Biomarqueurs émergents dans le cancer de prostate (à propos de la b-tubuline de classe III et du score urinaire PCA3)

Pas de résumé françaisPas de résumé anglaisPARIS-EST-Université (770839901) / SudocPARIS12-Bib. électronique (940280011) / SudocSudocFranceF

Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.</p> <p>Results</p> <p>Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.</p> <p>Conclusions</p> <p>Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.</p

Synthesis of Multifunctional Polymersomes Prepared by Polymerization-Induced Self-Assembly

Polymersomes are an exciting modality for drug delivery due to their structural similarity to biological cells and their ability to encapsulate both hydrophilic and hydrophobic drugs. In this regard, the current work aimed to develop multifunctional polymersomes, integrating dye (with hydrophobic Nile red and hydrophilic sulfo-cyanine5-NHS ester as model drugs) encapsulation, stimulus responsiveness, and surface-ligand modifications. Polymersomes constituting poly(N-2-hydroxypropylmethacrylamide)-b-poly(N-(2-(methylthio)ethyl)acrylamide) (PHPMAm-b-PMTEAM) are prepared by aqueous dispersion RAFT-mediated polymerization-induced self-assembly (PISA). The hydrophilic block lengths have an effect on the obtained morphologies, with short chain P(HPMAm)16 affording spheres and long chain P(HPMAm)43 yielding vesicles. This further induces different responses to H2O2, with spheres fragmenting and vesicles aggregating. Folic acid (FA) is successfully conjugated to the P(HPMAm)43, which self-assembles into FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes. The FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes entrap both hydrophobic Nile red (NR) and hydrophilic Cy5 dye. The NR-loaded FA-linked polymersomes exhibit a controlled release of the encapsulated NR dye when exposed to 10 mM H2O2. All the polymersomes formed are stable in human plasma and well-tolerated in MCF-7 breast cancer cells. These preliminary results demonstrate that, with simple and scalable chemistry, PISA offers access to different shapes and opens up the possibility of the one-pot synthesis of multicompartmental and responsive polymersomes

Fonctions de la protocadhérine-PC dans l'émergence du cancer de la prostate hormono-résistant

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer.

Androgen action in prostate and prostate cancer cells is dependent upon the androgen receptor (AR) protein that transcriptionally regulates the expression of androgen-dependent genes in the presence of a steroid ligand. Whereas the overall schema of androgen action mediated by this receptor protein appears to be relatively simple, androgen signaling is now known to be influenced by several other cell signal transduction pathways and here we review the evidence that the canonical Wnt signaling pathway also modulates androgen signaling at multiple levels. Wnt is a complex signaling pathway whose endpoint involves activation of transcription from LEF-1/TCF transcription factors and it is known to be involved in the development and progression of numerous human epithelial tumors including prostate cancer. beta-catenin protein, a particularly critical molecular component of canonical Wnt signaling is now known to promote androgen signaling through its ability to bind to the AR protein in a ligand-dependent fashion and to enhance the ability of liganded AR to activate transcription of androgen-regulated genes. Under certain conditions, glycogen synthase kinase-3beta (GSK-3beta), a protein serine/threonine kinase that regulates beta-catenin degradation within the Wnt signaling pathway, can also phosphorylate AR and suppress its ability to activate transcription. Finally, it was recently found that the human AR gene itself is a target of LEF-1/TCF-mediated transcription and that AR mRNA is highly upregulated by activation of Wnt signaling in prostate cancer cells. Paradoxically, Wnt activation also appears to stimulate Akt activity promoting an MDM-2-mediated degradation process that reduces AR protein levels in Wnt-stimulated prostate cancer cells. Collectively, this information indicates that the multifaceted nature of the interaction between the Wnt and the androgen signaling pathways likely has numerous consequences for the development, growth, and progression of prostate cancer

H2O2-Responsive Nanocarriers Prepared by RAFT-Mediated Polymerization-Induced Self-Assembly of N-(2-(Methylthio)ethyl)acrylamide for Biomedical Applications

H2O2-sensitive block copolymer nanoparticles (NPs) composed of a hydrophilic macro-chain transfer agent (macro-CTA) and a hydrophobic thioether-bearing block were prepared by polymerization-induced self-assembly (PISA) approach. The PISA process first involved the chain extension of poly((poly(ethylene glycol) methyl ether methacrylate)-co-(poly(ethylene glycol) methacrylate)) macro-CTA with a H2O2-responsive N-(2-(methylthio)ethyl)acrylamide (MTEAM) monomer, which self-assembled into P((PEGMA-co-PEGMAOH)-b-PMTEAM) block copolymer NPs. The polymerization kinetics indicated the evolution of particle size and morphology from spherical micelles, fused micelles, to vesicles over time. Upon incubation with 0.1 to 10 mM H2O2, spheres were fragmented due to the oxidation of the PMTEAM cores, thus transforming the hydrophobic thioethers into hydrophilic sulfoxides and disassociating the nanocarriers. 43% of the hydrophobic Nile red dye was encapsulated into the spherical micelles and demonstrated a controlled release in H2O2 incubation. Spherical micelles and vesicles displayed no cytotoxicity in MCF-7, DU145, and 22Rv1 cells. Both spheres and vesicles were efficiently internalized into MCF-7 cells, with spheres showing a higher level of uptake than vesicles due to the smaller sizes. In summary, PISA of P((PEGMA-co-PEGMAOH)-b-PMTEAM) allowed the direct formation and loading of hydrophobic dye into spherical micelles, which showed a controlled drug release in H2O2

Extracellular Vesicles in Advanced Prostate Cancer: Tools to Predict and Thwart Therapeutic Resistance

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. At first, advanced PCa is treated by androgen deprivation therapy with a good initial response. Nevertheless, recurrences occur, leading to Castrate-Resistance Prostate Cancer (CRPC). During the last decade, new therapies based on inhibition of the androgen receptor pathway or taxane chemotherapies have been used to treat CRPC patients leading to an increase in overall survival, but the occurrence of resistances limits their benefits. Numerous studies have demonstrated the implication of extracellular vesicles (EVs) in different cancer cellular mechanisms. Thus, the possibility to isolate and explore EVs produced by tumor cells in plasma/sera represents an important opportunity for the deciphering of those mechanisms and the discovery of biomarkers. Herein, we summarized the role of EVs in therapeutic resistance of advanced prostate cancer and their use to find biomarkers able to predict these resistances

Inflammation in benign prostatic hyperplasia: a 282 patients' immunohistochemical analysis.: BPH and inflammation

International audienceINTRODUCTION AND OBJECTIVES: Prostatic inflammation could be a key component in prostate enlargement and benign prostatic hyperplasia (BPH) progression. Our aim was to characterize inflammatory cells infiltrate within BPH tissue and to correlate inflammation and clinical data. MATERIAL AND METHODS: Inflammation was profiled on three clinical outcome tissue microarrays (TMAs), including 282 patients treated by surgery for a complicated and/or symptomatic BPH. Inflammation score was defined by combining six cytological parameters and five markers on immunohistochemistry (IHC). Cytological parameters were lymphocytes, macrophages, and polynuclears leukocytes infiltrates, and three glandular aspect modifications: glandular atrophy, glandular destruction, and tissue fibrosis. IHC markers were CD3, CD4, and CD8 decorating T-lymphocytes, CD20 decorating B-lymphocytes, and CD163 decorating macrophages. RESULTS: The majority of patients had inflammatory cells infiltrating BPH tissues: 81% had T-lymphocytes markers (CD3), 52% had B-lymphocytes markers (CD20), and 82% had macrophages markers (CD163). IPSS score (21 vs. 12; P = 0.02) and prostate volume (77 cm(3) vs. 62 cm(3); P = 0.002) were significantly higher in patients with high-grade prostatic inflammation. CONCLUSION: We characterized inflammatory cells infiltrate in a large cohort of surgically treated BPH specimens. The role of inflammation in BPH development was highlighted by the strong correlation between histological inflammation, IPSS, and prostate volume. Prostate enlargement due to chronic inflammatory process may progressively conduce to BPH progression. Therefore, inflammation is a therapeutic target for BPH

Transforming growth factor β-receptor II protein expression in benign prostatic hyperplasia is associated with prostate volume and inflammation.: TGFBR2 in benign prostatic hyperplasia

International audienceUNLABELLED: What's known on the subject? and What does the study add? Inflammation is known to play a role in BPH. Growth factors such as IGF and FGF are also known to play a role in the development of BPH. The paper shows that (1) TGFBR2, a member of the TGF family, has a protein expression related to prostate gland volume, and (2) highlights the interaction between inflammation and TGFBR2 for the development of BPH. OBJECTIVE: *  To assess transforming growth factor β-receptor II (TGFBRII) protein expression in benign prostatic hyperplasia (BPH) using immunohistochemistry analysis, and to compare the analysis with phenotypic properties. METHODS: *  TGFBRII protein expression was profiled using three clinical outcome tissue microarrays (TMAs), sampled from 231 patients who underwent surgery for BPH. *  Using these TMAs, five inflammatory cell markers were also assessed, including CD3, CD4, CD8, CD20, and CD163. *  The surgical procedure was open prostatectomy in 95 patients and transurethral resection of the prostate in 136 patients. RESULTS: *  TGFBRII protein expression was found in BPH epithelium cells for both basal and secretory cells, as well as in fibromuscular stromal cells. TGFBRII staining was also strong in most of the lymphocytes infiltrating the prostate. *  TGFBRII stromal staining was found to be significantly associated with prostate volume (P = 0.04), whereas TGFBRII epithelial staining was found to be significantly associated with 5-α-reductase-inhibitor medical therapy received by patients before surgery (P = 0.004). *  Both stromal and epithelial TGFBRII staining were found to be associated with CD4 T-lymphocyte infiltrate, independently of prostate volume (P < 0.001 and P = 0.002). CONCLUSIONS: *  TGFBRII protein expression in BPH is associated with prostate gland volume and with CD4 T-lymphocyte prostatitis. *  TGFBRII might be a promising therapeutic target to prevent prostate enlargement or even to decrease prostate volume