François Iborra

miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice.

Background Micro RNAs are small, non-coding, single-stranded RNAs that negatively regulate gene expression at the post-transcriptional level. Since miR-143 was found to be down-regulated in prostate cancer cells, we wanted to analyze its expression in human prostate cancer, and test the ability of miR-43 to arrest prostate cancer cell growth in vitro and in vivo. Results Expression of miR-143 was analyzed in human prostate cancers by quantitative PCR, and by in situ hybridization. miR-143 was introduced in cancer cells in vivo by electroporation. Bioinformatics analysis and luciferase-based assays were used to determine miR-143 targets. We show in this study that miR-143 levels are inversely correlated with advanced stages of prostate cancer. Rescue of miR-143 expression in cancer cells results in the arrest of cell proliferation and the abrogation of tumor growth in mice. Furthermore, we show that the effects of miR-143 are mediated, at least in part by the inhibition of extracellular signal-regulated kinase-5 (ERK5) activity. We show here that ERK5 is a miR-143 target in prostate cancer. Conclusions miR-143 is as a new target for prostate cancer treatment.

Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice

Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3α/β, the latter on being consistent with a decrease in β-catenin activity and mRNA levels of various β-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression. Mol Cancer Ther; 9(6); 1740–54. ©2010 AACR.

Peroxisome proliferator-activated receptor gamma regulates E-cadherin expression and inhibits growth and invasion of prostate cancer.

ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) might not be permissive to ligand activation in prostate cancer cells. Association of PPARγ with repressing factors or posttranslational modifications in PPARγ protein could explain the lack of effect of PPARγ ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPARγ agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPARγ agonists, defining a new class of PPARγ target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.

Prostate cancer in renal transplant recipients

BACKGROUND We conducted a retrospective multi-centre study to determine the characteristics of prostate cancer in renal transplant recipients (RTR) and to analyse the relation with immunosuppressive maintenance therapies. METHODS Patients from 19 French transplant centres diagnosed with prostate cancer at least 1 year after kidney transplantation were included in this study. Data regarding demographics, kidney transplantation, prostate cancer and immunosuppressive treatment were analysed. RESULTS Sixty-two patients met the eligibility criteria for this study. Thirty-eight patients (61.3%) received calcineurin inhibitors (CNI) and azathioprine (AZA) with or without steroids, twenty received CNI with or without steroids (32.2%) and four received CNI and mycophenolate mofetil (6.5%). Patients with CNI and AZA immunosuppressive therapy presented more high-stage cancer (T3 and T4) when compared to patients receiving CNI alone (47.5% versus 15%, respectively, P = 0.03). A non-significant increase in lymph node invasion was found in patients receiving CNI and AZA compared to patients receiving CNI alone (21% versus 5%, P = 0.16). In the multivariate analysis, the immunosuppressive regimen with CNI and AZA was the only independent risk factor for locally advanced disease (P = 0.007). CONCLUSION Our results showed that RTR are at risk for early occurrence and for locally advanced prostate cancer, especially when they received a CNI and AZA maintenance immunosuppressive therapy.

Liver metastases in prostate carcinoma: clinical characteristics and outcome

To assess the clinical characteristics and outcome of patients with liver metastases in prostate carcinoma.

Recommandations en Onco-Urologie 2010: Tumeurs germinales du testicule.

Le cancer du testicule est rare, mais avec une prise en charge adaptee, le taux de survie specifique a 5 ans de cette maladie est superieur a 90 %, tous stades confondus [1,2]. Dans ces recommandations, ne seront traitees que les tumeurs germinales testiculaires (TGT) comprenant les tumeurs germinales seminomateuses (TGS) et les tumeurs germinales non-seminomateuses (TGNS) qui restent les plus frequentes (95 % des cas).

Recommandations en onco-urologie 2013 du CCAFU : Tumeurs germinales du testicule

INTRODUCTION The objective of this article is to establish guidelines proposed by the external genital organ group of the CCAFU for the diagnosis, treatment and follow-up of the germ cell tumours of the testis. MATERIAL AND METHODS The multidisciplinary working party studied previous guidelines, exhaustively reviewed the literature, and evaluated references and their level of proof in order to attribute grades of recommendation. RESULTS The initial work-up of testicular cancer is based on clinical, laboratory (AFP, total hCG, LDH) and imaging assessment (scrotal ultrasound and chest, abdomen and pelvis computed tomography). Inguinal orchidectomy is the first-line treatment allowing characterization of the histological type, local staging and identification of risk factors for micrometastases. The management of stage I tumours must be adapted to the risk by explaining to the patient the benefits/disadvantages of active treatment or watchful waiting as a function of the risk of relapse. Treatment options for stage 1 seminomas comprise : watchful waiting, chemotherapy (1 cycle of carboplatin) or para-aortic radiotherapy. Treatment options for stage 1 nonseminomatous germ cell tumours comprise : watchful waiting, chemotherapy (2 cycles of BEP) or staging retroperitoneal lymphadenectomy. The management of metastatic tumours essentially comprises chemotherapy with 3 or 4 cycles of BEP according to the prognostic group. Radiotherapy may be indicated in seminomas with lymph node metastasis < 3 cm. Review 3 to 4 weeks post-chemotherapy is essentially based on tumour marker assays and chest, abdomen and pelvis computed tomography. Surgical retroperitoneal lymph node dissection is indicated for all residual NSGCT masses > 1 cm and for persistent residual seminoma masses > 3 cm with (18)F-FDG PET-CT uptake. CONCLUSIONS Germ cell tumours have an excellent survival rate based on precise initial staging, adapted and strictly defined treatment and close surveillance.

Tumor Grade Improves the Prognostic Ability of American Joint Committee on Cancer Stage in Patients With Penile Carcinoma

PURPOSE Penile cancer is rare. Thus, predicting cancer specific mortality may be difficult. We devised an accurate and yet easily applicable predictive rule that compares favorably with 2 previous models (73.8% and 74.7% accuracy, respectively). MATERIALS AND METHODS We identified patients treated with primary tumor excision for all stages of penile squamous cell carcinoma between 1998 and 2006. Disease stage definitions using Surveillance, Epidemiology and End Results stage, American Joint Committee on Cancer stage and TNM classification, and tumor grade were used to predict cancer specific mortality. Predictive accuracy estimates were compared using the DeLong method for related AUCs. RESULTS Surveillance, Epidemiology and End Results stage alone (1 predictor variable) was least accurate (74.5%). American Joint Committee on Cancer stage with tumor grade (2 predictor variables) was the most simple and most accurate (80.9%, p <0.001). A benefit similar to that of American Joint Committee on Cancer stage with tumor grade was seen for TNM classification and TG (80.7%, p = 0.8). However, this rule (4 predictor variables) was more complex than American Joint Committee on Cancer stage and tumor grade. CONCLUSIONS American Joint Committee on Cancer stage combined with tumor grade is the simplest, most accurate cancer specific mortality prediction rule after primary tumor excision for penile squamous cell carcinoma. This method is also more accurate than 2 previous cancer specific mortality prediction rules.

Impact of graft nephrectomy on outcomes of second kidney transplantation.

To determine the impact of renal graft nephrectomy on second kidney transplantation survival.

Cytogenetic Studies of 24 Renal Epithelial Tumors With von Hippel-Lindau and Fragile Histidine Triad Protein Expression Correlation

CONTEXT Deletion of the short arm of chromosome 3 (3p deletion) is a cytogenetic abnormality generally associated with clear cell renal cell carcinoma, the most aggressive form of renal epithelial tumor. OBJECTIVE To cytogenetically characterize 24 renal tumors in order to check the incidence and the type of 3p deletions, as well as to identify new genes putatively participating in renal tumorigenesis and test the protein products of the von Hippel-Lindau (VHL) and fragile histidine triad (FHIT) genes. DESIGN We analyzed 24 renal tumors by conventional cytogenetics, comparative genomic hybridization, and fluorescence in situ hybridization. We then performed a comparative expression study of the proteins pVHL and Fhit. RESULTS In our series of 24 renal tumors, the 3p deletion was the most frequent genetic alteration (15/24); the other features were partial trisomy 5q, 8p deletion, and monosomy 9 and 14. The 3p deletion was long and terminal, and no interstitial deletion was identified. By immunohistochemistry, we found that for the 2 genes of interest, VHL and FHIT, loss or decrease in protein expression were very frequently observed in clear cell renal cell carcinoma and not always associated with a 3p deletion (14/20 in clear cell renal cell carcinoma). CONCLUSIONS Our studies characterize the 3p deletion as long and terminal and identify no interstitial deletion in that chromosome. Fhit and pVHL protein expression loss appear to be independent, as they can be dissociated. Our data are supportive of a role for FHIT (in addition to VHL) in renal tumorigenesis. No other gene with particular potential interest in renal tumorigenesis could be identified among the selected genes.