* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Diapositiva 1
Gene expression programming wikipedia , lookup
BRCA mutation wikipedia , lookup
Designer baby wikipedia , lookup
Long non-coding RNA wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Gene expression profiling wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Epigenetics in stem-cell differentiation wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Cancer epigenetics wikipedia , lookup
Genome (book) wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Mir-92 microRNA precursor family wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
The physiopathological evolution of prostate cancer Antonello Di Paolo Dipartimento di Medicina Clinica e Sperimentale Università di Pisa Androgens are key players in prostate cancer proliferation Selective pharmacological pressure and adaptation in prostate cancer Selective pressure Adaptation Knudsen KE, Penning TM. Trends Endocrinol Metab 2010; 21: 315-324 CRPC is not androgen independent • Androgen-dependent signaling mediates prostate cancer growth despite castrate levels of serum testosterone • Mechanisms: • • • • • Increased androgen uptake Increased AR ligand synthesis Receptor overexpression/amplification AR mutations (eg, hypersensitivity) Ligand-independent AR activation Sharifi N, et al. J Investig Med. 2010;58:938-944. Dutt SS, et al. Future Oncol. 2009;5:1403-1413. CRPC is not androgen independent Knudsen KE, Penning TM. Trends Endocrinol Metab 2010; 21: 315-324 AR gene PTEN gene Tumor suppressor genes Grasso et al. Nature. 2012; 487: 239–243 AR mutation and gain of function LNCaP LNCaP-hr M.C. privo di androgeni LNCaP-cDx Bicalutamide Bicalutamide no 1 μM Hara et al. Cancer Res 2012; 63: 149-153 AR gene mutations Transactivation assays showed that bicalutamide worked as an agonist for both W741C and W741L mutant ARs Hara et al. Cancer Res 2012; 63: 149-153 Alternative splicing of AR gene Hu et al. Cancer Res 2009; 69: 16-22 High gene expression of AR splicing variants in hormone-refractory PCa HRPC, hormone-refractory PCa AR AR-V1 AR-V7 11x 22x 20x Hu et al. Cancer Res 2009; 69: 16-22 Post-translational modifications of AR Gioeli & Paschal. Mol Cell Endocrinol 2012; 352: 70–78 Post-translational modifications of AR Gioeli & Paschal. Mol Cell Endocrinol 2012; 352: 70–78 Cell cycle regulation from G0 to G1-S Mitogens Ras/Raf/MAPK D-type cyclins CDK4/6 CDK4/6-cyclin D CDK2 G1-S transition Cyclin E CDK2-cyclin E Phosphorylation of proteins involved in histone modification, DNA replication and repair, centrosome duplication and maturation pRB/p107/p130 DP(1,2) E2Fn-DPn E2F(1-6) Recruitment of repressor complexes such as histone deacetylases and chromosomal remodeling SWI/SNF complexes “…cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted ARdependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b–mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease…” Augello et al. J Clin Invest. 2013;123(1):493–508 Intracrine androgen synthesis Cancer Res 2006;66:2815-2825 “…the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5αandrostanedione, which is then converted to DHT…” Androstenedione sustains PCa xenograft growth in castrated mice Increased bioavailability of precursors -34T>C A1 [ T ] normal transcription activity A2 [ C ] increased transcription activity Median overall survival: A1, 7.6 years vs. A2, 8.9 years (p<0.040 by log-rank test) Hamada et al. Urology 2007; 70: 217-220 Increased cellular uptake in PCa “The superfamily of organic anion-transporting polypeptides (OATP), encoded by SLCO genes, mediates the … uptake of various endogenous compounds and drugs into cells… SLCO2B1 and SLCO1B3 have been shown to be involved in the steroid hormone uptake. SLCO2B1 … mediates the transport of steroid conjugates, such as DHEAS and estrone-3-sulfate. SLCO1B3 [is] involved in the uptake of several hormones including T” J Clin Oncol 2011; 29: 2565-2573 SLCO2B1 SNPs are associated with increased gene expression and cell growth in vitro Yang et al. J Clin Oncol 2011; 29: 2565-2573 SLCO2B1 SNPs and TTP Yang et al. J Clin Oncol 2011; 29: 2565-2573 SLCO2B1-SLCO1B3 SNPs and TTP Yang et al. J Clin Oncol 2011; 29: 2565-2573 Stem cells in prostate cancer Mimeault & Batra. Biochim Biophys Acta 2011; 1816: 25–37 Epigenetics in prostate cancer Shen & Pili. Cancer J 2008;14:46-53 Epigenetics in prostate cancer Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell–like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation. Zhao et al. Genome Res 2012; 22: 322-331 AR directly regulates a large number of target genes Zhao et al. Genome Res 2012; 22: 322-331 Expression of steroidogenic enzymes in castration-resistant metastases versus primary prostate Montgomery et al. Cancer Res 2008; 68: 4447-4454 29 Mean tissue androgen levels in castration-resistant metastases from anorchid patients versus primary prostate tissues from eugonadal men Montgomery et al. Cancer Res 2008; 68: 4447-4454 Conclusion • • • • Advanced prostate cancer is neither hormone refractory nor androgen independent and remains nuclear steroid receptor driven Several adaptive pathways may sustain cancer growth Androgen receptor acts as a transcriptional repressor, which maintains a stem cell-like undifferentiated state The complex and redundant biochemical network behind CRPC may offer several “drugable” targets and biomarkers for patients’ stratification