Hedgehog pathway ans steroid hormones interaction in normal and tumor prostate celles

Le cancer de la prostate (CaP) est le cancer le plus fréquent chez l'homme et représente la deuxième cause de mortalité par cancer. Cette pathologie est sensible aux androgènes des stades localisés aux stades métastatiques. Après le traitement des formes avancés de ce cIl est admit aujourd'hui que les androgènes seuls ne sont pas suffisants pour déclencher le cancer de la prostate. En effet, le rôle des œstrogènes dans la carcinogenèse prostatique est suggéré par plusieurs études. L'activation de la voie de signalisation Hedgehog (Hh) joue un rôle important dans le développement de plusieurs cancers, y compris le CaP. Une meilleure compréhension des mécanismes qui régulent l'activation de cette voie dans le CaP est nécessaire afin de définir de nouvelles stratégies thérapeutiques plus efficaces.Dans ce travail, nous mettons en évidence l'interaction entre la voie Hh et les hormones stéroïdiennes dans les cellules prostatiques. Nous avons observé : i) une activation de la voie Hh par l'œstrogène (sulfate d'œstrone (SE1)), atténuée par l'anti-œstrogène (ICI) et par l'inhibiteur de la voie Hh (KAAD-cyclopamine), ii) une régulation négative de la voie Hh par l'androgène (dihydrotestostérone (DHT)) et l'œstrogène (17β-œstradiol (E2)). Nous avons démontré que l'inhibition de la voie Hh induite par DHT et E2 est dépendante des récepteurs des androgènes (RA). Cependant, l'effet de SE1 sur la voie Hh pourrait être dépendante des récepteurs des œstrogènes (ER). Enfin, nous avons observé une inhibition de l'activité des RA par KAAD-cyclopamine. Les dérivés de cyclopamine pourraient donc représenter une nouvelle classe d'agents thérapeutiques ciblant le RA dans le cancer de la prostate. Une meilleure caractérisation des cibles potentielles de ces molécules semble être intéressante.Prostate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in men. This cancer is androgen sensitive in its development and progression to metastatic disease. Despite this, increasing evidence suggest that androgens alone are not able to induce PCa and estrogen signaling has a key role in prostate cancer progression. Hedgehog (Hh) pathway activation is important in the growth and development of various carcinomas including PCa. A better understanding of Hh pathway regulating mechanisms in PCa is important in order to identify new therapeutic strategies for this pathology. In this study we investigate the interaction between Hh pathway and steroid hormones in prostate cells. We showed: i) Hh pathway activation by the estrogen (estrone sulfate E1S), attenuated by the anti-estrogen (ICI) and by the Hh pathway inhibitor (KAAD-cyclopamine) ii) Hh pathway negative regulation by the androgen (dihydrotestostérone (DHT)) and the estrogen (17β-estradiol (E2)). Moreover, we showed that Hh pathway inhibition is androgen receptor (AR) dependent. However, E1S effect on this pathway might be estrogen receptor (ER) dependent. Finally, our results suggest that targeting AR signaling by cyclopamine derivatives could be promising therapeutic alternative in prostate cancer, which needs a further investigation

Inhibition of PI3K pathway increases immune infiltrate in muscle-invasive bladder cancer

International audienceAlthough immune checkpoint inhibitors have shown improvement in survival in comparison to chemotherapy in urothelial bladder cancer, many patients still fail to respond to these treatments and actual efforts are made to identify predictive factors of response to immunotherapy. Understanding the tumor-intrinsic molecular basis, like oncogenic pathways conditioning the presence or absence of tumor-infiltrating T cells (TILs), should provide a new rationale for improved anti-tumor immune therapies. In this study, we found that urothelial bladder cancer from human samples bearing PIK3CA gene mutations was significantly associated with lower expression of a defined immune gene signature, compared to unmutated ones. We identified a reduced 10-gene immune gene signature that discriminates muscle-invasive bladder cancer (MIBC) samples according to immune infiltration and PIK3CA mutation. Using a humanized mouse model, we observed that BKM120, a pan-PI3K inhibitor, significantly inhibited the growth of a human bladder cancer cell line bearing a PIK3CA mutation, associated to increased immune cell infiltration (hCD45+). Using qRT-PCR, we also found an increase in the expression of chemokines and immune genes in PIK3CA-mutated tumors from mice treated with BKM120, reflecting an active immune infiltrate in comparison to untreated ones. Moreover, the addition of BKM120 rendered PIK3CA-mutated tumors sensitive to PD-1 blockade. Our results provide a relevant rationale for combination strategies of PI3K inhibitors with immune checkpoint inhibitors to overcome resistance to immune checkpoint inhibitors

Prognostic impact of variant histologies in urothelial bladder cancer treated with radical cystectomy

Objectives: To evaluate variant histologies (VHs) for disease-specific survival (DSS) in patients with invasive urothelial bladder cancer (BCa) undergoing radical cystectomy (RC). Materials and Methods: We analysed a multi-institutional cohort of 1082 patients treated with upfront RC for cT1-4aN0M0 urothelial BCa at eight centres. Univariable and multivariable Cox’ regression analyses were used to assess the effect of different VHs on DSS in overall cohort and three stage-based analyses. The stages were defined as ‘organ-confined’ (≤pT2N0), ‘locally advanced’ (pT3-4N0) and ‘node-positive’ (pTanyN1-3). Results: Overall, 784 patients (72.5%) had pure urothelial carcinoma (UC), while the remaining 298 (27.5%) harboured a VH. Squamous differentiation was the most common VH, observed in 166 patients (15.3%), followed by micropapillary (40 patients [3.7%]), sarcomatoid (29 patients [2.7%]), glandular (18 patients [1.7%]), lymphoepithelioma-like (14 patients [1.3%]), small-cell (13 patients [1.2%]), clear-cell (eight patients [0.7%]), nested (seven patients [0.6%]) and plasmacytoid VH (three patients [0.3%]). The median follow-up was 2.3 years. Overall, 534 (49.4%) disease-related deaths occurred. In uni- and multivariable analyses, plasmacytoid and small-cell VHs were associated with worse DSS in the overall cohort (both P = 0.04). In univariable analyses, sarcomatoid VH was significantly associated with worse DSS, while lymphoepithelioma-like VH had favourable DSS compared to pure UC. Clear-cell (P = 0.015) and small-cell (P = 0.011) VH were associated with worse DSS in the organ-confined and node-positive cohorts, respectively. Conclusions: More than 25% of patients harboured a VH at time of RC. Compared to pure UC, clear-cell, plasmacytoid, small-cell and sarcomatoid VHs were associated with worse DSS, while lymphoepithelioma-like VH was characterized by a DSS benefit. Accurate pathological diagnosis of VHs may ensure tailored counselling to identify patients who require more intensive management

Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients

Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. Patients and methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off> 10%) and Ki-67 (cutoff> 20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). Results: pT-stage was < pT2 in 80, pT2 in 266, pT3 in 513 and pT4 in 199 patients, respectively. Cancer-positive nodes were found in 410 (39%) patients. An FGFR3 mutation was detected in 107 (10%) and aberrant p53 and Ki-67 expression in 718 (68%) and 581(55%) tumors, respectively. The FGFR3 mutation was associated with lower pT-stage (P< 0.001), lower grade (P< 0.001), pN0 (P=0.001) and prolonged DSS (P< 0.001). Aberrant Ki-67 and p53 expression were associated with higher pT-stage and G3-tumors, but not with pN-stage or worse DSS, even if these IHC-biomarkers were combined (P=0.81). Significant predictors for DSS in multivariable analysis were pT-stage (HR1.5, 95%CI:1.3-1.6; P< 0.001), lympho-vascular invasion (LVI) (HR1.4, 95%CI:1.2-1.7; P=0.001), pN-stage (HR1.9, 95%CI:1.6-2.4; P< 0.001) and FGFR3 mutation status (HR1.6, 95%CI:1.1-2.2; P=0.011). Conclusion: The FGFR3 mutation selectively identified patients with favorable BC at RC while p53 and Ki-67 were only associated with adverse tumor characteristics. Our results suggest that, besides tumor-stage, nodal-status and LVI, the oncogenic FGFR3 mutation may represent a valuable tool to guide adjuvant treatment and follow-up strategies after RC. (C) 2021 Elsevier Inc. All rights reserved

Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients

Objectives: To determine the association between the FGFR3 mutation status and immuno-histochemistry (IHC) markers (p53 and Ki-67) in invasive bladder cancer (BC), and to analyze their prognostic value in a multicenter, multi-laboratory radical cystectomy (RC) cohort. Patients and methods: We included 1058 cN0M0, chemotherapy-naive BC patients who underwent RC with pelvic lymph-node dissection at 8 hospitals. The specimens were reviewed by uro-pathologists. Mutations in the FGFR3 gene were examined using PCR-SNaPshot; p53 and Ki-67 expression were determined by standard IHC. FGFR3 mutation status as well as p53 (cut-off>10%) and Ki-67 (cut-off>20%) expression were correlated to clinicopathological parameters and disease specific survival (DSS). Results: pT-stage was <pT2 in 80, pT2 in 266, pT3 in 513 and pT4 in 199 patients, respectively. Cancer-positive nodes were found in 410 (39%) patients. An FGFR3 mutation was detected in 107 (10%) and aberrant p53 and Ki-67 expression in 718 (68%) and 581(55%) tumors, respectively. The FGFR3 mutation was associated with lower pT-stage (P<0.001), lower grade (P<0.001), pN0 (P=0.001) and prolonged DSS (P<0.001). Aberrant Ki-67 and p53 expression were associated with higher pT-stage and G3-tumors, but not with pN-stage or worse DSS, even if these IHC-biomarkers were combined (P=0.81). Significant predictors for DSS in multivariable analysis were pT-stage (HR1.5, 95%CI:1.3-1.6; P<0.001), lympho-vascular invasion (LVI) (HR1.4, 95%CI:1.2-1.7; P=0.001), pN-stage (HR1.9, 95%CI:1.6-2.4; P<0.001) and FGFR3 mutation status (HR1.6, 95%CI:1.1-2.2; P=0.011). Conclusion: The FGFR3 mutation selectively identified patients with favorable BC at RC while p53 and Ki-67 were only associated with adverse tumor characteristics. Our results suggest that, besides tumor-stage, nodal-status and LVI, the oncogenic FGFR3 mutation may represent a valuable tool to guide adjuvant treatment and follow-up strategies after RC