Androgen receptor and its splicing variant 7 expression in peripheral blood mononuclear cells and in circulating tumor cells in metastatic castration-resistant prostate cancer

Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation

Presencia improbable de Torillo Andaluz Turnix sylvatica en Cataluña en el siglo pasado

Historically, the nominate subspecies of the Andalusian Hemipode was distributed only in southern Iberia, North Africa and Sicily. However, some authors have mentioned uncertain records in Catalonia (NE Spain) during last century. In the Museum of Zoology of Barcelona there is a specimen trapped in Catalonia between 1891 and 1910. Four hypotheses for the origin of this individual are put forward and discussed: 1) it was an individual in dispersal from southern breeding areas; 2) a century ago the species bred in Catalonia; 3) the bird was introduced (for a collection, or with a view to hunting); 4) the label gives an erroneous collecting locality. On the basis of the information available we conclude that third and fourth hypotheses are the most probable.La Guatlla Andalusa es distribuïa antigament pel sud de la península Ibèrica, el nord d’Àfrica i Sicília. Hi ha algunes citacions durant el segle passat de l’espècie a Catalunya, tot i que actualment no estan acceptades. Al Museu de Zoologia de Barcelona hi ha un espècimen capturat a Catalunya entre 1891-1910. Es proposen i discuteixen quatre hipòtesis per l’origen d’aquest individu: 1) era un individu en dispersió des d’àrees de cria del sud; 2) l’espècie nidificava a Catalunya fa un segle; 3) va ser un individu importat (per a una col·lecció o amb finalitats cinegètiques); 4) hi ha un error en la seva etiqueta. D’acord amb la informació disponible, concloem que les dues darreres són les hipòtesis més probables.El Torillo Andaluz se distribuía antaño por el sur de la Península Ibérica, el norte de África y Sicilia. Existen algunas citas durante el siglo pasado para esta especie en Cataluña, aunque actualmente están rechazadas. En el Museo de Zoología de Barcelona existe un espécimen capturado en Cataluña entre 1891-1910. Proponemos y discutimos cuatro hipótesis para el origen del individuo: 1) era un individuo en dispersión desde áreas de cría meridionales; 2) la especie nidificaba en Cataluña hace un siglo; 3) era un individuo importado (para una colección o con fines cinegéticos); 4) existe un error en su etiqueta. En base a la información disponible, concluimos que las dos últimas hipótesis son las más probables

Presència improbable de la Guatlla Andalusa (Turnix sylvatica) a Catalunya al segle passat

La Guatlla Andalusa es distribuïa antigament pel sud de la península Ibèrica, el nord d’Àfrica i Sicília. Hi ha algunes citacions durant el segle passat per l’espècie a Catalunya, tot i que actualment no estan acceptades. Al Museu de Zoologia de Barcelona hi ha un espècimen capturat a Catalunya entre 1891-1910. Es proposen i discuteixen quatre hipòtesis per l’origen d’aquest individu: 1) era un individu en dispersió des d’àrees de cria del sud; 2) l’espècie nidificava a Catalunya fa un segle; 3) va ser un individu importat (per a una col•lecció o amb finalitats cinegètiques); 4) hi ha un error en la seva etiqueta. D’acord amb la informació disponible, concloem que les dues darreres són les hipòtesis més probables

Cell Plasticity-Related Phenotypes and Taxanes Resistance in Castration-Resistant Prostate Cancer

Càncer de pròstata resistent a la castració; Plasticitat cel·lular; Resistència als taxansCáncer de próstata resistente a la castración; Plasticidad celular; Resistencia a los taxanosCastration-resistant prostate cancer; Cell plasticity; Taxanes resistanceThe prostatic tumor cells plasticity is involved in resistance to hormone-therapy, allowing these cells to survive despite androgen receptor inhibition. However, its role in taxanes resistance has not been fully established. Gene expression of plasticity-related phenotypes such as epithelial-mesenchymal transition (EMT), stem cell-like and neuroendocrine (NE) phenotypes was studied in vitro, in silico, in circulating tumor cells (CTCs) (N=22) and in tumor samples (N=117) from taxanes-treated metastatic castration-resistant prostate cancer (mCRPC) patients. Docetaxel (D)-resistant cells presented a more pronounced EMT phenotype than cabazitaxel (CZ)-resistant cells. In silico analysis revealed ESRP1 down-regulation in taxane-exposed mCRPC samples. Cell plasticity-related changes occurred in CTCs after taxanes treatment. Tumor EMT phenotype was associated with lower PSA progression-free survival (PFS) to D (P<0.001), and better to CZ (P=0.002). High ESRP1 expression was independently associated with longer PSA-PFS (P<0.001) and radiologic-PFS (P=0.001) in D and shorter PSA-PFS in the CZ cohort (P=0.041). High SYP expression was independently associated with lower PSA-PFS in D (P=0.003) and overall survival (OS) in CZ (P=0.002), and high EZH2 expression was associated with adverse OS in D-treated patients (P=0.013). In conclusion, EMT profile in primary tumor is differentially associated with D or CZ benefit and NE dedifferentiation correlates with adverse taxanes clinical outcome.This work was supported by grants from Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación [PI12/01226, PI15/676 and PI18/714] and co-funded by the European Regional Development Fund (ERDF). Institutional funding from CERCA Programme/Generalitat de Catalunya is gratefully acknowledged. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain

Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer