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CANCER STEM CELLS |
1 Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan
2 Department of Pathology, Urology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan
* To whom correspondence should be addressed. E-mail: fsarkar{at}med.wayne.edu.
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Abstract |
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Majority of human malignancies are believed to have epithelial origin and the progression of cancer is often associated with a transient process named epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of epithelial markers and the gain of mesenchymal markers that are typical of "cancer stem-like cells", which results in increased cell invasion and metastasis in vivo. Therefore it is important to uncover the mechanistic role of factors that may induce EMT in cancer progression. Studies have shown that platelet derived growth factor (PDGF) signaling contributes to EMT, and more recently, PDGF-D have been shown to regulate cancer cell invasion and angiogenesis. However, the mechanism by which PDGF-D promotes invasion and metastases, and whether it is due to the acquisition of EMT phenotype remains elusive. For this study, we established stably transfected PC3 cells expressing high levels of PDGF-D, which resulted in the significant induction of EMT as shown by changes in cellular morphology concomitant with the loss of E-cadherin and ZO-1, and gain of vimentin. We also found activation of mTOR and NF-
B as well as Bcl-2 over-expression in PDGF-D PC3 cells, which was associated with enhanced adhesive and invasive behaviors. More importantly, PDGF-D over-expressing PC3 cells showed tumor growth in SCID mice much more rapidly than PC3 cells. These results provided a novel mechanism by which PDGF-D promotes EMT, which in turn increased tumor growth, and these results further suggest that PDGF-D could be a novel therapeutic target for the prevention and/or treatment of prostate cancer.
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Author contributions: D.K.: Conception and design, execution, collection of data and data analysis, manuscript writing; Z.W.: Experimental design and execution, and data analysis; S.H.S.: Experimental execution and collection of data; Y.L.: Experimental design, data analysis, manuscript writing; S.B.: Experimental design, execution of animal experiment and data analysis; A.S.: Animal experiments, data collection and data analysis; H.C.K.: Development of PC3 PDGF-D cell line and experimental design; M.L.C.: Animal experiment and data interpretation; F.H.S.: Principal investigator, conception and design, laboratory facility and financial support, experimental design, data collection and interpretation, manuscript writing and final approval of manuscript.
Key Words. platelet-derived growth factor-D, epithelial–mesenchymal transition, mammalian target of rapamycin, nuclear factor-B, E-cadherin, vimentin
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