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Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer
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Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer
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Journal Article
Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer
2015
Overview
Chemotherapy resistance observed in patients with colorectal cancer (CRC) may be related to the presence of cancer stem cells (CSCs), but the underlying mechanism(s) remain unclear. Carcinoma-associated fibroblasts (CAFs) are intimately involved in tumor recurrence, and targeting them increases chemo-sensitivity. We investigated whether fibroblasts might increase CSCs thus mediating chemotherapy resistance. CSCs were isolated from either patient-derived xenografts or CRC cell lines based on expression of CD133. First, CSCs were found to be inherently resistant to cell death induced by chemotherapy. In addition, fibroblast-derived conditioned medium (CM) promoted percentage, clonogenicity and tumor growth of CSCs (i.e., CD133+ and TOP-GFP+) upon treatment with 5-fluorouracil (5-Fu) or oxaliplatin (OXA). Further investigations exhibited that exosomes, isolated from CM, similarly took the above effects. Inhibition of exosome secretion decreased the percentage, clonogenicity and tumor growth of CSCs. Altogether, our findings suggest that, besides targeting CSCs, new therapeutic strategies blocking CAFs secretion even before chemotherapy shall be developed to gain better clinical benefits in advanced CRCs.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Animals
/ Biology
/ Blood
/ Cancer
/ Colorectal Neoplasms - metabolism
/ Colorectal Neoplasms - pathology
/ Complications and side effects
/ Culture Media, Conditioned - pharmacology
/ Drug Resistance, Neoplasm - drug effects
/ Exosomes
/ Female
/ Humans
/ Medicine
/ Neoplastic Stem Cells - drug effects
/ Neoplastic Stem Cells - pathology
/ Paracrine Communication - drug effects
/ Patients
/ Priming
/ Science
/ Surgery
/ Tumors
/ Wnt Signaling Pathway - drug effects
