Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer

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 chem...

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Bibliographic Details
Published in:PloS one 2015-05, Vol.10 (5), p.e0125625-e0125625
Main Authors: Hu, Yibing, Yan, Chang, Mu, Lei, Huang, Kaiyu, Li, Xiaolan, Tao, Deding, Wu, Yaqun, Qin, Jichao
Format: Article
Language:English
Subjects:
5-Fluorouracil
AC133 Antigen
Animals
Antigens, CD - metabolism
Biology
Blood
Bone marrow
Cancer
Care and treatment
Cell death
Cell Line, Tumor
Chemoresistance
Chemotherapy
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Complications and side effects
Conditioning
Culture Media, Conditioned - pharmacology
Drug resistance
Drug Resistance, Neoplasm - drug effects
Exosomes
Exosomes - drug effects
Exosomes - metabolism
Exosomes - ultrastructure
Female
Fibroblasts
Fibroblasts - drug effects
Fibroblasts - metabolism
Glycoproteins - metabolism
Health aspects
Hospitals
Humans
Medical research
Medicine
Metastasis
Mice, Nude
Neoplastic Stem Cells - drug effects
Neoplastic Stem Cells - pathology
Oxaliplatin
Paracrine Communication - drug effects
Patients
Peptides - metabolism
Priming
Science
Secretion
Stem cell research
Stem cells
Surgery
Tumors
Wnt Signaling Pathway - drug effects
Xenograft Model Antitumor Assays
Xenografts
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0125625