The colony morphology was unlike that of ES cells, and more like that of PC3 cancer cell line, which was established from a bone metastasis of high-grade undifferentiated prostate carcinoma. The small cells started to appear around day 10 post-transfection and multiplied until individual colonies were visible at day 21. No such cells were seen in mock transfected. The transcriptome of LuCaP 70CR* (* to indicate transfected progeny) was very different from that of parental LuCaP 70CR as measured by Δ=91.72 in a prostate principal components analysis space. Gene expression of LuCaP 70CR* was closest to that of LuCaP 145.1 by Δ=45.85 (vs. Δ=78.04 with ES cells). CONCLUSIONS The adenocarcinoma phenotype could be converted to that of small cell carcinoma-like by stem cell TF genes (as in reprogramming). Cancer progression can be characterized molecularly as cellular de-differentiation from differentiated adenocarcinoma to undifferentiated stem-like small cell carcinoma. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e819 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Gisely Borges More articles by this author Eneida Vencio More articles by this author Sue-Ing Quek More articles by this author Adeline Chen More articles by this author Diego Salvanha More articles by this author Ricardo Vencio More articles by this author Holly Nguyen More articles by this author Robert Vessella More articles by this author Christopher Cavanaugh More articles by this author Carol Ware More articles by this author Pamela Troisch More articles by this author Alvin Liu More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The value of touch imprint cytology of prostate core needle biopsy specimens – Kuwait experience

ObjectivesTouch imprint cytology (TIC) is a reliable, cost-effective technique for the diagnosis of cancer. The aim of this study was to determine the diagnostic value and accuracy of TIC of prostate core needle biopsy (CNB) specimens in predicting the final histology in patients with suspected prostate cancer. Subjects and methodsTIC was carried out on 354 core needle biopsy specimens taken from 59 patients with suspected prostate cancer as indicated by a high prostate serum antigen (PSA) level or abnormal findings on rectal examination. All biopsies were taken under transrectal ultrasound (TRUS) guidance. Two touch imprints were prepared from each CNB. The TIC results were correlated with CNB. ResultsTIC revealed evaluable results in 336/354 (94.9%) CNB specimens analyzed, with the following cytological diagnosis: malignancy in 40 (11.9%), atypical features in 47 (14%) and benign results in 249 (74.1%) specimens. Histopathological examination of the 40 CNB specimens showing malignant features on TIC confirmed the diagnosis of prostate cancer. In 24/47 (51.1%) cases with atypical cytology, histopathological assessment of the CNB specimens revealed benign features in 7 and prostatitis in 17, while high-grade prostatic intraepithelial neoplasia (HGPIN) and carcinoma were seen in 3 and 20 specimens, respectively. In 12/249 (4.8%) cases showing benign results on TIC, histopathological examination of the CNB specimens revealed an abnormal histology in the form of HGPIN in 9 (75%) and carcinoma in 3 (25%) cases. TIC accurately predicted the final histology in 336 cases with a sensitivity of 84% and a specificity of 90.8%. When excluding atypical cytology on TIC and HGPIN on CNB, the sensitivity and specificity were 93% and 100%, respectively. A strong correlation was seen between TIC and CNB (p<0.001). ConclusionsThe routine use of TIC complements CNB reports and helps to provide an immediate and reliable cytological diagnosis of prostate lesions. TIC and serial sectioning of CNB specimens significantly improve the diagnostic accuracy.

TNFα-mediated loss of β-catenin/E-cadherin association and subsequent increase in cell migration is partially restored by NKX3.1 expression in prostate cells.

Inflammation-induced carcinogenesis is associated with increased proliferation and migration/invasion of various types of tumor cells. In this study, altered β-catenin signaling upon TNFα exposure, and relation to loss of function of the tumor suppressor NKX3.1 was examined in prostate cancer cells. We used an in vitro prostate inflammation model to demonstrate altered sub-cellular localization of β-catenin following increased phosphorylation of Akt(S473) and GSK3β(S9). Consistently, we observed that subsequent increase in β-catenin transactivation enhanced c-myc, cyclin D1 and MMP2 expressions. Consequently, it was also observed that the β-catenin-E-cadherin association at the plasma membrane was disrupted during acute cytokine exposure. Additionally, it was demonstrated that disrupting cell-cell interactions led to increased migration of LNCaP cells in real-time migration assay. Nevertheless, ectopic expression of NKX3.1, which is degraded upon proinflammatory cytokine exposure in inflammation, was found to induce the degradation of β-catenin by inhibiting Akt(S473) phosphorylation, therefore, partially rescued the disrupted β-catenin-E-cadherin interaction as well as the cell migration in LNCaP cells upon cytokine exposure. As, the disrupted localization of β-catenin at the cell membrane as well as increased Akt(S308) priming phosphorylation was observed in human prostate tissues with prostatic inflammatory atrophy (PIA), high-grade prostatic intraepithelial neoplasia (H-PIN) and carcinoma lesions correlated with loss of NKX3.1 expression. Thus, the data indicate that the β-catenin signaling; consequently sub-cellular localization is deregulated in inflammation, associates with prostatic atrophy and PIN pathology.