Prostatic Intraepithelial Neoplasia Research Articles

Abstract LB324: STING protein expression is increased in intermediate luminal cells in proliferative inflammatory atrophy of the prostate (PIA) and is absent in the majority of primary prostatic adenocarcinomas

Abstract Unresolved chronic inflammation has been postulated to drive prostate cancer development. We have proposed that proliferative inflammatory atrophy (PIA) can lead to the development of preneoplastic high grade prostatic intraepithelial neoplasia (PIN) lesions and/or directly to adenocarcinoma at times. Additionally, some PIA cells harbor molecular alterations seen in PIN and invasive carcinoma lesions, with a low frequency of PIA cells showing MYC over-expression, partial promoter hypermethylation and silencing of GSTP1, and formation of ETS gene fusions. PIA appears to result from inflammatory injury and regeneration in which proliferative and atrophic epithelial cells have an intermediate cell phenotype with both luminal and basal cell features, including basal cell markers, keratin 5 and BCL2, as well as varying levels of prostate luminal enriched genes such as androgen receptor, PSA and NKX3.1. Also, a number of gene products that are apparently stress induced, which are not expressed in normal prostate are induced in at least a subset of intermediate luminal cells in PIA, including GSTA1, PTGS2, LTF and PIGR (PMIDs:17384581, 37550827). Stimulator of interferon genes (STING), encoded by TMEM173, is a multipass transmembrane ER associated protein, and is a critical hub for innate responses directed against numerous bacterial, viral and parasitic pathogens, and is important for the induction and maintenance of adaptive immunity in a number of situations. Here, we examined STING expression by IHC, using a genetically validated assay, and show that the majority of atrophic prostatic luminal epithelial cells in all PIA lesions (N=20) consistently express high levels of STING, which is present in normal prostatic basal epithelial cells yet absent in normal-appearing prostatic luminal cells. In primary prostatic adenocarcinomas (> 260 tumors), STING protein was either completely negative , or extremely low in ~ 95% of cases. That STING in PIA is activate is supported by single cell RNA sequencing (scRNAseq) data from human prostatectomy tissues that show cells with the phenotype of intermediate luminal cells, indicative of PIA, express a number of interferon response genes that are not expressed in normal luminal cells (PMID 37905029). To our knowledge this is the first systematic report of STING protein staining in human prostate cancer and benign tissues. We postulate that upregulation of STING in human intermediate cells in PIA represents an inflammatory response that can drive interferon stimulated gene expression and inflammation in PIA. This innate immune response is absent, potentially by gene silencing, in prostatic adenocarcinoma, which may help neoplastic cells evade the immune response and could help contribute to the long standing finding that most prostate cancers are immunologically cold. Citation Format: Thomas M. Steele, Alan K. Meeker, Mindy K. Graham, Rulin Wang, Carolina Gomes-Alexandre, William G. Nelson, Fernanda Caramella Pereiria, Sushant Kachhap, Srinivasan Yegnasubramanian, Angelo Michael De Marzo. STING protein expression is increased in intermediate luminal cells in proliferative inflammatory atrophy of the prostate (PIA) and is absent in the majority of primary prostatic adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB324.

Abstract 6849: Characterizing a discernible stromal fibroblastic gene signature in the shift from high-grade prostatic intraepithelial neoplasia to aggressive prostate cancer

Abstract Background: High-grade prostatic intraepithelial neoplasia (HGPIN) is a preneoplastic lesion that precedes the development of both indolent and aggressive variants of prostate cancer (PCa). However, the specific stromal molecular mechanisms underlying the progression of HGPIN and their contribution to epithelial cancer cell motility and invasiveness remain poorly understood. This study aims to elucidate the driver genomic alterations involved in shaping the perineoplastic stroma of HGPIN, with the goal of unraveling their role in promoting cancer invasion, and metastasis. Methods: We performed gene expression profiling on laser capture microdissected perineoplastic stroma of HGPIN and PCa in tissue samples from 25 PCa cases, including 12 low-grade (Gleason 6) and 13 high-grade (Gleason >/= 8) cases. We used the standard moderated t-test from the Bioconductor limma package to assess the statistical significance of differential gene expression between perineoplastic stroma high grade PCa and perineoplastic stroma HGPIN, as well as between perineoplastic stroma low grade PCa and HGPIN. The -log10 p-values represents the level of statistical significance for each gene, while the log2 fold change represents the magnitude of gene expression difference between the two comparison groups. Additionally, we computed Gene Set Enrichment Analysis (GSEA) scores using the Bioconductor package and discerned the leading-edge genes among the pathways. This study is supported by the NIH-NCI-T32 program for next-generation pathologists at our institution. Results: In the gene expression analysis comparing High Grade PCa and HGPIN, several genes, including POSTN, BGN, GREM1, C1QA, THBS4, COL1A1, COL1A2, SFRP4, RNU6-847P, FCGR2P, and TOMM22, exhibited the highest level of both biological and statistical significance. GSEA revealed that the multi-invasive pathway had the highest enrichment score (>2). Notably, the top overexpressed genes in this pathway exhibited a fibroblastic signature (in bold), including POSTN, BGN, GREM1, FBN1, COL1A2, COL3A1, COL5A2, ASPN, SPARC, VCAN, COMP, INHBA, THBS2, and SFRP4. The presence of this signature indicates the invasiveness of the disease. Importantly, these genes were not associated with the progression to low grade PCa, indicating their exclusive association with the aggressive variant. Conclusion: To our knowledge, this study is the first to explore the stroma's role in HGPIN-to-aggressive PCa progression. It highlights a key stromal pathway enriched with fibroblastic gene signature. These findings offer potential biomarkers for targeted therapies and improved care through HGPIN patient stratification. Citation Format: Mohammad K. Alexanderani, Lucio Queiroz, Mohamed Omar, Claudio Zanettini, Hubert Pakula, Luigi Marchionni, Massimo Loda. Characterizing a discernible stromal fibroblastic gene signature in the shift from high-grade prostatic intraepithelial neoplasia to aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6849.

Abstract 1448: Investigating the effects of estrogen on the initiation of prostate cancer

Abstract Background: Prostate cancer (PCa) is responsible for ~10% of cancer-related deaths in men. Nkx3.1 is an androgen-regulated gene expressed primarily in the prostate, which encodes a tumor suppressor protein important for male reproductive development. Loss of nkx3.1 is thought to lead to prostatic intraepithelial neoplasia (PIN), the pre-invasive form of prostatic adenocarcinoma. Previous evidence suggests that estrogenic dysregulation and testosterone imbalance play a significant role in PCa initiation and progression. Objectives/Aims: We aimed to investigate how estrogen impacts the progression of PIN in the anterior prostate of mice lacking nkx3.1. Methods: To investigate the effect of long-term exposure to 17β-estradiol (E2), nkx3.1+/+ and nkx3.1−/− 12-week-old mice were given 2 mg/day of E2 over 90 days by subdermal implantation of 90-day extended-release tablets. After 90 days, the anterior prostate lobes of the mice were harvested and analyzed post-treatment for signs of pre-cancerous tissue. The immediate, early effect of E2 exposure was also investigated by the subcutaneous injection of 8- and 20-week-old mice with 0.300 mg/kg of E2. Within two hours, the anterior prostate lobes were harvested, and ~500 ng/μL of RNA was isolated from the tissues. cDNA was reverse-transcribed, in triplicate, from the RNA and the expression of c-myc, p53, estrogen receptor ERα (ESR1), and ERβ (ESR2) were assessed via qRT-PCR. Three technical replicates from three biological replicates were performed for each treatment. Results: Nkx3.1−/− mice chronically exposed to elevated E2 developed PIN following E2 treatment, while the placebo group had tissue hyperplasia. Nkx3.1+/+ mice had normal prostate tissue regardless of E2 treatment. In response to immediate exposure to E2, the prostates of 8-week-old nkx3.1+/+ mice showed reduced c-myc expression. 8-week-old nkx3.1−/− mice showed no changes in expression of any of the four genes assayed, in response to E2 as compared to the placebo treatment. In contrast, regardless of exposure to E2, c-myc, p53, and ESR2 were significantly elevated in these mice compared to the nkx3.1+/+ groups. Furthermore, c-myc and p53 expression was suppressed in 20-week-old nkx3.1−/− mice in response to E2, while ESR1 and ESR2 remained unchanged. Conclusion: Our evidence suggested that prolonged exposure of wild-type mice to E2 had no pathohistological impact on the anterior prostate tissue. In nkx3.1-deficient mice, however, E2 exposure promoted the onset of PIN, and caused immediate differential expression of estrogen-responsive genes, suggesting a role of nkx3.1 in protecting the prostate in the presence of a hormonal imbalance. Citation Format: Nash S. Denic, Ashlyn Swift-Gallant, Kenneth R. Kao. Investigating the effects of estrogen on the initiation of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1448.

Abstract 2975: Vitamin D receptor signaling limits DNA damage at early stage of prostate tumorigenesis and prevents tumor aggressiveness

Abstract Prostate cancer (PCa) is the most common visceral neoplasm and the second leading cause of cancer-related deaths in male of western societies. Low circulating vitamin D levels and reduced expression of its receptor (VDR) correlate with PCa risk and severity, but the clinical use of vitamin D is limited by its pro-calcemic activities. To characterize the role of VDR in PCa, PTEN(i)pe-/− mice, that recapitulate the human disease and in which the tumor suppressor gene PTEN is selectively inactivated in prostatic epithelial cells (PECs) at adulthood, were compared to PTEN/VDR(i)pe-/− mice in which PECs are PTEN and VDR-deficient. Histological analysis showed that prostatic intraepithelial neoplasia (PIN) are formed between 1-3 months after gene inactivation (AGI). Importantly, VDR-deficiency increased by 2-fold the PECs proliferation rate as early as 1-month AGI. At this stage, RNA-seq and immunohistochemistry analysis revealed the presence of oxidative DNA damage selectively in VDR-deficient PINs. Moreover, a 4-week supplementation with the antioxidant N-acetyl cysteine reduced oxidative DNA damage in PTEN/VDR(i)pe-/- prostates, and normalized the number of Ki-67+ cells to the levels of PTEN(i)pe-/- ones. After 3 months AGI, both PTEN(i)pe-/- and PTEN/VDR(i)pe-/- tumors entered in a latency phase characterized by cellular senescence. However, the prostate weight in PTEN/VDR(i)pe-/− mice was 2-fold higher than in PTEN(i)pe-/− mice 12 months AGI. In addition, tumors of PTEN(i)pe-/− were mostly composed of non-invasive PIN-like adenocarcinoma, whereas invasive adenocarcinoma, sarcomatoid and squamous-cell carcinoma were observed in those of PTEN/VDR(i)pe-/- mice. Using single cell and spatial transcriptomics, we unraveled the presence of epithelial cells with epithelial-mesenchymal transition (EMT) hallmarks in PTEN/VDR(i)pe-/− prostate 10 months AGI. In addition, immunophenotyping revealed a higher infiltration of neutrophils, also termed as myeloid-derived suppressive cells and implicated in EMT and metastasis dissemination, in PTEN/VDR(i)pe-/− prostates compared to PTEN(i)pe-/− ones. Moreover, pan-cytokeratin-positive micro-metastasis were detected in lymph nodes and livers of PTEN/VDR(i)pe-/− mice, but not in those of PTEN(i)pe-/- mice, demonstrating that VDR-deficiency in PECs promotes aggressive PCa. Thus, VDR signaling exerts a protective role on PTEN-deficient PECs by limiting the oxidative-stress and proliferation during PINs initiation, and prevents PCa progression. Citation Format: Kateryna Len, Justine Gantzer, Nicolas Le May, Christelle Thibault-Carpentier, Daniel Metzger, Gilles Laverny. Vitamin D receptor signaling limits DNA damage at early stage of prostate tumorigenesis and prevents tumor aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2975.

Abstract 1246: Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features

Abstract Translocations of the ETS family transcription factor ERG are found in nearly 150,000 newly diagnosed prostate cancers (PCas) each year in the United States underscoring the importance of defining the mechanism by which ERG promotes prostate epithelial transformation. A consequence of nearly all ERG translocations is the aberrant expression of ERG in prostate luminal cells under transcriptional control of TMPRSS2. Multiple lines of evidence implicate ERG translocations as an initiating event in prostate cancer. ERG expression is seen in prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy; expression in cancers is typically uniform; and, in the context of PI3K pathway activation, ERG is sufficient to induce cancers in mice. Yet, despite extensive research the mechanism by which ERG initiates prostate cancer is unclear. To gain insight into how ERG translocations cause prostate cancer, we performed both transcriptional profiling (scRNA-seq) and chromatin accessibility via Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) in single cells of an autochthonous mouse model at an early stage of disease initiation. Surprisingly, we observed in prostate epithelial cells broadly expressing ERG enhanced proliferation primarily in a hybrid subpopulation of cells having basal identity but with luminal morphology and cytokeratin expression. Through a series of lineage tracing and primary prostate epithelial transplantation experiments, we confirmed tumor initiating activity resided within a subpopulation of basal cells expressing luminal genes (e.g., Tmprss2 and Nkx3-1). A trajectory analysis from single-cell Chromatin accessibility indicated Erg+ cells began to lose basal (Trp63) accessibility and gained in STAT/NFAT TFs while retaining the ability to rapidly differentiate into luminal cells that reflect the lineage of ERG-positive cancers. These findings help resolve a preexisting debate about the cell of origin of ERG-driven prostate cancer and narrow the focus for future mechanistic studies to a basal-luminal subpopulation of tumor initiating cells. Citation Format: Erik Ladewig, Weiran Feng, Christina Leslie, Charles Sawyers. Erg-driven prostate cancer emerges from a basal subset of cells with luminal transcriptomic features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1246.

Abstract 3409: AGEing and lifestyle after a cancer diagnosis: A balanced equilibrium for survivorship

Abstract In the US, over 18 million people are living with a cancer diagnosis and that number may double by 2050. There is a need to unite research across the cancer continuum to address the needs of cancer survivors to ensure optimal quality of life and improve mortality outcomes. Health constructs that influence cancer survivorship are multifactorial, highly dynamic, and vary across the lifespan. This makes assigning their impact on the well-being and future outcomes of cancer survivors challenging. As a pathophysiological process that lies at the intersection between societal, environmental, and biological constructs, it is proposed that the irreversible accumulation of metabolites called advanced glycation end products (AGEs) can inform on quality of life and mortality outcomes for cancer survivors. It is proposed that AGE accumulation as a result of societal, environmental, and biological constructs overwhelm the fragile equilibrium that maintains AGE homoeostasis to impact tumor biology and cancer outcomes. The relationships between health constructs and AGE exposure are epitomized by nutritional behavior. The consumption of cheaper unhealthier often ultra-processed foods are inherently AGE laden and the excessive consumption of foods high in fats and sugars that promote obesity and increase cancer risk readily provide reactive intermediates that fuel AGE formation in cells and tissues. Our collaborative epidemiological studies assign high levels of AGE consumption with increased breast cancer risk, aggressiveness, and mortality, which is supported by translational studies showing that circulating AGE levels in breast cancer patients correlate with worse disease-free survival and other poor prognosis indicators. Critically, this group has also shown that chronic AGE consumption by mice increases prostate tumor growth (p<0.001), and causes a rapid progression through prostate intra-epithelial neoplasia (p=0.049), adenocarcinoma (p=0.042) and metastasis (p=0.001). Consumption of the high AGE diet caused a regulatory program of stromal activation conducive for tumor growth. As a bio-social determinant of health AGE accumulation and its pathogenic effects serve as informative and/or functional markers indicative of the current health status and well-being of cancer survivors and may inform of potential future outcomes. Our studies show that physical activity and dietary intervention (cardiac rehabilitation) reduced systemic AGE levels in breast cancer survivors. Therefore, prevention and control interventions aimed at reducing AGE exposure represent viable strategies for improving quality of life and disease recurrence for cancer survivors. This research was made possible in part by Grant Numbers R01-CA259415, R01-CA245143, R21-CA194469, and U54-CA210962 from NIH-NCI. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH. Citation Format: David P. Turner, Bradley A. Krisanits, Marvella E. Ford, Lindsay L. Peterson, Susan E. Steck, Paula D. Bos, Victoria J. Findlay. AGEing and lifestyle after a cancer diagnosis: A balanced equilibrium for survivorship [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3409.

Abstract 5581: The DACH1 gene, frequently co-deleted with BRCA2 in prostate cancer, governs PARP inhibitor resistance

Abstract Background: Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities (1,2). The DACH1 gene, in the 13q21.31-q21.33 region, encodes a winged helix/Forkhead DNA-binding protein that governs cell-fate determination that is deleted in ~ 18% of human PCa, where it is associated with poor prognosis (3). Prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN). Methods: Analysis of DACH1 gene deletion and expression was conducted from public data bases and human prostate cancer samples. Cells derived from Dach1 gene deletion mice and human prostate cancer cell lines with DACH1 overexpression were analyzed for PARP inhibitor responses and mechanisms of PARPi resistance. Transgenic prostate Oncomice were generated in which the Dach1 gene was deleted in the prostate. Results: Herein, DACH1 was shown to be co-deleted with BRCA2 in each of 8 separate cohorts (N=2,186 patients), in ~3-12% of patients. Dach1 gene deletion or knockdown conferred PARP inhibitor resistance (talazoparib > niraparib > olaparib > rucaparib > veliparib). DACH1 enhanced PARP sensitivity through several mechanisms affecting replication stress, PARP1 binding, inhibiting G9a (reducing H3K9me2), inhibiting CHK1p and CDK1p and inducing expression of snoRNA, specifically the snoRNA known to bind PARP. PARP1 has a BRCT (BRCA1 C-terminus 1) homology domain governing PARP1 dimerization and binding to intact DNA in a complex within a nucleosome. DACH1 binding to PARP1 requires the BRCT domain. Conclusions: There is a correlation between DACH1a-/- and PARPi resistance, correlating with PARPi trapping ability. As reduced Dach1a expression may define a subclass of PCa that warrants specific therapies, testing for DACH1a may be warranted.

Abstract 1147: Sub-cellular spatial resolution of immune and stromal interactions underlying prostate cancer progression

Abstract Prostate cancer boasts a complex morphological structure and diverse cellular composition, yet current technology falls short in resolving the detailed spatial interactions among cells within the environment. In this study, we employed the Xenium platform, coupled with the 3D reconstruction tool Mushroom, to examine high-resolution spatial cellular interactions within the prostate cancer microenvironment. Our investigation focused on the transition of molecular characteristics from normal to high-grade prostatic intraepithelial neoplasia (HGPIN, pre-cancer), spanning the spectrum of Gleason Grades 3 to 4 and advancing to metastatic prostate cancer. We identified genes with unique spatial and grade-dependent expression profiles, including MYC, CP, and UHCL1. Evaluating sub-cellular imaging facilitated a comprehensive characterization and quantification of immune and stromal interactions, unveiling distinct spatial niches across transition stages. These findings underscore the nuanced immune interactions within the tumor microenvironment and offer crucial insights into the development of immunotherapeutic approaches tailored to the specific spatial and immune dynamics observed in advanced prostate cancer. This research contributes to the evolving understanding of prostate cancer progression, providing a foundation for the development of targeted therapies that disrupt specific cellular interactions. Citation Format: Chia-Kuei Mo, Reyka G. Jayasinghe, Ateih Abedin do, Xiang Li, Cody Weimholt, Eric H. Kim, Russell Pachynski, Feng Chen, Li Ding. Sub-cellular spatial resolution of immune and stromal interactions underlying prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1147.

(248) Analysis of Biomarkers (MMP-9, TIMP-1, Ki-67 and Type IV Collagen) in the Diagnosis of Prostate Diseases

Abstract Introduction The combination of inflammatory, benign and malignant processes in the prostate reduces the sensitivity, specificity and diagnostic accuracy of modern examination methods. The development of immunohistochemical methods (IHC) promotes the search for molecular markers that are diagnostically significant in various processes in the prostate. This will improve the detection of malignant neoplasms and reduce the number of "unnecessary" prostate biopsies. Objective to study in biopsies of patients with various prostate diseases the relationship of type 9 metalloproteinase (MMP-9) and its inhibitor (TIMP-1), the role of the Ki-67 protein proliferation level and the diagnostic value of the type IV collagen distribution indicator. Methods The study included 263 patients. They were divided into 4 groups: chronic prostatitis - 21 patients (mean age 65.2 ± 0.7 years), benign prostatic hyperplasia (BPH) - 65 patients (69.3 ± 1.1 years), BPH + prostatic intraepithelial neoplasia (PIN) - 59 patients (68.9 ± 0.9 years), prostate adenocarcinoma (PC) - 118 patients (68.2 ± 0.9 years). IHC was used to analyze type 9 metalloproteinase (MMP-9) and its inhibitor (TIMP-1), the role of the Ki-67 protein proliferation level and the diagnostic value of the type IV collagen distribution indicator. Results BPH is characterized by high production of MMP-9 (intensity 3 points), lack of proliferative activity of the secretory cell layer (Ki-67 less than 3.24 ± 0.61%) and degradation of collagen IV of the basement membranes, which associated with a compensatory increase in the activity of the inhibitor of matrix metalloproteinases TIMP-1 (intensity 3 points). In prostate cancer, as neoplastic changes increase, the production of the Ki-67 protein significantly increases, reflecting the proliferative activity of the secretory cell layer (from 5.3 + 1.1% to 17.2 + 9.4%). With an increase in the Gleason number over the 3rd grade, collagen fibers around the tumor cells completely disappear. The production of MMP-9 type in adenocarcinomas is significantly reduced and the destruction of collagen IV of the basement membrane of glandular structures and stroma occurs due to a progressive (up to an intensity of 0.8 + 0.4 points as anaplastic changes increase) decrease in the production of the inhibitor of matrix metalloproteinases TIMP-1 (p≤0.05). High production of MMR-9 in BPH is blocked by a high content of the TIMP-1 inhibitor. In adenocarcinomas, the production of MMP-9 is significantly reduced, but this protease destroys collagen IV of the basement membrane of glandular structures due to the absence or weak production of TIMP-1, which blocks the proteolytic effect of this enzyme on connective tissue collagen. The low production of the TIMP-1 inhibitor in adenocarcinomas can also explain the invasive properties of these tumors. Conclusions Comprehensive analysis of biomarkers in IHC can improve the diagnosis of prostate cancer and reduce the number of "unnecessary" biopsies. Disclosure No.

A hospital-based study of prostate biopsy results in Indian males.

The prostate is a gland belonging to the male reproductive system. Aging results in the dysfunction of the prostate that may present as inflammation, enlargement, and cancer. Additionally, the diseases of the prostate including cancers are slow in progression, and therefore, it is difficult to diagnose them early. Hence, it is increasingly important for physicians to recommend histopathological examination of the prostate gland to identify, manage, and treat prostate cancers. This study was conducted to assess prostate diseases among biopsy specimen collected from patients with signs of prostate diseases. This prospective study was conducted in the Department of Pathology, Deccan College of Medical Sciences, Owaisi Hospital, Hyderabad, between June 2012 and September 2014. All gross specimens (n = 300) of the prostate such as the needle biopsies of the prostate, transurethral resection of the prostate (TURP) chips, and excised specimens of the prostate were included in the study. Histopathological examinations of the biopsies were performed for nuclear size, chromatin material, nucleoli, membrane thickness, irregularity, cytoplasmic granularity, staining, and cell border conspicuity. The biopsies were also assessed for lobule formation, secretions, polymorphonuclear leukocytes, lymphocytes, macrophages, connective tissue stromal cells, their arrangements, and acellular connective tissue material. Of 300 total prostatic biopsies performed, 56 (18.66%) were identified as inflammatory lesions of the prostate (prostatitis), 98 (32.66%) revealed benign prostatic lesions (benign prostatic hyperplasia (BPH)), 112 (37.33%) were identified as BPH with premalignant lesions, and 34 (11.33%) were revealed as malignant tumors of the prostate. Chronic prostatitis (67.85%) was the common inflammatory lesion. The majority (91.42%) revealed epithelial lesions compared to stromal lesions (08.58%). BPH was predominantly (28.00%) noticed among patients in the age group of 61-70 years. Prostatic intraepithelial neoplasia (PIN) was observed majorly (53.35%) in the age group of 61-70 years. Most of the prostatic cancers were identified as adenocarcinomas. However, three variants were also categorized as small cell carcinoma, signet ring cell carcinoma, and transitional cell carcinomas. The results reveal that prostatic adenocarcinomas are predominant among the study population. Additionally, prostatic diseases including cancer are commonly noticed among people belonging to the age group of 61-70 years. More than one-third of patients showed BPH with premalignant lesions, and a majority of the study population showed evidence of chronic prostatitis.

Association between preradiation therapy prostate-specific antigen levels and radiation therapy failure after prostatectomy: a propensity score matched analysis

PurposeWe sought to determine the association between the pre-radiation therapy prostate-specific antigen (pre-RT PSA) 0.5 and RT failure in post-radical prostatectomy (post-RP) patients. Our study also investigated the prognostic factors for the failure of RT given concurrently with hormone therapy (HT) after RP. Materials and methodsWe retrospectively reviewed our institutional RP data from July 2004 to November 2021. Patients without concurrent hormone therapy were excluded. Propensity score matching was performed. Kaplan–Meier (KM) curve analysis was employed for RT failure-free survival, overall survival (OS), and cancer-specific survival (CSS). Cox regression analysis was used for the RT failure hazard ratio (HR). ResultsAfter propensity score matching, 193 patients were assigned to the pre-RT PSA ≥0.5 (high-P) arm, and 193 patients were assigned to the pre-RT PSA <0.5 (low-P) arm. There were no significant differences between the two arms after propensity score matching in terms of baseline characteristics and pathologic outcomes. High-P was associated with RT failure-free survival (P = 0.004), OS (P = 0.046), and CSS (P = 0.027). In a multi-variable Cox proportional hazards regression analysis, seminal vesicle invasion, lymph node invasion, the absence of prostatic intraepithelial neoplasia (PIN), and high-P were identified as significant risk factors for RT failure. ConclusionHigh-P was significantly unfavorable with RT failure-free survival, OS, and CSS in patients who underwent RT after radical prostatectomy with concurrent HT. Seminal vesicle invasion, lymph node invasion, and the absence of PIN were identified as significant prognostic factors for RT failure.

HISTOPATHOLOGICAL SPECTRUM OF PROSTATIC LESIONS AND THEIR CORRELATION WITH SERUM PROSTATE SPECIFIC ANTIGEN LEVELS

Objectives: The present study is conducted to find out the histopathological spectrum of different prostatic biopsies and compare them with respective serum prostate-specific antigen (PSA) levels and grading, scoring of malignant lesions according to Gleason’s group grading system. Methods: A total 165 prostatic biopsies from patients of &gt;50 years of age groups were included in the study. This cross-sectional study was conducted in the Department of Pathology, R.N.T. Medical College, Udaipur, over a period of 1 year. The specimens were examined for various prostatic pathologies by doing histopathological examination and their serum PSA values were correlated. Results: On histopathological examination, 76.9% of cases were of benign lesions, 14% of cases had prostatic malignancy, 6.6% of cases of inflammatory lesions, and 2.4% of cases of prostatic intraepithelial neoplasia. Majority of inflammatory lesions, prostate intraepithelial neoplasia, benign prostatic hyperplasia (BPH), and BPH with prostatitis had PSA level &lt;4 ng/mL. In malignant cases, majority had PSA levels above 10 ng/mL. In prostatic adenocarcinoma, 56.32% of cases were found moderately differentiated grade (G2) followed by 30.43% of cases were of well-differentiated grade (G1) and 13.04% of cases of poorly differentiated grade (G3-G4). Conclusion: The study showed a statistically positive correlation between histological diagnosis and serum PSA level.

Relationship between Mental Disorders, Smoking or Alcoholism and Benign Prostate Disease.

Mental disorders, smoking, or alcoholism and benign prostate disease are highly prevalent in men. To identify the relationship between mental disorders, smoking, or alcoholism and benign prostate disease. A prospective multicenter study that evaluated prostate health status in 558 men from the community. Groups: GP-men who request a prostate health examination and whose medical history includes a mental disorder, smoking, or alcoholism prior to a diagnosis of benign prostate disease; GU-men who request a prostate health examination and whose medical history includes a benign prostate disease prior to a diagnosis of mental disorder, smoking, or alcoholism. age, body mass index (BMI), prostate specific antigen (PSA), follow-up of the mental disorder, smoking or alcoholism, time elapsed between urological diagnosis and the mental disorder, smoking or alcoholism diagnosis, status of the urological disease (cured or not cured), concomitant diseases, surgical history, and concomitant treatments. Descriptive statistics, Student's t-test, Chi2, multivariate analysis. There were no mental disorders, smoking, or alcoholism in 51.97% of men. Anxiety, smoking, major depressive disorder, pathological insomnia, psychosis, and alcoholism were identified in 19.71%, 13.26%, 5.73%, 4.30%, 2.87%, and 2.15% of individuals, respectively. Nonbacterial prostatitis (31.54%), urinary tract infection (other than prostatitis, 24.37%), prostatic intraepithelial neoplasia (13.98%), and prostatodynia (1.43%) were prostate diseases. Unresolved symptomatic benign prostate disease was associated with anxiety, depression, and psychosis (p = 0.002). Smoking was the disorder that men managed to eliminate most frequently. The dominant disorder in patients with symptomatic benign prostatic disease was alcoholism (p = 0.006). Unresolved symptomatic benign prostatic disease is associated with anxiety, depression, and psychosis. Alcoholism is associated with a worse prognosis in the follow-up of symptomatic benign prostatic disease.

Expression of the microtubule-associated protein 2 (MAP2) as a potential independent prognostic marker in prostate cancer

PurposeInvestigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer.Material and MethodsMAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay.ResultsMAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001).ConclusionThe present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities.

Enhanced Chemoprevention of Prostate Cancer by Combining Arctigenin with Green Tea and Quercetin in Prostate-Specific Phosphatase and Tensin Homolog Knockout Mice.

The low bioavailability of most phytochemicals limits their anticancer effects in humans. The present study was designed to test whether combining arctigenin (Arc), a lignan mainly from the seed of Arctium lappa, with green tea (GT) and quercetin (Q) enhances the chemopreventive effect on prostate cancer. We performed in vitro proliferation studies on different cell lines. We observed a strong synergistic anti-proliferative effect of GT+Q+Arc in exposing androgen-sensitive human prostate cancer LNCaP cells. The pre-malignant WPE1-NA22 cell line was more sensitive to this combination. No cytotoxicity was observed in normal prostate epithelial PrEC cells. For an in vivo study, 3-week-old, prostate-specific PTEN (phosphatase and tensin homolog) knockout mice were treated with GT+Q, Arc, GT+Q+Arc, or the control daily until 16 weeks of age. In vivo imaging using prostate-specific membrane antigen (PSMA) probes demonstrated that the prostate tumorigenesis was significantly inhibited by 40% (GT+Q), 60% (Arc at 30 mg/kg bw), and 90% (GT+Q+Arc) compared to the control. A pathological examination showed that all control mice developed invasive prostate adenocarcinoma. In contrast, the primary lesion in the GT+Q and Arc alone groups was high-grade prostatic intraepithelial neoplasia (PIN), with low-grade PIN in the GT+Q+Arc group. The combined effect of GT+Q+Arc was associated with an increased inhibition of the androgen receptor, the PI3K/Akt pathway, Ki67 expression, and angiogenesis. This study demonstrates that combining Arc with GT and Q was highly effective in prostate cancer chemoprevention. These results warrant clinical trials to confirm the efficacy of this combination in humans.

MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression.

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type-specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by 2 orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Association of WHSC1/NSD2 and T-cell infiltration with prostate cancer metastasis and prognosis

Progress in immunotherapy for prostate cancer (PCa) lags that for other cancers, mainly because of limited immune infiltration in PCa. This study aimed to assess the feasibility of NSD2 as an immunotherapeutic target in PCa. Immunohistochemistry was performed to evaluate the expression pattern of NSD2 in 34 cases of benign prostatic hyperplasia (BPH), 36 cases of prostatic intraepithelial neoplasia (PIN), and 57 cases of PCa, including 19 cases of metastatic castration-resistant prostatic cancer (mCRPC). Single-cell RNA sequencing and gene set enrichment analysis (GSEA) were used to correlate NSD2 with certain downstream pathways. Furthermore, the Immuno-Oncology-Biological-Research (IOBR) software package was used to analyze the potential roles of NSD2 in the tumor microenvironment. We found that the positive expression rate of NSD2 increased progressively in BPH, PIN and PCa. mCRPC had the highest staining intensity for NSD2. High NSD2 expression was positively correlated with the infiltration level of CD4+ tumor-infiltrating lymphocytes (TILs) and negatively correlated with that of CD8+ TILs. Importantly, a new immune classification based on NSD2 expression and CD4+ TILs and CD8+ TILs was successfully used to stratify PCa patients based on OS.PSA and CD4+ TILs are independent risk factors for PCa bone metastasis. This study demonstrates a novel role for NSD2 in defining immune infiltrate on in PCa and highlights the great potential for its application in immunotherapy response evaluation for prostate malignancies.

Therapeutic effects of finasteride: inhibition of disease progression and serum prostate-specific antigen reduction in patients with prostatic intraepithelial neoplasia.

The objective of this study was to evaluate the impact of finasteride on the progression of prostate intraepithelial neoplasia and levels of prostate-specific antigen (PSA) in patients. A total of 120 patients with high-grade prostatic intraepithelial neoplasia were included in this study from January 2013 to January 2018. All patients underwent prostate biopsies. Among them, 60 patients were assigned to the observation group and received a daily dosage of 5mg finasteride for 60 months, while the remaining 60 patients were assigned to the control group and did not receive finasteride. PSA levels were measured every six months, and imaging scans were conducted throughout the five-year study period. Additional biopsies were performed if PSA levels exceeded 10ng/mL or imaging suggested the presence of prostate cancer. Statistical analysis was applied to the collected data. In total, 25 cases of prostate cancer were identified in this study. Of these cases, 7 patients belonged to the observation group, whereas the remaining 18 patients were from the control group. The observation group exhibited significantly lower levels of total serum PSA (p <0.001) and Gleason scores (p <0.001) compared to the control group. Our study, which involved 120 participants, demonstrated that finasteride effectively reduces serum PSA levels and mitigates the severity of prostate cancer. These findings suggest that finasteride holds potential as a treatment option for patients with -high-grade prostatic intraepithelial neoplasia.

UTILITY OF P63 IMMUNO-EXPRESSION IN DISTINGUISHING BENIGN MIMICKER LESIONS FROM ADENOCARCINOMA PROSTATE-AN OBSERVATIONAL ANALYTICAL STUDY

In men, prostate cancer (PCA) is the second most common malignancy and is the sixth leading cause of death amongst them. Differentiation of benign mimicker lesions (BML) of the prostate from PCA can be challenging sometimes, especially when limited amount of tissue is available. Several immuno-histochemical (IHC) markers are recommended for distinguishing such lesions; which becomes expensive for the patient. The present study was planned to study the utility of P63 IHC marker for diagnosis of benign, BML and adenocarcinoma of the prostate (ACP). The present - observational and analytical study - was conducted on 50 biopsy specimens of the prostate in the Department of Pathology at IIMSR, Lucknow during the period January 2017 to September 2022. The lesions included were: 20 specimens of benign prostatic hyperplasia (BPH), 17 of BML, 3 of prostatic intraepithelial neoplasia (PIN) and 10 of PCA. In the BML group, 5 specimens of basal cell hyperplasia (BCH), 4 specimens of simple atrophy (SA), 3 specimens of post atrophic hyperplasia (PAH) and 5 specimens of adenosis were studied. In the present study, all specimens of BPH and BML are positive for P63 expression on IHC staining. In the PIN group, 2 out of 3 specimens were positive for P63. All 10 specimens of adenocarcinoma prostate were negative for P63 expression. We conclude that use of P63 IHC staining is adequate for distinguishing benign and BMLof prostate fromACPin majority of the specimens.

Enhancing Prostate Tumor Biobanking Reliability with Improved Sampling Technique and Histological Characterization.

Acquiring fresh and well-characterized tumor tissue samples is critical for conducting high-quality "omics" studies. However, it can be particularly challenging in the context of prostate cancer (PC) due to the unique nature of this organ and the high heterogeneity associated with this tumor. On the other hand, histopathologically characterizing samples before their storage without causing significant tissue alterations is also an intriguing challenge. In this context, we present a new method for acquiring, mapping, characterizing, and micro-dissecting resected prostate tissue based on anatomopathological criteria. Unlike previously published protocols, this method reduces the time required for histopathological analysis of the prostate specimen without compromising its structure, which is crucial for assessing surgical margins. Furthermore, it enables the delineation and micro-macro dissection of fresh prostate tissue samples, with a focus on histological tumor areas defined by pathological criteria such as Gleason score, precursor lesions (high-grade prostatic intraepithelial neoplasia - PIN), and inflammatory lesions (prostatitis). These samples are then stored in a Biobank for subsequent research analyses.