Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

Abstract Background The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment. Methods Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder. Results The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes. Conclusion CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.

Quantification of fractal dimension and Shannon’s entropy in histological diagnosis of prostate cancer

Background: Prostate cancer is a serious public health problem that affects quality of life and has a significant mortality rate. The aim of the present study was to quantify the fractal dimension and Shannon’s entropy in the histological diagnosis of prostate cancer. Methods: Thirty-four patients with prostate cancer aged 50 to 75 years having been submitted to radical prostatectomy participated in the study. Histological slides of normal (N), hyperplastic (H) and tumor (T) areas of the prostate were digitally photographed with three different magnifications (40x, 100x and 400x) and analyzed. The fractal dimension (FD), Shannon’s entropy (SE) and number of cell nuclei (NCN) in these areas were compared. Results: FD analysis demonstrated the following significant differences between groups: T vs. N and H vs. N groups (p < 0.05) at a magnification of 40x; T vs. N (p < 0.01) at 100x and H vs. N (p < 0.01) at 400x. SE analysis revealed the following significant differences groups: T vs. H and T vs. N (p < 0.05) at 100x; and T vs. H and T vs. N (p < 0.001) at 400x. NCN analysis demonstrated the following significant differences between groups: T vs. H and T vs. N (p < 0.05) at 40x; T vs. H and T vs. N (p < 0.0001) at 100x; and T vs. H and T vs. N (p < 0.01) at 400x. Conclusions: The quantification of the FD and SE, together with the number of cell nuclei, has potential clinical applications in the histological diagnosis of prostate cancer.

Underexpression of MMP-2 and its regulators, TIMP2, MT1-MMP and IL-8, is associated with prostate cancer

OBJECTIVE: Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their regulators. The purpose of this study was to investigate whether MMP-2 and its specific regulators, TIMP-2, MT1-MMP and IL-8, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis and clinical outcome of prostate cancer (PCa). MATERIALS AND METHODS: MMP-2, TIMP-2, MT1-MMP and IL-8 expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in freshly frozen malignant and benign tissue specimens collected from 79 patients with clinically localized PCa who underwent radical prostatectomies. The control group consisted of 11 patients with benign prostate hyperplasia (BPH). The expression profile of the MMP-2 and its regulators were compared using Gleason scores, pathological stage, pre-operative PSA levels and the final outcome of the PCa. RESULTS: The analysis of 79 specimens of PCa revealed that MMP-2, TIMP-2, MT1-MMP and IL-8 were underexpressed at 60.0%, 72.2%, 62.0% and 65.8%, respectively, in malignant prostatic tissue in relation to BPH samples. Considering the prognostic parameters, we demonstrated that high Gleason score tumors (> 7) overexpressed MMP-2 (p = 0.048) and TIMP-2 (p = 0.021), compared to low Gleason score tumors (< 7). CONCLUSION: We have demonstrated that MMP-2 and its regulators are underexpressed in PCa. Alternatively, overexpression of MMP-2 and TIMP-2 was related to higher Gleason score tumors. We postulate that alterations in metalloproteinase expression may be important in the control of tissue homeostasis related to prostate carcinogenesis and tumor behavior.

Analysis of cone-beam ct dose in image-guided radiation therapy for brain and prostate cancer patients via gpu-based Monte Carlo simulations

La radioterapia guidata da immagini (IGRT), grazie alle ripetute verifiche della posizione del paziente e della localizzazione del volume bersaglio, si è recentemente affermata come nuovo paradigma nella radioterapia, avendo migliorato radicalmente l’accuratezza nella somministrazione di dose a scopo terapeutico. Una promettente tecnica nel campo dell’IGRT è rappresentata dalla tomografia computerizzata a fascio conico (CBCT). La CBCT a kilovoltaggio, consente di fornire un’accurata mappatura tridimensionale dell’anatomia del paziente, in fase di pianificazione del trattamento e a ogni frazione del medisimo. Tuttavia, la dose da imaging attribuibile alle ripetute scansioni è diventata, negli ultimi anni, oggetto di una crescente preoccupazione nel contesto clinico. Lo scopo di questo lavoro è di valutare quantitativamente la dose addizionale somministrata da CBCT a kilovoltaggio, con riferimento a tre tipici protocolli di scansione per Varian OnBoard Imaging Systems (OBI, Palo Alto, California). A questo scopo sono state condotte simulazioni con codici Monte Carlo per il calcolo della dose, utilizzando il pacchetto gCTD, sviluppato sull’architettura della scheda grafica. L’utilizzo della GPU per sistemi server di calcolo ha permesso di raggiungere alte efficienze computazionali, accelerando le simulazioni Monte Carlo fino a raggiungere tempi di calcolo di ~1 min per un caso tipico. Inizialmente sono state condotte misure sperimentali di dose su un fantoccio d’acqua. I parametri necessari per la modellazione della sorgente di raggi X nel codice gCTD sono stati ottenuti attraverso un processo di validazione del codice al fine di accordare i valori di dose simulati in acqua con le misure nel fantoccio. Lo studio si concentra su cinquanta pazienti sottoposti a cicli di radioterapia a intensità modulata (IMRT). Venticinque pazienti con tumore al cervello sono utilizzati per studiare la dose nel protocollo standard-dose head e venticinque pazienti con tumore alla prostata sono selezionati per studiare la dose nei protocolli pelvis e pelvis spotlight. La dose media a ogni organo è calcolata. La dose media al 2% dei voxels con i valori più alti di dose è inoltre computata per ogni organo, al fine di caratterizzare l’omogeneità spaziale della distribuzione.

CYP17A1 polymorphisms and clinical outcome of patients with metastatic castration-resistant prostate cancer treated with abiraterone

Background. Abiraterone acetate is a potent inhibitor of cytochrome P450 17 α-hydrolase (CYP17A1) that causes a reduction in the synthesis of testosterone in the adrenal glands, testes and tumor microenvironment. Blocking androgen production, abiraterone has been shown to prolong progression-free survival (PFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) previously submitted to chemotherapy. The aim of our study was to verify the role of single nucleotide polymorphisms (SNPs) in predicting clinical outcome in CRPC patients treated with abiraterone after chemotherapy. Methods. We analyzed 48 CRPC consecutive patients treated with abiraterone after at least one chemotherapeutic regimen with docetaxel. DNA was extracted from peripheral blood and genotyped for four polymorphisms in the CYP17A1 gene (rs743572, rs10883783, rs17115100, rs284849). PFS and OS survival curves were used to identify statistical associations between haplotypes and clinical outcome. Results. Forty-eight Caucasian patients with metastatic CRPC treated with abiraterone were genotyped for polymorphisms in the CYP17A1 gene. All samples were evaluable for both sequencing and TaqMan Genotyping assay. The CRPC patients treated with abiraterone had a median PFS and OS of 7.6 months (95% CI: 4.3-10.5) and 17.6 months (95% CI: 10.5-19.0), respectively Statistical analyses highlighted a difference approaching statistical significance (log-rank test p = 0.0534) between rs10883783 and PFS. Other polymorphisms were not associated with a benefit from treatment with abiraterone. Conclusions. In our case series of 48 treated patients, rs10883783 only was identified as a possible predictive marker, results showing a trend toward statistical significance. Further analysis of this polymorphism is needed in larger series of patients to confirm our findings.

IGF system, CD99 and tumor-specific chromosomal translocations: evaluation of their cross-talk and definition of their role in Ewing sarcoma and prostate cancer

Aberrant expression of ETS transcription factors, including FLI1 and ERG, due to chromosomal translocations has been described as a driver event in initiation and progression of different tumors. In this study, the impact of prostate cancer (PCa) fusion gene TMPRSS2-ERG was evaluated on components of the insulin-like growth factor (IGF) system and the CD99 molecule, two well documented targets of EWS-FLI1, the hallmark of Ewing sarcoma (ES). The aim of this study was to identify common or distinctive ETS-related mechanisms which could be exploited at biological and clinical level. The results demonstrate that IGF-1R represents a common target of ETS rearrangements as ERG and FLI1 bind IGF-1R gene promoter and their modulation causes alteration in IGF-1R protein levels. At clinical level, this mechanism provides basis for a more rationale use of anti-IGF-1R inhibitors as PCa cells expressing the fusion gene better respond to anti-IGF-1R agents. EWS-FLI1/IGF-1R axis provides rationale for combination of anti-IGF-1R agents with trabectedin, an alkylator agent causing enhanced EWS-FLI1 occupancy on the IGF-1R promoter. TMPRSS2-ERG also influences prognosis relevance of IGF system as high IGF-1R correlates with a better biochemical progression free survival (BPFS) in PCa patients negative for the fusion gene while marginal or no association was found in the total cases or TMPRSS2-ERG-positive cases, respectively. This study indicates CD99 is differentially regulated between ETS-related tumors as CD99 is not a target of ERG. In PCa, CD99 did not show differential expression between TMPRSS2-ERG-positive and –negative cells. A direct correlation was anyway found between ERG and CD99 proteins both in vitro and in patients putatively suggesting that ERG target genes comprehend regulators of CD99. Despite a little trend suggesting a correlation between CD99 expression and a better BPFS, no clinical relevance for CD99 was found in the field of prognostic biomarkers.

MR spectroscopy in human prostate: in vitro and in vivo measurements to optimize new quantification algorithms

Il cancro della prostata (PCa) è il tumore maligno non-cutaneo più diffuso tra gli uomini ed è il secondo tumore che miete più vittime nei paesi occidentali. La necessità di nuove tecniche non invasive per la diagnosi precoce del PCa è aumentata negli anni. 1H-MRS (proton magnetic resonance spectroscopy) e 1H-MRSI (proton magnetic resonance spectroscopy imaging) sono tecniche avanzate di spettroscopia in risonanza magnetica che permettono di individuare presenza di metaboliti come citrato, colina, creatina e in alcuni casi poliammine in uno o più voxel nel tessuto prostatico. L’abbondanza o l’assenza di uno di questi metaboliti rende possibile discriminare un tessuto sano da uno patologico. Le tecniche di spettroscopia RM sono correntemente utilizzate nella pratica clinica per cervello e fegato, con l’utilizzo di software dedicati per l’analisi degli spettri. La quantificazione di metaboliti nella prostata invece può risultare difficile a causa del basso rapporto segnale/rumore (SNR) degli spettri e del forte accoppiamento-j del citrato. Lo scopo principale di questo lavoro è di proporre un software prototipo per la quantificazione automatica di citrato, colina e creatina nella prostata. Lo sviluppo del programma e dei suoi algoritmi è stato portato avanti all’interno dell’IRST (Istituto Romagnolo per lo Studio e la cura dei Tumori) con l’aiuto dell’unità di fisica sanitaria. Il cuore del programma è un algoritmo iterativo per il fit degli spettri che fa uso di simulazioni MRS sviluppate con il pacchetto di librerie GAMMA in C++. L’accuratezza delle quantificazioni è stata testata con dei fantocci realizzati all’interno dei laboratori dell’istituto. Tutte le misure spettroscopiche sono state eseguite con il nuovo scanner Philips Ingenia 3T, una delle machine di risonanza magnetica più avanzate per applicazioni cliniche. Infine, dopo aver eseguito i test in vitro sui fantocci, sono stati acquisiti gli spettri delle prostate di alcuni volontari sani, per testare se il programma fosse in grado di lavorare in condizioni di basso SNR.

Human prostate fibroblasts induce growth and confer castration resistance and metastatic potential in LNCaP Cells

The tumor microenvironment is important for progressive and metastatic disease.

Androgen receptors are differentially expressed in Gleason patterns of prostate cancer and down-regulated in matched lymph node metastases

Androgen receptor (AR) expression profile in the different Gleason patterns (GP) of primary prostate cancers and nodal metastases is unknown. More information about AR distribution is needed to optimize evaluation methods and to better understand the role of AR in development and progression of prostate cancer.

Matrix metalloproteinases and angiogenic factors: predictors of survival after radical prostatectomy for clinically organ-confined prostate cancer?

The aim of the present study was to investigate whether biomarkers improve the prediction of recurrence-free, disease-specific, and overall survival in patients with clinically localized prostate cancer. A tissue microarray was constructed from prostate specimens of 278 patients who underwent open radical retropubic prostatectomy for clinically localized prostate cancer. For immunohistochemical studies, antibodies were used against matrix metalloproteinase (MMP)-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-19, as well as against vascular endothelial growth factor, hypoxia-induced factor 1 , basic fibroblast growth factor, and cluster of differentiation 31. Univariate and multivariable analyses were performed to evaluate the potential predictors of overall, disease-specific, and recurrence-free survival. In univariate analysis of patients with clinically organ-confined prostate cancer, only higher expression levels of MMP-9 (hazard ratio [0.6], 95% CI 0.45-0.8) had a protective effect in terms of overall survival. This positive effect of high MMP-9 expression was also observed for recurrence-free (HR 0.88, 95% CI 0.78-0.99) and disease-specific survival (HR 0.5, 95% CI 0.36-0.73). In multivariable analysis, none of these potential markers was found to be an independent prognostic factor of survival. Of all MMPs and angiogenic factors tested, MMP-9 expression has the potential as a prognostic marker in patients undergoing radical prostatectomy for clinically organ-confined cases of prostate cancer.

High-dose (80 Gy) intensity-modulated radiation therapy with daily image-guidance as primary treatment for localized prostate cancer

to report acute and late toxicity in prostate cancer patients treated by high-dose intensity-modulated radiation therapy (IMRT) with daily image-guidance.

Urethral toxicity vs. cancer control-Lessons to be learned from high-dose rate brachytherapy combined with intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer

To describe biochemical relapse-free survival (BRFS) and late toxicity after combined high-dose rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT) in intermediate- and high-risk prostate cancer patients.

The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer

Choline positron emission tomography (PET)/computed tomography (CT) is a currently used diagnostic tool in restaging prostate cancer (PCa) patients with increasing prostate-specific antigen (PSA) after either radical prostatectomy (RP) or external-beam radiation therapy (EBRT). However, no final recommendations have been made on the use of this modality for patient management.