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Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer.

ABSTRACT: Corpora amylacea (CA) are a frequent microscopic finding in radical prostatectomy specimens from men undergoing treatment for prostate cancer. Although often observed histologically to be associated with inflammation, the contribution of CA to prostatitis-related symptoms of unknown etiology or to prostate carcinogenesis remains unclear. Prostatic calculi (PC), which potentially represent calcified forms of CA, are less common but can cause urological disease including urinary retention and prostatitis. We conducted a comprehensive compositional analysis of CA/PC to gain insight into their biogenesis. Infrared spectroscopy analysis of calculi collected from 23 patients confirmed a prevalence of calcium phosphate in the form of hydroxyapatite. This result sets PC apart from most urinary stones, which largely are composed of calcium oxalate. Tandem mass spectrometry-based proteomic analysis of CA/PC revealed that lactoferrin is the predominant protein component, a result that was confirmed by Western blot analysis. Other proteins identified, including calprotectin, myeloperoxidase, and alpha-defensins, are proteins contained in neutrophil granules. Immunohistochemistry (IHC) suggested the source of lactoferrin to be prostate-infiltrating neutrophils as well as inflamed prostate epithelium; however, IHC for calprotectin suggested prostate-infiltrating neutrophils as a major source of the protein, because it was absent from other prostate compartments. This study represents a definitive analysis of the protein composition of prostatic CA and calculi and suggests that acute inflammation has a role in their biogenesis--an intriguing finding, given the prevalence of CA in prostatectomy specimens and the hypothesized role for inflammation in prostate carcinogenesis.

SUBMITTER: Sfanos KS

PROVIDER: S-EPMC2651291 | biostudies-other | 2009 Mar

REPOSITORIES: biostudies-other

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Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer.

Sfanos Karen S KS Wilson Brice A BA De Marzo Angelo M AM Isaacs William B WB

Proceedings of the National Academy of Sciences of the United States of America 20090206 9

Corpora amylacea (CA) are a frequent microscopic finding in radical prostatectomy specimens from men undergoing treatment for prostate cancer. Although often observed histologically to be associated with inflammation, the contribution of CA to prostatitis-related symptoms of unknown etiology or to prostate carcinogenesis remains unclear. Prostatic calculi (PC), which potentially represent calcified forms of CA, are less common but can cause urological disease including urinary retention and pros ...[more]

PMID: 19202053

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Project description:BackgroundCorpora amylacea (CAM), in benign prostatic acini, contain acute-phase proteins. Do CAM coincide with carcinoma?MethodsWithin 270 biopsies, 83 prostatectomies, and 33 transurethral resections (TURs), CAM absence was designated CAM 0; corpora in less than 5% of benign acini: CAM 1; in 5% to 25%: CAM 2; in more than 25%: CAM 3. CAM were compared against carcinoma presence, clinicopathologic findings, and grade groups (GG) 1 to 2 vs 3 to 5. The frequency of CAM according to anatomic zone was counted. A pilot study was conducted using paired initial benign and repeat biopsies (33 benign, 24 carcinoma).ResultsA total of 68.9% of biopsies, 96.4% of prostatectomies, and 66.7% of TURs disclosed CAM. CAM ≥1 was common at an older age (P = .019). In biopsies, 204 cases (75%) had carcinoma; and CAM of 2 to 3 (compared to 0-1) were recorded in 25.0% of carcinomas but only 7.4% of benign biopsies (P = .005; odds ratio [OR] = 5.1). CAM correlated with high percent Gleason pattern 3, low GG (P = .035), and chronic inflammation (CI). CI correlated inversely with carcinoma (P = .003). CAM disclosed no association with race, body mass index, serum prostate specific antigen (PSA), acute inflammation (in biopsies), atrophy, or carcinoma volume. With CAM 1, the odds of GG 3 to 5 carcinoma, by comparison to CAM 0, decreased more than 2× (OR = 0.48; P = .032), with CAM 2, more than 3× (OR = 0.33; P = .005), and with CAM 3, almost 3× (OR = 0.39, P = .086). For men aged less than 65, carcinoma predictive model was: Score = (2 × age) + (5 × PSA) - (20 × degree of CAM); using our data, area under the ROC curve was 78.17%. When the transition zone was involved by cancer, it showed more CAM than in cases where it was uninvolved (P = .012); otherwise zonal distributions were similar. In the pilot study, CAM ≥1 predicted carcinoma on repeat biopsy (P < .05; OR = 8), as did CAM 2 to 3 (P < .0001; OR = 30). CI was not significant, and CAM retained significance after adjusting for CI.ConclusionCAM correlate with carcinoma. Whether abundant CAM in benign biopsies adds value amidst high clinical suspicion, warrants further study.

Project description:Current protocols for the screening of prostate cancer cannot accurately discriminate clinically indolent tumors from more aggressive ones. One reliable indicator of outcome has been the determination of organ-confined versus nonorgan-confined disease but even this determination is often only made following prostatectomy. This underscores the need to explore alternate avenues to enhance outcome prediction of prostate cancer patients. Fluids that are proximal to the prostate, such as expressed prostatic secretions (EPS), are attractive sources of potential prostate cancer biomarkers as these fluids likely bathe the tumor. Direct-EPS samples from 16 individuals with extracapsular (n = 8) or organ-confined (n = 8) prostate cancer were used as a discovery cohort, and were analyzed in duplicate by a nine-step MudPIT on a LTQ-Orbitrap XL mass spectrometer. A total of 624 unique proteins were identified by at least two unique peptides with a 0.2% false discovery rate. A semiquantitative spectral counting algorithm identified 133 significantly differentially expressed proteins in the discovery cohort. Integrative data mining prioritized 14 candidates, including two known prostate cancer biomarkers: prostate-specific antigen and prostatic acid phosphatase, which were significantly elevated in the direct-EPS from the organ-confined cancer group. These and five other candidates (SFN, MME, PARK7, TIMP1, and TGM4) were verified by Western blotting in an independent set of direct-EPS from patients with biochemically recurrent disease (n = 5) versus patients with no evidence of recurrence upon follow-up (n = 10). Lastly, we performed proof-of-concept SRM-MS-based relative quantification of the five candidates using unpurified heavy isotope-labeled synthetic peptides spiked into pools of EPS-urines from men with extracapsular and organ-confined prostate tumors. This study represents the first efforts to define the direct-EPS proteome from two major subclasses of prostate cancer using shotgun proteomics and verification in EPS-urine by SRM-MS.

Dataset Information

Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer.

Publications

Acute inflammatory proteins constitute the organic matrix of prostatic corpora amylacea and calculi in men with prostate cancer.

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