Abstract
Metastasis is the cause of most prostate cancer (PCa) deaths and has been associated with circulating tumor cells (CTCs). The presence of ≥5 CTCs/7.5mL of blood is a poor prognosis indicator in metastatic PCa when assessed by the CellSearch® system, the “gold standard” clinical platform. However, ~35% of metastatic PCa patients assessed by CellSearch® have undetectable CTCs. We hypothesize that this is due to epithelial-to-mesenchymal transition (EMT) and subsequent loss of necessary CTC detection markers, with important implications for PCa metastasis. Two pre-clinical assays were developed to assess human CTCs in xenograft models; one comparable to CellSearch® (EpCAM-based) and one detecting CTCs semi-independent of EMT status via combined staining with EpCAM/HLA (human leukocyte antigen). In vivo differences in CTC generation, kinetics, metastasis and EMT status were determined using 4 PCa models with progressive epithelial (LNCaP, LNCaP-C42B) to mesenchymal (PC-3, PC-3M) phenotypes. Assay validation demonstrated that the CellSearch®-based assay failed to detect a significant number (~40-50%) of mesenchymal CTCs. In vivo, PCa with an increasingly mesenchymal phenotype shed greater numbers of CTCs more quickly and with greater metastatic capacity than PCa with an epithelial phenotype. Notably, the CellSearch®-based assay captured the majority of CTCs shed during early-stage disease in vivo, and only after establishment of metastases were a significant number of undetectable CTCs present. This study provides important insight into the influence of EMT on CTC generation and subsequent metastasis, and highlights that novel technologies aimed at capturing mesenchymal CTCs may only be useful in the setting of advanced metastatic disease.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed cancer and second most common cause of cancer death in American men [1]
Detection of circulating tumor cells (CTCs) in the blood is correlated with metastatic disease burden and reduced overall survival [3,4,5,6], with ≥5 CTCs/7.5ml of blood being indicative of poor prognosis in metastatic prostate cancer (PCa) patients [6]
We observed that that E-cadherin was expressed in PC-3, it was aberrantly localized to the cytoplasm, likely due to a lack of α-catenin expression which is necessary for appropriate E-cadherin membrane localization [31]
Summary
Prostate cancer (PCa) is the most commonly diagnosed cancer and second most common cause of cancer death in American men [1]. The majority of prostate cancer deaths result from metastasis, since current therapies are non-curative in the metastatic setting [2]. Detection of circulating tumor cells (CTCs) in the blood is correlated with metastatic disease burden and reduced overall survival [3,4,5,6], with ≥5 CTCs/7.5ml of blood being indicative of poor prognosis in metastatic PCa patients [6]. Changes in CTC number throughout treatment have been demonstrated to reflect therapy response [7]. Due to the rare nature of CTCs (~1 CTC/105-107 leukocytes in metastatic patients), extremely sensitive technologies are required for accurate CTC detection [8]. Several techniques have been employed to enrich www.impactjournals.com/oncotarget
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