Low-grade Prostatic Intraepithelial Neoplasia Research Articles

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.

Long exposure to a mixture of endocrine disruptors prediposes the ventral prostate of rats to preneoplastic lesions.

Endocrine disruptors (ED) are compounds dispersed in the environment that modify hormone biosynthesis, affecting hormone-dependent organs such as the prostate. Studies have only focused on evaluating the effects of ED alone or in small groups and short intervals and have not adequately portrayed human exposure. Therefore, we characterized the prostate histoarchitecture of rats exposed to an ED mixture (ED Mix) mimicking human exposure. Pregnant females of the Sprague-Dawley strain were randomly distributed into two experimental groups: Control group (vehicle: corn oil, by gavage) and ED Mix group: received 32.11mg/kg/day of the ED mixture diluted in corn oil (2ml/kg), by gavage, from gestational day 7 (DG7) to post-natal day 21 (DPN21). After weaning at DPN22, the male pups continued to receive the complete DE mixture until they were 220days old when they were euthanized. The ED Mix decreased the epithelial compartment, increased the fractal dimension, and decreased glandular dilation. In addition, low-grade prostatic intraepithelial neoplasia was observed in addition to regions of epithelial atrophy in the group exposed to the ED Mix. Exposure to the mixture decreased both types I and III collagen area in the stroma. We concluded that the ED Mix was able to cause alterations in the prostatic histoarchitecture and induce the appearance of preneoplastic lesions.

Abstract A044: Generation of a new mouse model to study the role of oncofetal Cripto in aggressive lethal prostate cancer

Abstract Introduction: Early stages of prostate cancer (PCa) are commonly treated with surgery and androgen-deprivation therapy, but PCa can turn castration resistant due to pre-existing stem cell-like cells which might re-initiate tumor growth and lead to metastasis. Previously, it has been shown that human tumors express high levels of Cripto, an oncofetal protein, for this reason our hypothesis is that Cripto might play a role in PCa initiation and progression. We aim to study its oncogenic features in GEMMs models that are representative of early and late metastatic PCa. Methods: We performed conditional Cripto (CRIPTOflox/flox) knock out on N (Nkx3.1CreERT2, R26 LSL-YFP/LSL-YFP), NP (Nkx3.1CreERT2; Ptenflox/flox, R26 LSL-YFP/LSL-YFP) and NPK (Nkx3.1CreERT2; Ptenflox/flox; KrasLSL-G12D/+, R26 LSL-YFP/LSL-YFP) to generate respectively NC, NPC and NPKC. N animals mirror normal epithelium, whereas first stage of the disease, high-grade prostatic intraepithelial neoplasia (PIN)/carcinoma lesions with local invasive epithelium, are seen in NP. More advanced stage with invasive prostate adenocarcinoma with metastasis are developed in NPK. In vivo experiments’ workflow was the following: 8-weeks old mice were castrated and induced one month later with 5 daily injections of tamoxifen, after 2.5 weeks, animals were weekly treated with testosterone (10 weeks). Organoids were generated from YFP+/− single cell population recovered by FACS sorting. Results: Histopathological evaluation of newly generated NPC and NPKC showed presence of mPIN (100%, nNPC= 6, nNPKC=2), with a dominant cribriform morphology. NPKC additionally, features invasive PCa with an extent dominant pattern of 100%, showing portions with dense stroma forming whorl-like structures and occasional sheet-like accumulations of polygonal in stroma of regions with mPIN. In general, NPC and NPKC feature a more reactive stroma with a mild/moderate inflammation compared to the published models. OrganoidsYFP+ recapitulate molecular prostate tissue features, expressing luminal and basal markers. Organoids’ morphology varies consistently: N and NC are low in density and present a more cystic morphology, which is consistent with low-grade PIN phenotypes, whereas NP and NPK organoids are solid and denser which mimics an oncogenic transformation. In general, NC, NPC and NPKC organoids present a higher percentage of hollow organoids compared to N, NP and NPK respectively. Conclusions: NPC and NPKC phenotype specifically, showed important stromal alterations suggesting that Cripto might play a role not only on the epithelial compartment as well as in the stroma. For this reason, studies on secreted Cripto inhibition with ALK4-Fc are on-going. Our results show that organoids are an efficient in vitro model replicating different phenotypes seen in vivo. Citation Format: Elisa Rodrigues Sousa, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, Marianna Kruithof-de Julio. Generation of a new mouse model to study the role of oncofetal Cripto in aggressive lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A044.

MP20-14 GENERATION OF A NEW GEMMs MODEL TO EXPLORE THE ROLE OF ONCOFETAL CRIPTO IN PROSTATE CANCER PROGRESSION

You have accessJournal of UrologyCME1 Apr 2023MP20-14 GENERATION OF A NEW GEMMs MODEL TO EXPLORE THE ROLE OF ONCOFETAL CRIPTO IN PROSTATE CANCER PROGRESSION Elisa Rodrigues Sousa, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, and Marianna Kruithof-de Julio Elisa Rodrigues SousaElisa Rodrigues Sousa More articles by this author , Eugenio ZoniEugenio Zoni More articles by this author , Mario ScarpaMario Scarpa More articles by this author , Marta De MennaMarta De Menna More articles by this author , Allen Abey AlexanderAllen Abey Alexander More articles by this author , Simone De BrotSimone De Brot More articles by this author , George N. ThalmannGeorge N. Thalmann More articles by this author , and Marianna Kruithof-de JulioMarianna Kruithof-de Julio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003245.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Early stages of prostate cancer (PCa) are treated with surgery and androgen-deprivation therapy, but PCa can turn castration resistant possibly due to stem cell-like cells that re-initiate PCa growth and lead to metastasis. Given that Cripto is highly expressed in human tumors, we hypothesise that Cripto might play a role in tumor initiation and late progression, so we knockout Cripto in PCa GEMMs models with the aim of studying its oncogenic role. METHODS: N ( Nkx3.1CreERT2, R26 LSL-YFP/ LSL-YFP), NP (Nkx3.1CreERT2; Ptenflox/flox, R26 LSL-YFP/ LSL-YFP) and NPK (Nkx3.1CreERT2; Ptenflox/flox; KrasLSL-G12D/+, R26 LSL-YFP/ LSL-YFP) were crossed with conditional Cripto knockout (CRIPTOflox/flox) to generate NC, NPC and NPKC. N mice mirror normal epithelium, NP mimic the first stage of the disease, with high-grade prostatic intraepithelial neoplasia (PIN)/carcinoma lesions with local invasive epithelium, while NPK have invasive prostate adenocarcinoma with metastasis. In vivo experiments’ workflow is the following: castration of 8-weeks old mice and induction after 1 month with 5 daily injections of tamoxifen, after 2.5 weeks mice were treated with weekly testosterone (10 weeks). Single cells were isolated from prostate tissue and the YFP+/- population recovered by FACS sorting and cultured as organoids. RESULTS: Histopathological evaluation of NPC and NPKC showed presence of mPIN (100%) with a dominant cribriform morphology. NPKC feature invasive PCa with an extent dominant pattern of 100% and portions with dense stroma forming whorl-like structures and occasional sheet-like accumulations of polygonal in mPIN regions. NPC and NPKC, compared to NP and NPK, present a more reactive stroma with a mild/moderate inflammation reaction. Organoids express luminal and basal markers mirroring molecular features of matched tissues. Morphology varies consistently: NP, NPC, NPK and NPKC organoids are solid which is consistent with an oncogenic transformation, whereas N and NC organoids present a cystic morphology, with lower densities, which correlates with low-grade PIN phenotypes. NC, NPC and NPKC organoids feature a higher percentage of hollow organoids compared to N, NP and NPK respectively. CONCLUSIONS: Stromal alterations in NPC and NPKC might suggest a role for Cripto not only restricted to prostate epithelium. For this reason, studies on secreted Cripto inhibition with ALK4-Fc are planned. Our finding support that organoids are an efficient in vitro model replicating in vivo phenotypes. Source of Funding: United States Department of Defense © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e281 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elisa Rodrigues Sousa More articles by this author Eugenio Zoni More articles by this author Mario Scarpa More articles by this author Marta De Menna More articles by this author Allen Abey Alexander More articles by this author Simone De Brot More articles by this author George N. Thalmann More articles by this author Marianna Kruithof-de Julio More articles by this author Expand All Advertisement PDF downloadLoading ...

DIAGNOSTIC UTILITY OF IMMUNOHISTOCHEMICAL EXPRESSION OF KI-67, P63 AND AMACR IN PROSTATE INTRAEPITHELIAL NEOPLASIA

The aim: To determine malignant transformation and progression ability of high grade and low grade prostate intraepithelial neoplasia with the help of immunohistochemical method. Materials and methods: The results of examination of 93 patients with PIN (50 patients with high grade PIN and 43 patients with low grade PIN) were assessed comparatively using immunohistochemical markers. Semiquantitative method was used to evaluate !"-67, #63 and AMACR tissue expression with four grades from "+" to "++++" or from 1 to 4 points: '+' - low reaction, '++' - poor reaction, '+++' - moderate reaction and '++++" - intense reaction. Results: There were statistically significant differences in immunohistochemical expression rates between HGPIN and LGPIN. Patients with HGPIN had higher Ki-67 and AMACR expression rate and lower p63 expression rate than patients with LGPIN. Intense and moderate Ki-67 expression was detected in HGPIN more often, in 24 % and 11 % respectively. Low and moderate AMACR expression was determined in HGPIN more often, in 28 % and 5 % respectively. Low and not evident p63 expression was observed in HGPIN more often, in 36 % and 8 % respectively. Conclusions: HGPIN has common morphological peculiarities with prostate adenocarcinoma. Immunohistochemical detection of Ki-67, p63 and AMACR is aimed to differentiate among patients with PIN a group of high malignant transformation risk.

Incidence of prostatic intraepithelial neoplasia in TURP specimens with special reference to p63 expression in various lesions of prostate

Introduction: Prostate cancer is the second common malignancy in men. Prostatic intraepithelial neoplasia (PIN) is the precursor lesion of prostatic carcinoma. Histopathological examination is necessary to diagnose PIN lesions. Objective: The aim of the study is to determine the incidence of Prostatic intraepithelial neoplasia and to analyse the usefulness of basal cell marker p63 expression in various lesions of prostate. Methods: This is a two-year prospective study of 65 transurethral resection specimens of prostate, carried out in the Department of pathology, Dr B R Ambedkar Medical College, Bangalore. mmunohistochemical marker p63 is used and its expression in various lesions was analysed. Results: Out of 65 cases studied, 4 were inflammatory lesions, 52 were benign prostatic hyperplasia (BPH) and 9 were malignant lesions. Low grade PIN was identified in 8(12.3%) cases of BPH. High grade PIN was seen in 9(13.8%) cases and tufting pattern was the commonest. HGPIN was predominantly associated with adenocarcinoma. p63 was expressed in all the benign glands in BPH and HGPIN. Malignant glands were negative for p63 expression.

Estrogen receptor expression is modulated in human and mouse prostate epithelial cells during cancer progression

Substantial data posit estrogen receptors (ERs) as promising targets for prostate cancer (PCa) therapeutics. However, the trials on assessing the chemo-preventive or therapeutic potential of ER targeting drugs or selective estrogen receptor modulators (SERMs) have not yet established their clinical benefits. This could be ascribed to a possible modulation in the ER expression during PCa progression. Further it is warranted to test various ER targeting drugs in appropriate preclinical models that simulate human ER expression pattern during PCa progression. The study was undertaken to revisit the existing data on the epithelial ER expression pattern in human cancerous prostates and experimentally determine whether these patterns are replicated in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice, a model for human PCa. Estradiol (E2) binding to the plasma membrane of the epithelial cells and its modulation during the PCa progression in TRAMP were also investigated.A reassessment of the existing data revealed a trend towards downregulation in the epithelial expression of wild-type ESR1 transcripts in high-grade PCa, compared to non-cancerous prostate in humans. Next, epithelial cell-enriched populations from TRAMP prostates (TP) displaying low-grade prostatic intraepithelial neoplasia (LGPIN), high-grade PIN (HGPIN), HGPIN with well-differentiated carcinoma (PIN + WDC), WDC (equivalent to grade 2/3 human PCa), and poorly-differentiated carcinoma (PDC-equivalent to grade 4/5 human PCa) revealed significantly higher Esr1 and Esr2 levels in HGPIN and significantly reduced levels in WDC, compared to respective age-matched control prostates. These patterns for the nuclear ERs were similar to the trend shown by E2 binding to the plasma membrane of the epithelial cells during PCa progression in TRAMP. E2 binding to epithelial cells (EpCAM+), though significantly higher in TPs displaying LGPIN, decreased significantly as the disease progressed to WDC. The study highlights a reduction in the epithelial ESR level with the PCa progression and this pattern was evident in both humans and TRAMP. These observations may have major implications in refining PCa therapeutics targeting ER.

Elevated expression of the colony-stimulating factor 1 (CSF1) induces prostatic intraepithelial neoplasia dependent of epithelial-Gp130.

Macrophages are increased in human benign prostatic hyperplasia and prostate cancer. We generate a Pb-Csf1 mouse model with prostate-specific overexpression of macrophage colony-stimulating factor (M-Csf/Csf1). Csf1 overexpression promotes immune cell infiltration into the prostate, modulates the macrophage polarity in a lobe-specific manner, and induces senescence and low-grade prostatic intraepithelial neoplasia (PIN). The Pb-Csf1 prostate luminal cells exhibit increased stem cell features and epithelial-to-mesenchymal transition. Human prostate cancer patients with high CSF-1 expression display similar transcriptional alterations with the Pb-Csf1 model. P53 knockout alleviates senescence but fails to progress PIN lesions. Ablating epithelial Gp130 but not Il1r1 substantially blocks PIN lesion formation. The androgen receptor (AR) is downregulated in Pb-Csf1 mice. ChIP-Seq analysis reveals altered AR binding in 2482 genes although there is no significant widespread change in global AR transcriptional activity. Collectively, our study demonstrates that increased macrophage infiltration causes PIN formation but fails to transform prostate cells.

Clinical significance of high grade and low grade prostate intraepithelial neoplasia

Such premalignant conditions of prostate cancer (PC) as prostate intraepithelial neoplasia (PIN) are classified between benign and malignant ones. Contemporary evidence wheather PIN develops malignancy is limited and (LGPIN) data present varied results. Morphological and clinical differencies between high (HGPIN) and low grade PIN specimens in the prostate remain unclear. Aim of the work – to determine clinical significance and progression ability of high grade and low grade prostate intraepithelial neoplasia. The results of examination of 276 patients with PIN (152 patients with high grade PIN and 134 patients with low grade PIN) were assessed comparatively. During a 3 year follow-up repeated prostate biopsies were performed with 6 months interval to detect PC. Initial and repeated multifocal transrectal prostate biopsies from 12 samples were performed under transrectal ultrasonic guidance. There were statistically significant differences in PC detection rates between HGPIN and LGPIN. Patients with HGPIN had  malignization rate of 42.1% during a 3-year follow-up that was by 33.9% higher than in LGPIN patients. The spread of HGPIN lesions within prostate gland is a malignization risk factor. The mean malignization term of HGPIN is 18 months and of LGPIN – 30 months. Low and high grade PIN are gradual stages of cancerogenesis. PIN grade determines its clinical significance, while LGPIN has low malignization potential, HGPIN possesses morphological and clinical prostate characteristics similar to adenocarcinima.

PROGNOSTIC SIGNIFICANCE OF MAGNETIC RESONANCE IMAGING IN PATIENTS WITH PROSTATE INTRAEPITHELIAL NEOPLASIA

The aim: To determine prognostic significance of mpMRI in prostate intraepithelial neoplasia (PIN) diagnostics. Materials and methods: The results of examination of 52 patients with PIN were assessed in mpMRI using PIRADS criteria. The total number of samples with PIN amounted 166. According to PIRADS MRI assessment of central and peripherial zones was made separately. The use of T2WI, DWI, DCE in patients with high grade and low grade PIN was studied. MRI was performed before prostate biopsy (MRI cognitive fusion biopsy). During 3-year follow-up rebiopsies were performed with prostate cancer detection. PIRADS values of PIN lesions with malignisation were compared with those without following tumor transformation. Results: There was a difference in values of PIRADS characteristics between PIN and benign prostatic tissue. The mean of PIRADS gradation in samples with PIN was 2,1. Among them 47 (28,3 %) PIN samples had gradation 3 (the presence of clinically significant cancer is equivocal), in 8 (4,8 %) cases - gradation 4 (clinically significant cancer is likely to be present). The mean of PIRADS gradation was in 24 % larger in cases with subsequent PC detection than in cases without malignisation. Conclusions: MRI parameters in PIN cases differ from normal prostate tissue. PIRADS assessment has prognostic significance of following malignisation of PIN pieces that have similar properties on MRI as prostate cancer. Further study is required to stratify all PIN patients into groups of high malignisation risk in order to perform detailed examination and treatment.

Abstract C031: Regular physical activity can prevent the oncogenic effects of lifestyle-associated advanced glycation end products

Abstract Advanced glycation end-products (AGEs), are reactive metabolites produced endogenously as a consequence of glucose metabolism. AGEs accumulate in tissues and organs as we grow older to promote multiple chronic disease phenotypes. AGE pathogenic effects are mediated through modification of protein function, genetic fidelity, stress responses and cellular signaling pathways. Critically, cancer disparity factors such as a sedentary lifestyle, obesity and an unhealthy diet are external influences that have been shown to contribute to the accumulation of AGEs. This research group examined circulating and tumor AGE levels in clinical specimens of prostate cancer and identified a race specific, tumor-dependent pattern of accumulation. AGE levels were highest in aggressive tumors, especially those from men with African ancestry. As our understanding of tumor biology advances, it is becoming increasingly clear that these lifestyle factors have distinct molecular consequences on the biologic make up of tumors, altering cell signaling events and gene expression profiles to contribute to cancer disparity outcomes such as earlier development or its progression to more aggressive disease. Increased AGE levels correlated with an up-regulation in the receptor for advanced glycation end products (RAGE) and activated NFkB. In a syngeneic sub-cutaneous prostate cancer mouse model, chronic consumption of AGE resulted in a 3-fold increase in tumor growth. Dietary-AGE mediated increases in tumor growth were accompanied by a cytoplasmic accumulation of AR, elevation in MYC, RAGE, and AGE as well as increased cell proliferation. Given the links between lifestyle and AGEs we examined the effects of regular physical activity on AGE induced tumor growth in our syngeneic sub-cutaneous dietary-AGE prostate cancer model. Mice exposed to physical activity for 1 hour, 5 days per week showed a significant decrease in AGE induced tumor growth. We also examined the effects of dietary-AGEs on tumor progression using the FVB-Tg(C3-1-TAg)cJeg/JegJ (C3-Tag) transgenic spontaneous prostate cancer mouse model. This model progresses to low grade prostate intraepithelial neoplasia (PIN) at 24 weeks. However, chronic consumption of AGE resulted in increased progression towards moderate to high grade PIN at this same time point. When regular physical activity was introduced, we observed delayed progression of PIN in both dietary groups, but most significantly in the high AGE fed mice. These studies support the concept that AGEs represent a biological consequence of the socioeconomic and environmental factors that promote cancer disparity, which may be at least in part reversed via physical activity. This may have the greatest impact for African American patients who tend to have poorer survival, and where a lack of physical activity, poor diet, and high obesity rates are more prevalent. Citation Format: Bradley A Krisanits, Pamela M Woods, Dion Foster, Lourdes M Nogueira, Laura Spruill, Marvella E Ford, Victoria J Findlay, David P Turner. Regular physical activity can prevent the oncogenic effects of lifestyle-associated advanced glycation end products [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C031.

Cordia lutea L. Flowers: A Promising Medicinal Plant as Chemopreventive in Induced Prostate Carcinogenesis in Rats.

The objective of this study was to evaluate the chemopreventive effect of the ethanolic extract of Cordia lutea flowers (EECL) on N-methyl-N-nitrosourea- (MNU), cyproterone-, and testosterone-induced prostate cancer in rats. 40 Holtzman male rats were used and assigned to 5 groups (n = 8). In Group I, rats received normal saline (10 mL/Kg); Group II: rats were induced for prostate cancer with cyproterone, testosterone, and NMU; Groups III, IV, and V: rats received EECL daily, at doses of 50, 250, and 500 mg/kg body weight, respectively. After the period of treatment, animals were sacrificed by an overdose of pentobarbital and blood samples were collected for determination of prostate-specific antigen (PSA). The prostate was dissected and weighed accurately. The ventral lobe of the prostate was processed for histopathology analysis. The somatic prostate index decreased with EECL at dependent dose, from 0.34 ± 0.04 to 0.23 ± 0.05 (P < 0.05). The PSA levels also decreased significantly at doses of 250 and 500 mg/kg. Histopathological analysis showed a decrease in the number of prostatic layers with high-grade prostatic intraepithelial neoplasia (HG-PIN) and low-grade prostatic intraepithelial neoplasia (LG-PIN) at the dose of 500 mg/kg. The ethanolic extract of Cordia lutea flowers had a chemopreventive effect on induced prostate cancer in rats.

Hexane Insoluble Fraction from Purple Rice Extract Retards Carcinogenesis and Castration-Resistant Cancer Growth of Prostate Through Suppression of Androgen Receptor Mediated Cell Proliferation and Metabolism

Prostate cancer and castration-resistant prostate cancer (CRPC) remain major health challenges in men. In this study, the inhibitory effects of a hexane insoluble fraction from a purple rice ethanolic extract (PRE-HIF) on prostate carcinogenesis and CRPC were investigated both in vivo and in vitro. In the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model, 1% PRE-HIF mixed diet-fed rats showed a significantly higher percentage of low-grade prostatic intraepithelial neoplasia and obvious reduction in the incidence of adenocarcinoma in the lateral lobes of the prostate. Additionally, 1% PRE-HIF supplied diet significantly suppressed the tumor growth in a rat CRPC xenograft model of PCai1 cells. In LNCaP and PCai1 cells, PRE-HIF treatment suppressed cell proliferation and induced G0/G1 cell-cycle arrest. Furthermore, androgen receptor (AR), cyclin D1, cdk4, and fatty acid synthase expression were down-regulated while attenuation of p38 mitogen-activated protein kinase, and AMP-activated protein kinase α activation occurred in PRE-HIF treated prostate cancer cells, rat prostate tissues, and CRPC tumors. Due to consistent results with PRE-HIF in PCai1 cells, cyanidin-3-glucoside was characterized as the active compound. Altogether, we surmise that PRE-HIF blocks the development of prostate cancer and CRPC through the inhibition of cell proliferation and metabolic pathways.

Abstract LB-131: Mast cells promote local angiogenic and structural remodeling, a precursor to prostate cancer

Abstract Prostate cancer (PCa) is the second cancer-cause of death of men in the USA. Upon transformation, prostatic epithelial cells (EC) gradually evolve from benign, premalignant, to malignant phenotypes. Prostatic Intraepithelial Neoplasia (PIN) is an abnormal growth of EC progressing from Low grade (L) PIN to High grade (H) PIN. Twenty percent of patients with HPIN advance to PCa, therefore, most studies focus on the HPIN-PCa progression. We hypothesized that the less-studied LPIN stage may feature unique remodeling processes that also predispose to PCa. Perivascular and prostate-resident mast cells (MC) are first-line sources of preformed tumor-promoting mediators, including angiogenic vascular endothelial growth factor-A (VEGF) and sphingosine-1-phosphate (S1P), a sphingolipid metabolite produced by sphingosine kinase (SphK). Using the C3(1)/SV40Tag transgenic (C3) mouse model that mimics human PCa initiation and progression, we sought to investigate remodeling in LPIN. We designed a novel quantitative method of image analysis to measure in situ angiogenesis in prostate sections that integrates capillary-restricted CD31 quantification and morphometric parameters. Increased angiogenesis was discovered in LPIN and MC were located near the newly generated blood capillaries. LPIN sections featured augmented MC numbers, more activated in LPIN, than normal C3 or wild-type littermate sections. Moreover, local mRNA coding for Sphk, Vegfa and matrix metalloproteinase (Mmp) 9 were significantly increased in LPIN samples, accompanied with elevation of S1P. Additional evidence of structural remodeling in LPIN samples included a substantial increase in mRNA coding for collagens type I and III (Col1a1 and Col3a1). Importantly, we established a novel computer-aided imaging method to quantify cell-associated VEGF protein expression in tissue sections based on signal intensity measured through conversion to a gray-scale value then area-under-the-curve calculation. Remarkably, local VEGF expression was exclusively restricted to MC in all experimental groups and was more elevated in LPIN samples. Next, transcriptomics for remodeling genes conducted with human patient samples revealed that, for each patient, cancer-bearing biopsies also featured significant increases in SPHK, VEGF, MMP9, COL1 and COL3 mRNA expressions, compared to normal biopsies. Altogether, our preclinical and human data provides a new strategic paradigm to untangle the link between MC, early local remodeling observed in LPIN and PCa. Surveillance of MC and their mediators may lead to new diagnostic and precision medicine modalities for the clinical targeting of MC and for early interception of PCa. Citation Format: Ahmed Aladhami, Michael Hobensack, Nabihah I. Kumte, Alena P. Chumanevich, Taryn L. Cranford, Alexander Sougiannis, Reilly T. Enos, Kandy T. Velázquez, Ioulia Chatzistamou, John W. Fuseler, Angela Murphy, Carole A. Oskeritzian. Mast cells promote local angiogenic and structural remodeling, a precursor to prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-131.

The application value of SonoLiver software in differential diagnosis of the nodules within prostatic inner gland

Objective To provide objective basis for the diagnosis on nodules of prostatic inner gland by SonoLiver software with the dynamic vascular pattern (DVP) and the parameters of contrast-enhanced ultrasonography(CEUS). Methods In a reprospective study, CEUS was performed in 104 cases with nodules of prostatic inner gland that were divided into four groups including the benign prostatic hypertrophy(BPH) group (n=26) and prostate cancer(PCa) group (n=29), the others in high grade prostate intraepithelial neoplasia(HGPIN, n=25) and low grade prostate intraepithelial neoplasia(LGPIN, n=24) that developed from BPH. The SonoLiver software was used to analyze the CEUS of nodules to get the DVP and parameters of CEUS. Results Among the four groups, the prostate specific antigen (PSA) level and nodule maximal size were significant different(P 0.05). The nodules in BPH and LGPIN group mostly were cold-warm colour, also as only cold colour(P>0.05). The difference of DVP among the four groups was significant (P<0.05). Conclusions The application of SonoLiver software with DVP and parameters of CEUS is valuable to diagnose the nodules of prostatic inner gland. Key words: Contrast-enhanced ultrasound; Prostatic neoplasms; Diagnosis; Dynamic vascular pattern

Differential immunohistochemical expression of AMACR and ERG in prostatic lesions

Introduction Alpha-methylacyl-CoA (AMACR) is an enzyme of the mitochondria and perixosomes. It was found that it showed great overexpression in prostatic adenocarcinoma, even with minimal foci. TMPRSS2/ERG fusion is one of the common genetic anomalies affecting PCa. A great correlation between positive immunohistochemical (IHC) expression for ERG and the state of fusion has been found, but the diagnostic and prognostic importance of ERG IHC remains undetected. This study aimed to evaluate the differential diagnostic and prognostic significance of both AMACR and ERG in PCa with correlation to the clinicopathological variables.Materials and methods TThe authors reviewed 70 prostatic lesions. Prostatic adenocarcinoma (50 cases), prostatic intraepithelial neoplasia (PIN) (15 with high-grade PIN, five with low-grade PIN), and benign prostatic hyperplasia (10 cases) that were used as a control. Immunohistochemical staining for AMACR and ERG was done. Follow-up of the cases for 18 months was also done.Results A statistically significant difference in the expression of ERG among the examined cases was found. It was negative in control benign prostatic hyperplasia and low-grade PIN cases), positive in 20% of high-grade PIN, and 74% of prostatic adenocarcinoma cases (P<0.01). No statistically significant correlation was found between ERG expression and tumor volume, Gleason sum score, stage, surgical margin, presence of lymphovascular invasion, perinural invasion, distant metastasis, and survival (P>0.05). Regarding AMACR expression, a statistically significant difference in the expression of AMACR among the examined cases was found (negative in benign prostatic hyperplasia, and low PIN cases) to be positive in 33.3% of high-grade PIN and in 62% of prostatic adenocarcinoma cases (P<0.01). A statistically significant correlation was found between AMACR expression and tumor volume, Gleason sum score, surgical margin, presence of lymphovascular invasion, and survival (P<0.05).Conclusion The study provides an additional evidence that IHC expression of AMACR has a role in prostatic carcinoma development. IHC expression of AMACR was absent in benign prostatic lesions. AMACR is an essential tumor marker for the diagnosis and prognosis of prostatic lesions. IHC expression of ERG may have a role in the diagnosis and biological stratification of prostate cancer.

Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration.

Purpose: Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer.Experimental Design: By using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer.Results: Treating TRAMP mice with metformin delays prostate cancer progression from low-grade prostatic intraepithelial neoplasia to high-grade PIN, undifferentiated to well-differentiated, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after androgen deprivation therapy (ADT) induced by surgically castration in mice, bicalutamide treatment in patients, and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells.Conclusions: Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting the COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment. Clin Cancer Res; 24(22); 5622-34. ©2018 AACR.

Outcomes of Prostate Atypical Small Acinar Proliferation and High-Grade Prostate Intraepithelial Neoplasm Patients

Objective: Atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HGPIN) are two pathological findings occasionally noted in prostate biopsies. Previous Western studies reported that they were associated with prostate cancer. However, none Taiwanese series report the subsequent cancer detection in ASAP and HGPIN patients. This study aimed to examine the results of repeated biopsies in the patients with ASAP and HGPIN. Materials and Methods: A total of 220 consecutive patients with ASAP and/or HGPIN at our institute between January 1990 and December 2010 were enrolled. Patient demographics and clinical information were extracted from the electronic database of our institute. Prostate biopsies were performed through transrectal ultrasound guidance. The patients who had concurrent prostate cancer (n = 51) and no repeated prostate biopsies (n = 103) were excluded from the study. Patients with biopsy pathologies reporting low-grade prostatic intraepithelial neoplasia (n = 2) were also excluded. The remaining 64 patients were available for the final analysis. Results: Nearly, 38, 24, and 2 patients were initially diagnosed as ASAP, HGPIN, and ASAP along with HGPIN, respectively. After 10 years of follow-up, 36.8% patients in ASAP group developed prostate cancer, while 16.7% in HGPIN group and 100% in ASAP + HGPIN group. Median time to developing prostate cancer were 20 months in ASAP group, 31 months in HGPIN group, and 48 months in ASAP + HGPIN group. There was no significant difference of prostate cancer development between ASAP and HGPIN group (P = 0.291). Only older age, classified by 65 years, was significantly associated with a higher detection rate of prostate cancer. Conclusion: Patients with the initial diagnosis of ASAP or PIN has a high risk of developing prostate cancer. Therefore, those patients should be well announced and followed regularly.

Histopathological findings of prostatic autopsy in a sample of over 50 years old men in Baghdad, Iraq

Background: Incidental carcinoma of the prostate is very important is one of the major life-threatening condition for men at all ages. The incidence was found to increase with age. The aim of this study was to evaluate prostatic autopsy samples from Iraqi men over 50 years of age.Methods: 100 autopsy samples of whole prostate were collected from the Institute of Forensic Medicine in Baghdad. All the autopsy cases over 50 years of age died from causes unrelated to prostatic disease.Results: Age ranges from 50-80 years and the mean age was 59.3 years. Benign prostatic hyperplasia was the common pathological finding (92%). Forty-eight cases of benign prostatic hyperplasia were associated with chronic non-specific prostatitis (CNP), 6 cases were associated with low grade prostatic intraepithelial neoplasia and 2 cases with infarction and 6 cases of low grade prostatic intraepithelial neoplasia. Prostatic adenocarcinoma was detected in 6% of the cases. The mean weight was 39.9gm. The mean ellipsoid volume was 34.9cm3. The mean spheroid volume was 36.1cm3. The majority of benign prostatic hyperplasia cases were found in the 6th decade.Conclusions: From the present study, we can conclude that the majority of cases were in the 6th decade, benign prostatic hyperplasia was the most common finding, the most common association with benign prostatic hyperplasia was chronic nonspecific prostatitis, a low frequency of prostatic carcinoma and it was not associated with benign prostatic hyperplasia.

Characteristics of serum PSA in HGPIN patients and the effect of the number of the first time biopsy HGPIN positive needles on the detection rate of second biopsy PCa

Objective To investigate characteristics of serum prostate specific antigen (PSA) in HGPIN patients and the effect of the number of the first time biopsy high grade prostatic intraepithelial neoplasia (HGPIN) positive needles on the detection rate of secondary biopsy prostate cancer (PCa). Methods A total of 320 patients who underwent prostate biopsy in our hospital from February 2013 to December 2015 were selected. Ultrasound guided prostate biopsy was performed in all patients, and the differences of serum PSA was analyzed, non PCa patients after 6 months of treatment underwent the secondary biopsy. Results All patients for the first time biopsy results showed: 80 patients with HGPIN ( 51 cases of solitary type and 29 cases of multifocal type ), 45 cases of low grade prostatic intraepithelial neoplasia (LGPIN), 128 cases of benign prostatic hyperplasia (BPH), 67 cases of PCa. Serum PSA of patients with PCa was significantly higher than that of BPH, LGPIN, solitary and multifocal HGPIN patients (P 0.05). PCa proportion of secondary biopsy in multifocal HGPIN patients was 38.46%, significantly higher than BPH, LGPIN and solitary HGPIN patients (P 0.05). Conclusions Serum PSA level of multifocal HGPIN patients is higher than solitary HGPIN, BPH and LGPIN, but still lower than PCa. Detection rates of secondary biopsy PCa in multifocal HGPIN patients are significantly higher than other patients. Key words: Prostatic Neoplasms; Prostate-Specific Antigen; Biopsy, Needle