Abstract
BackgroundCurrent management of patients diagnosed with prostate cancer (PCa) is very effective; however, tumor recurrence 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 for designing novel therapies. The recurrence and the metastasis of PCa are tightly linked with the biology of prostate cancer stem 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-like cells.Methodology/Principal FindingsIn this study, we found that PCa cells with EMT phenotype displayed stem-like cell features characterized by increased expression of Sox2, Nanog, Oct4, Lin28B and/or Notch1, consistent with enhanced clonogenic and sphere (prostasphere)-forming ability and tumorigenecity in mice, which was associated with decreased expression of miR-200 and/or let-7 family. Reversal of EMT by re-expression of miR-200 inhibited prostasphere-forming ability of EMT-type cells and reduced the expression of Notch1 and Lin28B. Down-regulation of Lin28B increased let-7 expression, which was consistent with repressed self-renewal capability.Conclusions/SignificanceThese results suggest that miR-200 played a pivotal role in linking the characteristics of cancer stem-like cells with EMT-like cell signatures in PCa. Selective elimination of cancer stem-like cells by reversing the EMT phenotype to Mesenchymal-Epithelial Transition (MET) phenotype using novel agents would be useful for the prevention of tumor recurrence especially by eliminating those cells that are the “Root Cause” of tumor development and recurrence.
Highlights
Emerging evidence suggest that most solid tumors including prostate cancer (PCa) may arise from cancer stem cells [1]
We found that platelet derived growth factor (PDGF)-D over-expressing PC3 cells acquired Epithelial to Mesenchymal Transition (EMT) phenotype and shared stem-like cell features characterized by increased expression of stem cell markers such as Notch1, Sox2, Nanog, Oct4 and Lin28B, which was consistent with enhanced clonogenic, prostasphere-forming ability as well as increased tumorigenicity in mice
The results from Western blot analysis and cell morphology as well as our published data have demonstrated that over-expression of PDGF-D induced EMT phenotype in PC3 cells [26,28] (Fig. 1A), which was consistent with higher levels of PDGF-D in cell lysates and conditioned medium (CM) from PC3 PDGF-D cells compared with PC3 Neo cells (Fig. S1A and S1B)
Summary
Emerging evidence suggest that most solid tumors including prostate cancer (PCa) may arise from cancer stem cells [1]. The cancer stem cells are cells within a tumor that possess the capacity of self-renewal and tumor-initiating capacity, and differentiate into the heterogeneous lineages of cancer cells that comprise in a tumor mass. These tumor-initiating cells could provide a reservoir for cells that cause tumor recurrence after therapy. Origin of PCa cells needs to be fully elucidated, a number of mounting evidence suggest that tumor-initiating cells or cancer stem cells play a critical role in the progression and recurrence of PCa to castrate resistant prostate cancer (CRPC) and its subsequent metastasis. Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-like cells
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