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Journal of Translational Medicine

, 12:313

Disease Biomarkers

Abstract

BackgroundMany current therapies for metastatic castration-resistant prostate cancer mCRPC are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells CTCs offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC.

MethodsFifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting FACS was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX.

ResultsWe found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve.

ConclusionsAs our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.

KeywordsProstate neoplasms Androgen receptor Circulating tumor cells Castration-resistant prostate cancer AbbreviationsCTCsCirculating tumor cells

mCRPCMetastatic castration-resistant prostate cancer

FACSFluorescence-activated cell sorting

ARAndrogen Receptor

PCRPolymerase chain reaction

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-014-0313-z contains supplementary material, which is available to authorized users.

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Autor: Edwin E Reyes - David J VanderWeele - Masis Isikbay - Ryan Duggan - Alexa Campanile - Walter M Stadler - Donald J Vande

Fuente: https://link.springer.com/







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