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

• Published in: PloS one Vol. 5; no. 8; p. e12445
• Main Authors: Kong, Dejuan, Banerjee, Sanjeev, Ahmad, Aamir, Li, Yiwei, Wang, Zhiwei, Sethi, Seema, Sarkar, Fazlul H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.08.2010; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Animals; Base Sequence; Bioavailability; Biomarkers - metabolism; Cancer; Cancer metastasis; Cell Biology/Cell Signaling; Cell Biology/Gene Expression; Cell Differentiation; Cell Line, Tumor; Cell self-renewal; Development and progression; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Epithelial Cells - pathology; Forming; Gene Expression Profiling; Genotype & phenotype; Health aspects; Homeodomain Proteins - metabolism; Humans; Lymphokines - metabolism; Male; Medicine; Mesenchyme; Mesoderm - pathology; Metastases; Metastasis; Mice; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; Nanog Homeobox Protein; Neoplastic Stem Cells - pathology; Notch1 protein; Oct-4 protein; Octamer Transcription Factor-3 - metabolism; Oncology; Oncology/Prostate Cancer; Pancreatic cancer; Pathology; Phenotype; Platelet-Derived Growth Factor - metabolism; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; RNA-Binding Proteins; Signatures; SOXB1 Transcription Factors - metabolism; Stem cell transplantation; Stem cells; Studies; Tumors; Vascular endothelial growth factor; Detroit Michigan; United States > US; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012445

Current 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. In 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. These 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.