Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells

Abstract

Background: Current management of patients diagnosed with prostate cancer (PCa) is very effective; however, tumorrecurrence with Castrate Resistant Prostate Cancer (CRPC) and subsequent metastasis lead to poor survival outcome,suggesting that there is a dire need for novel mechanistic understanding of tumor recurrence, which would be critical fordesigning novel therapies. The recurrence and the metastasis of PCa are tightly linked with the biology of prostate cancerstem cells or cancer-initiating cells that is reminiscent of the acquisition of Epithelial to Mesenchymal Transition (EMT)phenotype. Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-likecells.Methodology/Principal Findings: In this study, we found that PCa cells with EMT phenotype displayed stem-like cellfeatures characterized by increased expression of Sox2, Nanog, Oct4, Lin28B and/or Notch1, consistent with enhancedclonogenic and sphere (prostasphere)-forming ability and tumorigenecity in mice, which was associated with decreasedexpression of miR-200 and/or let-7 family. Reversal of EMT by re-expression of miR-200 inhibited prostasphere-formingability of EMT-type cells and reduced the expression of Notch1 and Lin28B. Down-regulation of Lin28B increased let-7expression, which was consistent with repressed self-renewal capability.Conclusions/Significance: These results suggest that miR-200 played a pivotal role in linking the characteristics of cancerstem-like cells with EMT-like cell signatures in PCa. Selective elimination of cancer stem-like cells by reversing the EMTphenotype to Mesenchymal-Epithelial Transition (MET) phenotype using novel agents would be useful for the prevention oftumor recurrence especially by eliminating those cells that are the ''Root Cause'' of tumor development and recurrence. © 2010 Kong et al.