6 research outputs found
Hedgehog pathway ans steroid hormones interaction in normal and tumor prostate celles
Le cancer de la prostate (CaP) est le cancer le plus frĂ©quent chez l'homme et reprĂ©sente la deuxiĂšme cause de mortalitĂ© par cancer. Cette pathologie est sensible aux androgĂšnes des stades localisĂ©s aux stades mĂ©tastatiques. AprĂšs le traitement des formes avancĂ©s de ce cIl est admit aujourd'hui que les androgĂšnes seuls ne sont pas suffisants pour dĂ©clencher le cancer de la prostate. En effet, le rĂŽle des ĆstrogĂšnes dans la carcinogenĂšse prostatique est suggĂ©rĂ© par plusieurs Ă©tudes. L'activation de la voie de signalisation Hedgehog (Hh) joue un rĂŽle important dans le dĂ©veloppement de plusieurs cancers, y compris le CaP. Une meilleure comprĂ©hension des mĂ©canismes qui rĂ©gulent l'activation de cette voie dans le CaP est nĂ©cessaire afin de dĂ©finir de nouvelles stratĂ©gies thĂ©rapeutiques plus efficaces.Dans ce travail, nous mettons en Ă©vidence l'interaction entre la voie Hh et les hormones stĂ©roĂŻdiennes dans les cellules prostatiques. Nous avons observĂ© : i) une activation de la voie Hh par l'ĆstrogĂšne (sulfate d'Ćstrone (SE1)), attĂ©nuĂ©e par l'anti-ĆstrogĂšne (ICI) et par l'inhibiteur de la voie Hh (KAAD-cyclopamine), ii) une rĂ©gulation nĂ©gative de la voie Hh par l'androgĂšne (dihydrotestostĂ©rone (DHT)) et l'ĆstrogĂšne (17ÎČ-Ćstradiol (E2)). Nous avons dĂ©montrĂ© que l'inhibition de la voie Hh induite par DHT et E2 est dĂ©pendante des rĂ©cepteurs des androgĂšnes (RA). Cependant, l'effet de SE1 sur la voie Hh pourrait ĂȘtre dĂ©pendante des rĂ©cepteurs des ĆstrogĂšnes (ER). Enfin, nous avons observĂ© une inhibition de l'activitĂ© des RA par KAAD-cyclopamine. Les dĂ©rivĂ©s de cyclopamine pourraient donc reprĂ©senter une nouvelle classe d'agents thĂ©rapeutiques ciblant le RA dans le cancer de la prostate. Une meilleure caractĂ©risation des cibles potentielles de ces molĂ©cules semble ĂȘtre intĂ©ressante.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 (dihydrotestostĂ©rone (DHT)) and the estrogen (17ÎČ-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 Coxâ 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 âorgan-confinedâ (â€pT2N0), âlocally advancedâ (pT3-4N0) and ânode-positiveâ (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