Proliferative Inflammatory Atrophy Research Articles

EGF Receptor Expression in Canine Prostate with Proliferative Inflammatory Atrophy and Carcinoma

EGF Receptor Expression in Canine Prostate with Proliferative Inflammatory Atrophy and Carcinoma

Abstract B89: The significance of Vitamin D deficiency and anaerobes in prostate cancer

Abstract Objective: Long-term sun exposure estimates correlate with risk of PC possibly due to long-term Vitamin D deficiency diminishing macrophage function allowing persistence of low grade pathogens causing chronic inflammation leading to Proliferative Inflammatory Atrophy and then cancer. Recently infection with two low grade pathogenic organisms, teenage acne associated Vitamin D sensitive anaerobic bacterium Propionibacterium.acnes (PA) and protozoan Trichomonas vaginalis (TA), have been notable exceptions. This presentation reports a systematic review of reports on anaerobes, circumcision and the association of sun exposure in causation of PC and considers how these observations could contributing to increased PC in Africa Methods: Pubmed searches using terms prostate or prostatic, sunshine or UVB or Vitamin D and acne or PA or TA were performed Results: Two systematic reviews of PC and Vitamin D failed to produce a consistent association. 4/4 studies of index of long-term sun exposure involving 1568 patients and 9/12 geographic studies demonstrated that high UVB exposure reduced PC risk. 4/5 publications on PA and PC and 2/3 publications on TV and PC showed consistent increase risk of PC associated with infection. Ten studies involving 5681 patients demonstrated significant reduction of PC in circumcised individuals (OR 0.87), including one in African American Men showing lower incidence of circumcision possibly contributing to their higher frequency Conclusion: Reduced long-term Vitamin D mediated non-specific macrophage surveillance against low-grade pathogenic anaerobes could explain these associations with PC and increasing urbanisation could be a factor in the health inequality as measured by prostate cancer incidence in African-American men. Citation Format: Tim Oliver, Lucy Blackburn, Frank Chinegwundoh. The significance of Vitamin D deficiency and anaerobes in prostate cancer. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B89.

Polyomavirus BK and prostate cancer: a complex interaction of potential clinical relevance.

Several studies associating BK polyomavirus (BKPyV) and prostate cancer (PCa) suggested that this virus may exert its oncogenic activity at early stages of cancer development. The BKPyV oncogene, the large T antigen (LTag), has frequently been detected in areas of proliferative inflammatory atrophy, which is considered a precursor lesion leading to prostatic intraepithelial neoplasia and overt PCa. In a recently updated systematic review, the presence of BKPyV was significantly higher in PCa tissues than in healthy control tissues, providing an indication for a link between BKPyV infection and cancer risk. In addition, recent original investigations highlighted an association between expression of the virus and the clinical course of PCa. For example, by studying immune responses elicited against BKPyV LTag, a significant association between LTag positive cancer lesions and a peculiar regulatory profiling has been observed in PCa patients with evidence of disease recurrence after surgical radical prostatectomy. Lastly, a study carried out in a larger cohort of patients undergoing radical prostatectomy revealed the IgG response against LTag as an independent predictor of disease recurrence. Although a full picture of the mechanisms potentially responsible for the involvement of BKPyV in PCa is not available yet, continuing work on this topic should help to refine the potential role of BKPyV in PCa patients, perhaps revealing unsuspected associations with the clinical course of this disease.

Clinical significance of proliferative inflammatory atrophy finding in prostatic biopsies.

Proliferative inflammatory atrophy (PIA) has been involved in prostatic carcinogenesis. However, little is known about the clinical significance of a PIA finding in prostatic biopsies (PBs). The aim of this study is to determine the incidence of prostate inflammatory atrophy (PIA) in prostate biopsies (PBs), its association to high-grade prostatic intraepithelial neoplasia (HGPIN), prostate cancer (PCa), and tumor aggressiveness. Prospective and observational study of PIA lesion in 528 extended PBs and 200 radical prostatectomy specimens (RPS). PIA, HGPIN, PCa incidence, Gleason score, clinical and pathologic tumor stage and insignificant tumor rate. Univariate and multivariate analysis. Overall incidence of PIA and HGPIN was 30.3% and 54%. In RPS, the incidence was 30.5% and 72%, respectively. No significant association was found between PIA and HGPIN. Overall PCa detection rate in PBs was 38.1%. PCa was found in 27.5% PBs with PIA and 42.7% of those without PIA, P < 0.001. In contrast, PCa was detected in 50.9% of PBs with HGPIN and 23% of those without HGPIN, P = 0.001. Multivariate analysis revealed that PIA decreased the risk of PCa, OR:0.59 (95%CI:0.37-0.95), P = 0.029, while HGPIN increased OR:3.16 (95%CI:2.04-4.90), P = 0.001. PIA was not related to Gleason grade and clinical stage, however it was associated to an insignificant tumors increase, OR:3.08 (95%CI:1.09-8.7), P = 0.033. The information in RPS suggests that PIA is associated with less aggressive tumors and a higher probability of insignificant tumors. PIA is present in one third of PBs, HGPIN in one half of them, and no association exists between both lesions. Contrary to HGPIN, PIA finding is associated to lower risk of PCa detection. Tumors accompanying PIA seem to be less aggressive and have a greater probability of being insignificant.

Inflammation in prostate cancer progression and therapeutic targeting.

Chronic inflammation contributes to the onset and progression of human cancer, via modifications in the tumor microenvironment by remodeling the extracellular matrix (ECM) and initiating epithelial mesenchymal transition (EMT). At the biological level, chronically inflamed cells release cytokines that are functionally dictating a constitutively active stroma, promoting tumor growth and metastasis. In prostate cancer, inflammation correlates with increased development of “risk factor” lesions or proliferative inflammatory atrophy (PIA). Chronic inflammation in benign prostate biopsy specimens can be associated with high-grade prostate tumors in adjacent areas. In this article, we discuss the current understanding of the incidence of inflammation in prostate cancer progression and the significance of the process in therapeutic targeting of specific inflammatory signaling pathways and critical effectors during tumor progression. Further understanding of the process of chronic inflammation in prostate tumor progression to metastasis will enable development and optimization of novel therapeutic modalities for the treatment of high-risk patients with advanced disease.

Study of Various Histopathological Patterns in Turp Specimens and Incidental Detection of Carcinoma Prostate

Background (Aims and Objective): Study of various histopathological patterns in TURP specimens diagnosed as Benign Prostatic Hyperplasia, identifying type and grade of inflammation, incidental detection of carcinoma prostate and application of modified Gleason system. Materials and Methods: From January 2014 to August 2015 a total of 50 TURP specimens were evaluated. The tissue blocks and H&E stained slides of the tissues were retrieved and slides reviewed. Various patterns of proliferation, types and grade of inflammation were studied and classified using standard methods. Incidentally identified carcinoma prostate were classified using WHO Classification and graded using modified Gleason system. Results: 48(96%) were BPH with co-existing chronic prostatitis 12(24%) granulomatous prostatitis 1(2%) and acute prostatitis 2(8%). Papillary hyperplasia was predominant finding 17(34%). Less frequent finding was basal cell hyperplasia, 6(12%) atypical adenomatous hyperplasia 4(8%) and cribriform hyperplasia 1 (2%). Proliferative inflammatory atrophy constituted 3 cases(6%).Scattered necrotic glands were present in 20(40%) cases, periglandular lymphoid aggregation was a frequent finding in these necrotic glands. we reported two cases of adenocarcinoma prostate with modified Gleason score of one (5+4=9) and another score of (5+3=8). Conclusion: With increase in the incidence and mortality rates from prostate cancer, every effort should be made to improve diagnosis. It is necessary to review periodically all TURP in order to identify premalignant lesions, proliferative activity, and grade of inflammation. Efforts should be made to apply modified Gleason system to improve management facility. We also conclude that proliferative activity and invasiveness increases from benign to the malignant end in the spectrum of prostatic lesion. Keywords: Benign Prostatic Hyperplasia, Prostate Carcinoma, Aah, Pia, Chronic Prostatitis.

Impact of Prostate Inflammation on Lesion Development in the POET3+Pten+/− Mouse Model of Prostate Carcinogenesis

Evidence linking prostatitis and prostate cancer development is contradictory. To study this link, the POET3 mouse, an inducible model of prostatitis, was crossed with a Pten-loss model of prostate cancer (Pten(+/-)) containing the ROSA26 luciferase allele to monitor prostate size. Prostatitis was induced, and prostate bioluminescence was tracked over 12 months, with lesion development, inflammation, and cytokine expression analyzed at 4, 8, and 12 months and compared with mice without induction of prostatitis. Acute prostatitis led to more proliferative epithelium and enhanced bioluminescence. However, 4 months after initiation of prostatitis, mice with induced inflammation had lower grade pre-neoplastic lesions. A trend existed toward greater development of carcinoma 12 months after induction of inflammation, including one of two mice with carcinoma developing perineural invasion. Two of 18 mice at the later time points developed lesions with similarities to proliferative inflammatory atrophy, including one mouse with associated carcinoma. Pten(+/-) mice developed spontaneous inflammation, and prostatitis was similar among groups of mice at 8 and 12 months. Analyzed as one cohort, lesion number and grade were positively correlated with prostatitis. Specifically, amounts of CD11b(+)Gr1(+) cells were correlated with lesion development. These results support the hypothesis that myeloid-based inflammation is associated with lesion development in the murine prostate, and previous bouts of CD8-driven prostatitis may promote invasion in the Pten(+/-) model of cancer.

Abstract 88: Epithelial-mesenchymal transition occurs in preneoplastic and neoplastic lesions of canine prostate

Abstract Background: The epithelial-mesenchymal transition (EMT) is an essential process in the tumor progression and metastasis. In human prostate carcinoma (PCa), the upregulation of cytokeratin and E-cadherin and down-regulation of vimentin have been associated with aggressive phenotype and poor prognosis. Due to the importance of canine cancer model it was evaluated the immunoexpression of AE1/AE3, E-cadherin and vimentin in canine prostatic lesions. Patients and Methods: A total of 75 prostatic tissues formalin-fixed paraffin embedded from dogs was selected: 10 normal prostatic tissues, 20 benign prostatic hyperplasia (BPH), 25 proliferative inflammatory atrophy (PIA) and 20 PCa. AE1/AE3 was detected with a monoclonal antibody (Invitrogen, 180132) at a 1:300 dilution, applied for 45 min at room temperature (RT). The antibody against Vimentin (V9, Invitrogen) and E-cadherin (NCH-38, Dako cytomatiomn) were monoclonal mouse antibodies, used at a 1:300 and 1:200, respectively, for 45 min at RT. The immunolabelling was performed by a polymer method (Histofine, Nichirei Biosciences,). A negative control was performed for all antibodies by omitting the primary antibody and substituting with Tris-buffered saline. The percentage of C-MYC, E-cadherin, and p63- positive cells per lesion was evaluated according to Prowatke et al. (2007). The samples were scored separately according to staining intensity and graded semi-quantitatively as negative, weakly positive, moderately positive, and strongly positive. The score was done in one 400 magnification field, considering only the lesion, since this was done in a TMA core of 1 mm. For statistical analyses, the immunostaining classifications were reduced to two categories: negative and positive. The negative category included negative and weakly positive staining. Chi-square or Fisher exact test was used to determine the association between the categorical variables. Results: All prostatic normal and BPH tissue were positive for cytokeratin, E-cadherin and negative for vimentin. Similarly, all PIA samples were positive for AE1/AE3. From those samples, 48% (12/25) were also positive for vimentin. 55% of PCa (11/25) was positive for vimentin and among these samples 75% (6/11) was also positive for AE1/AE3 and 45% (5/11) was negative for AE1/AE3. PIA and PCa presented a higher number of vimentin positive cells when compared with normal tissue (p=0.032). E-cadherin expression had no statistical difference among diagnosis groups, but we found a higher number of positive cases, with more than 51% of positive immunostaining in BPH and PIA (81.25% and 78.60% of the cases, respectively) than in PCa (55.55%). Conclusion: The carcinogenesis process regarding prostatic epithelial cells in dogs showed higher vimentin protein expression associated with concomitant loss of the cytokeratin and E-cadherin, similar in humans. Financial Support: Sao Paulo State Foundation (FAPESP) and CNPq. Citation Format: Carlos Eduardo Fonseca-Alves, Igor Simoes Tiagua Vicente, Luis Gabriel Rivera Calderon, Andre Augusto Justo, Silvia Regina Rogatto, Renée Laufer-Amorim. Epithelial-mesenchymal transition occurs in preneoplastic and neoplastic lesions of canine prostate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 88. doi:10.1158/1538-7445.AM2014-88

Prostate cancer and new insights in angiogenesis.

Prostate cancer and new insights in angiogenesis.

Expression of phosphorylated-mTOR during the development of prostate cancer.

The PI3K pathway plays a significant role in the progression of prostate cancer (PCa) to an advanced stage. Mouse models suggest that the downstream effector molecule of the PI3K pathway, mTOR, is also important in the development of PCa, where it plays a pivotal role in forming precursor lesions such as high grade prostatic intraepithelial neoplasia (HGPIN). This study was conducted to determine the status of phosphorylated-mTOR (p-mTOR the activated state of mTOR) across the PCa progression model by looking at expression in normal prostate tissue, proliferative inflammatory atrophy (PIA), HGPIN, and PCa. Expression of p-mTOR was evaluated by immunohistochemistry on tissue microarrays constructed from 120 archival formalin-fixed paraffin embedded radical prostatectomy tissue specimens. Levels of expression were recorded as the percentage of positive epithelial cells multiplied by the intensity of staining scored as 0-3. p-mTOR expression was found to increase across the progression model with mean staining in non-neoplastic samples of 40 compared to 98 in PIA, 107 in HGPIN, and 136 in cancer (P < 0.001), but without significant increase between HGPIN and PIA. Correlation of high p-mTOR expression with outcome in PCa showed a trend towards worse prognosis, but this was not statistically significant. This study demonstrates that p-mTOR signaling has a potential role in both the initiation and progression of PCa. These data provide support for further research into the possible use of rapamycin analogues in the treatment of PCa, and raise the possibility that mTOR might be a potential target for chemoprevention.

Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells.

Chronic inflammation of the prostate contributes to the increased risk of prostate cancer. Microbial pathogens in the prostate cause inflammation that leads to prostatitis and proliferative inflammatory atrophy frequently associated with the development of prostate cancer. Bacterial lipopolysaccharides and DNA mediate immune responses by engaging Toll-like receptor (TLR) 4 and 9, respectively. Synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) mimic bacterial DNA and signal through TLR9 to initiate innate immune responses. Here, we show that stimulation of DU145, PC3, or LnCap prostate cancer cells by the TLR9 agonists, CpG-ODN, induces mRNA expression of IL-6, IL-8, CXCL1, IP-10, CCL5, and TGFβ. In addition, activity of matrix metalloproteinase (MMP)-9 and -2 and cell migration increased on CpG-ODN treatment. Induction of cytokines and chemokines was mediated by NF-κB activation and translocation to the nucleus. Treatment with epigallocatechin-3-gallate (EGCG), the major constituent of green tea, prior to CpG-ODN stimulation, inhibits cytokine and chemokine gene induction, activity of MMP-9 and -2, and cell migration. EGCG treatment sequesters the p65 subunit of transcription factor NF-κB in the cytoplasm and inhibits transcriptional activity of the NF-κB-driven promoter in response to CpG-ODN. Our results suggest that the ability of the TLR9 agonists, CpG-ODN, to induce cytokines, chemokines, and MMP activity, as well as suppression by EGCG are independent of the androgen receptor and p53 status of the cells. EGCG may provide protective effects against inflammation in the prostate and benefit prostate cancer treatment.

MP41-07 PROLIFERATIVE INFLAMMATORY ATROPHY IS ASSOCIATED TO LESS AGGRESSIVE AND INSIGNIFICANT TUMORS IN RADICAL PROSTATECTOMY SPECIMENS

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2014MP41-07 PROLIFERATIVE INFLAMMATORY ATROPHY IS ASSOCIATED TO LESS AGGRESSIVE AND INSIGNIFICANT TUMORS IN RADICAL PROSTATECTOMY SPECIMENS Pol Servian, Ana Celma, Jacques Planas, José Placer, Inés M. de Torres, Maria T. Quilez, Maria A. Arbos, and Juan Morote Pol ServianPol Servian More articles by this author , Ana CelmaAna Celma More articles by this author , Jacques PlanasJacques Planas More articles by this author , José PlacerJosé Placer More articles by this author , Inés M. de TorresInés M. de Torres More articles by this author , Maria T. QuilezMaria T. Quilez More articles by this author , Maria A. ArbosMaria A. Arbos More articles by this author , and Juan MoroteJuan Morote More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1224AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Proliferative inflammatory atrophy (PIA) has been proposed to be involved in prostate carcinogenesis by suggesting that it may rise to prostatic carcinoma (PCa) either directly or indirectly by first developing into high grade prostatic intraepithelial neoplasm (HGPIN)1. We have studied the PIA genetic signature 2 and more recently we have learned that PIA incidence in prostatic biopsies is around 30%, and it is associated to lower PCa detection and less aggressive tumors 3. The objectives of this study were to assess the incidence of PIA lesion in radical prostatectomy (RP) specimens and to confirm the hypothesis that PIA is associated to less aggressive tumors. Methods A retrospective study conducted in 200 consecutive patients subjected to RP was done. A single pathologist identified PIA in all specimens and this finding was related with: age, serum PSA, prostate volume, Gleason score, pathologic stage, percentage of tumor in the gland, maximal length of index tumor, perineural invasion, multifocality, bilaterality, insignificant cancer, positive margins, and HGPIN. Mann-Witney U test and Chi-square Pearson test were used to compare data. Results PIA was present in 64 specimens (32%). Age, serum PSA and prostate volume were similar in patients with and without PIA. Respectively, high Gleason grade was present in 34.4% and 49.3%, p=0.033; non-organ confine disease in 10.9% and 16.9%, p=0.187; perineural invasion in 59.4 and 74.3%, p=0.025; multifocal tumors in 59.4% and 74.3%, p=0.001; bilateral tumors in 46.9% and 70.5%, p=0.005; insignificant tumors in 17.2% and 6.6%, p=0.022; HGPIN in 92.2% and 90.4%, p=0.456. Conclusions This study confirms that the incidence of PIA in RP specimens was similar to the one observed previously in prostatic biopsies (32% versus 30%). PIA was not associated to HGPIN. PIA was associated to many pathologic characteristics of less aggressive tumors. Of great clinical interest could be the finding that PIA is associated to unilaterial, unifocal, low grade, and insignificant tumors. 1 De Marzo et al. Am J Pathol 1999; 155: 1985-92. 2 Morote et al. Annual EAU Congress 2012; P-848. 3 Morote el al. Annual AUA Meeting 2013; P-2226. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e453 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Pol Servian More articles by this author Ana Celma More articles by this author Jacques Planas More articles by this author José Placer More articles by this author Inés M. de Torres More articles by this author Maria T. Quilez More articles by this author Maria A. Arbos More articles by this author Juan Morote More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Heat Shock Protein 90 is Associated with Hyperplasia and Neoplastic Transformation of Canine Prostatic Epithelial Cells

Heat shock protein 90 (HSP90) is a molecular chaperone that regulates critical signalling proteins of cancer development and progression. Abnormal levels of HSP90 have been observed in human prostatic carcinoma (PC), with prognostic and therapeutic implications. Since spontaneously arising canine PC is a valuable model for the human disease, the aim of this study was to evaluate the immunohistochemical expression of HSP90 in two normal canine prostates, 17 canine prostates with benign prostatic hyperplasia (BPH) and five canine prostates with PC. HSP90 was expressed in the cytoplasm of epithelial cells in all samples, with a significant increase in labelled cells in PCs. Nuclear labelling was observed occasionally in normal tissue, but was increased in BPH and PC. HSP90 immunoreactivity in preneoplastic lesions (proliferative inflammatory atrophy and prostatic intraepithelial neoplasia) was similar to that in PCs. Increased HSP90 expression in canine PCs suggests the involvement of this molecule in carcinogenesis and tumour progression, supporting HSP90 as a potential target for therapeutic intervention.

Molecular mechanism in the development and progression of prostate cancer

The incidence of prostate cancer has been greatly increased in China and it has ranked the 5th of the malignant tumors in Chinese males.Continuous environment stimulation causes chronic prostatic inflammation,and infiltration of inflammatory cytokines such as INF-γ,TNF-α,and TGF-βcan cause damage and repair of prostatic tissues,leading to proliferative inflammatory atrophy(PIA).Then a small subset of cells will develop somatic genome alterations,including overexpression of MYCand the loss of NKX3.1and PTEN,which can promote PIA into prostatic intraepithelial neoplasia.Androgen receptor mutation and ERG-TMPRSS2 fusion will drive progression of prostatic cancer.

Clinical significance of proliferative inflammatory atrophy in prostate biopsy

IntroductionProliferative inflammatory atrophy (PIA) is a frequently observed lesion in prostate biopsies and some authors have postulated its involvement in prostate carcinogenesis. However, the mechanisms that would permit its neoplastic transformation and the clinical significance of its finding in a prostate biopsy are currently not well known. ObjectiveTo analyze the characteristics of the PIA lesion, its possible role in prostate carcinogenesis and its relation with the tumor aggressiveness. Materials and methodA systematic review was made of the literature in PubMed with the terms «proliferative inflammatory atrophy» or «PIA» and «prostate.» The most important findings are summarized in accordance with the study objective. ResultsPIA seems to be involved in prostate carcinogenesis. This hypothesis is based on its frequent association to cancer lesions (CaP) and on some genetic alterations that are common to the high grade prostatic intraepithelial neoplasia (HGPIN) and to the CaP, fundamentally deficit in GSTP1 expression and overexpression of AGR2. Currently, there are no epidemiological studies that evaluate the incidence of PIA or its association with HGPIN and CaP. Only one study, carried out by our group, has determined the global incidence of PIA in 30% of the prostate biopsies, a lower association to CaP than the HGPIN lesion and an association between PIA and tumors of lower and insignificant grade. ConclusionsPIA shares genetic alterations with HGPIN and CaP. Currently, there is no epidemiologic evidence to consider that the PIA is associated to a greater incidence of CaP and the genetic and epidemiological data available suggest its association to not very aggressive tumors.

Significado clínico de la atrofia proliferativa inflamatoria en la biopsia prostática

IntroductionProliferative inflammatory atrophy (PIA) is a frequently observed lesion in prostate biopsies and some authors have postulated its involvement in prostate carcinogenesis. However, the mechanisms that would permit its neoplastic transformation and the clinical significance of its finding in a prostate biopsy is currently not well known. ObjectiveTo analyze the characteristics of the PIA lesion, its possible role in prostate carcinogenesis and its relation with the tumor aggressiveness. Material and methodA systematic review was made of the literature in PubMed with the terms «proliferative inflammatory atrophy» or «PIA» and «prostate.» The most important findings are summarized in accordance with the study objective. ResultsPIA seems to be involved in prostate carcinogenesis. This hypothesis is based on its frequent association to cancer lesions (CaP) and on some genetic alterations that are common to the high grade prostatic intraepithelial neoplasia (HGPIN) and to the CaP, fundamentally deficit in GSTP1 expression and overexpression of AGR2. Currently, there are no epidemiological studies that evaluate the incidence of PIA or its association with HGPIN and CaP. Only one study, carried out by our group, has determined the global incidence of PIA in 30% of the prostate biopsies, a lower association to CaP than the HGPIN lesion and an association between PIA and tumors of lower and insignificant grade. ConclusionsPIA shares genetic alterations with HGPIN and CaP. Currently, there is no epidemiologic evidence to consider that the PIA is associated to a greater incidence of CaP and the genetic and epidemiological data available suggest its association to not very aggressive tumors.

Alterations of C-MYC, NKX3.1, and E-cadherin expression in canine prostate carcinogenesis

The dog (canis lupus familiaris) is the only other species besides humans that develop spontaneous prostatic carcinomas (PCa) at a high frequency. The canine model is primarily utilized for the study of the PCa molecular mechanisms and provides a natural animal model for the study of potential therapies. In humans, the PCa frequently exhibits mutations in the C-MYC and a reduced expression of the E-cadherin and NKX3.1 proteins. This study's objective was to evaluate the NKX3.1, C-MYC, and E-cadherin expression in the canine normal prostate, benign prostatic hyperplasia (BPH), proliferative inflammatory atrophy (PIA) and PCa and to verify differences in expression and subcellular localization of these proteins in the prostatic carcinogenesis. A tissue microarray (TMA) slide was constructed, and immunohistochemistry with antibodies raised against C-MYC, NKX3.1, E-cadherin and p63 was performed using the peroxidase and DAB methods. The C-MYC protein expression was elevated in the cytoplasm and nuclei of the canine PCa and PIA compared with the normal prostate (P = 0.004. The NKX3.1 protein expression was reduced in 94.75% of the PCa and 100% of the PIA compared with the normal prostate (P = 0.0022). In fact, the expression of E-cadherin trended towards a decrease in carcinomas when compared to normal prostate and PIA. By immunohistochemistry, more p63-positive basal cells were observed in the PCa and PIA when compared with the normal prostate (P = 0.0002). This study has demonstrated that the carcinogenesis of canine prostatic tissue may be related to basal cell proliferation, the gain of C-MYC function and the loss of NKX3.1 protein expression.

EXPRESSÃO DE uPAR NA PRÓSTATA CANINA NORMAL E COM LESÕES PROLIFERATIVAS

Prostatic lesions such as prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy (PIA) are studied in human and canine species due to their malignance potential. The plasminogen activator (PA) system has been suggested to play a central role in cell adhesion, angiogenesis, inflammation, and tumor invasion. The urokinase-type plasminogen activator receptor (uPAR) is a component of the PA, with a range of expression in tumor and stromal cells. In this study, uPAR expression in both canine normal prostates and with proliferative disorders (benign prostatic hyperplasia-BPH, proliferative inflammatory atrophy-PIA, prostatic intraepithelial neoplasia-PIN, and carcinoma-PC) was evaluated by immunohistochemistry in a tissue microarray (TMA) slide to establish the role of this enzyme in extracellular matrix (ECM) remodeling and in the processes of tissue invasion. A total of 298 cores and 355 diagnoses were obtained, with 36 (10.1%) normal prostates, 46 (13.0%) with BPH, 128 (36.1%) with PIA, 74 (20.8%) with PIN and 71 (20.0%) with PC. There is variation in the expression of uPAR in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in tissue with PIA, PIN and PC. The high expression of uPAR in inflammatory and neoplastic microenvironment indicates increased proteolytic activity in canine prostates with PIA, PIN, and PC.KEYWORDS: CD87; PIA; PIN; prostatic carcinoma; TMA.

Matrix metalloproteinases 2 and 9 expression in canine normal prostate and with proliferative disorders

In this study the expression of metalloproteinases 2 (MMP-2) and 9 (MMP-9) in canine normal prostates and with proliferative disorders was evaluated to verify the role of these enzymes in extracellular matrix remodeling (ECM) and in the tissue invasion process. A total of 355 prostatic samples were obtained, from which 36 (10.1%) were normal prostates, 46 (13.0%) with benign prostatic hyperplasia (BPH), 128 (36.1%) with proliferative inflammatory atrophy (PIA), 74 (20.8%) with prostatic intraepithelial neoplasia (PIN), and 71 (20.0%) with prostatic carcinoma (PC). Difference in cytoplasmic immunohistochemical staining of MMP-2 and MMP-9 between acinar epithelium and periacinar stroma was found regarding the different diagnosis. The correlation between MMP-2 and MMP-9 expression in relation to the number of labeled cells in acinar epithelium and periacinar stroma, as well as to the staining intensity in the periacinar stromal cells was evidenced in canine prostates with PIA. In conclusion, MMP-2 and MMP-9 expression has a variation in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in those with PIA, PIN and PC. Moreover, the inflammatory microenvironment of the PIA has influence in the activity of both enzymes.

Abstract 2870: Prostatic inflammation and proliferative inflammatory atrophy: Are there any associations with prostatic cancer.

Abstract Background: Prostate cancer (PCa) is the second most common worldwide neoplasm in men [1]. Proliferative inflammatory atrophy (PIA) is proposed as a “risk factor lesion” as it has an important inflammatory component and the associated oxidative stress has been suggested to have a role in prostatic carcinogenesis [2,3] Objectives: To determine correlations between pathological findings of inflammation and proliferative inflammatory atrophy (PIA), in prostate biopsy specimens and to compare their prevalence in biopsies with and without prostate adenocarcinoma. Methods: A prospective study was conducted between December 2010 and June 2012 in the Hospital Universitario del Caribe, Cartagena, Colombia. Patients referred for transrectal ultrasound-guided prostate needle biopsy for suspected PCa were invited to participle and signed an informed consent. Initial prostate biopsies were examined for the presence of PCa, chronic inflammation and atrophy. The inflammation was scored for grade, localization and extension using the classification system of the CPCRN and IPCN consensus [4]. Atrophy was classified according to “Working Group Classification of Focal Prostate Atrophy Lesions” [5], and grade of atrophy was graduated using categories described by Postma [6]. For statistical analysis we compared parameters between groups with and without PCa. This study was approved for the Ethical Review Board of the participating institutions. Results: 97 patients were included, between the ages of 47 and 87 years (mean age: 68.32, SD: 8.9). Adenocarcinoma was identified in 50 of the 97 (51.5%) biopsies examined. There was a significant age difference between the PCa and benign groups (p=0.0031) and PSA levels were significantly higher in patients with cancer. Inflammation was detected in 95.87% of biopsies. Inflammation grade was significantly different between PCa and benign samples (p=0.038) but extension and localization of inflammation was not different between the groups. PIA was observed in 61 cases (62.8%) of which 23 had PCa. Atrophy grade and type were not different between groups and simple atrophy was the most frequently observed type. Morphological transition PIA-HGPIN was significantly more frequent in PCa group (p=0.0002) Conclusions: Our data provide evidence for a role of PIA as a PCa precursor lesion as we observed a strong association between morphological transition PIA-HGPIN and PCa. As inflammation was observed in the vast majority of patient samples, our analysis did not detect an association with PCa. Likewise, a clear association between atrophy and PCa was not observed. Citation Format: Ines Benedetti, Oscar Correa, Jan Geliebter, Raj Tiwari, Niradiz Reyes. Prostatic inflammation and proliferative inflammatory atrophy: Are there any associations with prostatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2870. doi:10.1158/1538-7445.AM2013-2870