Home LiteratureArticle Details
PMID: 25938772 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

PloS one ·Vol. 10 ·No. 5 ·2015-00-00 ·Pages e0125625

Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, Wu Y, Qin J

Abstract

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.

MeSH Terms
AC133 Antigen Animals Antigens, CD/metabolism Cell Line, Tumor Colorectal Neoplasms/metabolism,pathology Culture Media, Conditioned/pharmacology Drug Resistance, Neoplasm/drug effects Exosomes/drug effects,metabolism,ultrastructure Female Fibroblasts/drug effects,metabolism Glycoproteins/metabolism Humans Mice, Nude Neoplastic Stem Cells/drug effects,pathology Paracrine Communication/drug effects Peptides/metabolism Wnt Signaling Pathway/drug effects Xenograft Model Antitumor Assays
Chemicals
AC133 Antigen Antigens, CD Culture Media, Conditioned Glycoproteins PROM1 protein, human Peptides Prom1 protein, mouse
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hu Yibing
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yan Chang
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Mu Lei
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Huang Kaiyu
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Li Xiaolan
Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Tao Deding
Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Wu Yaqun
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Qin Jichao
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
References (43)
43 references, click to expand
  1. Identification of c-MYC as a target of the APC pathway.
    Science. 1998 Sep 4;281(5382):1509-12 PMID: 9727977
  2. The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer.
    PLoS One. 2010;5(5):e10714 PMID: 20502714
  3. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.
    Cell. 2005 May 6;121(3):335-48 PMID: 15882617
  4. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.
    Leukemia. 2006 May;20(5):847-56 PMID: 16453000
  5. Impaired DICER1 function promotes stemness and metastasis in colon cancer.
    Oncogene. 2014 Jul 24;33(30):4003-15 PMID: 24096488
  6. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells.
    Blood. 2014 Jul 24;124(4):555-66 PMID: 24928860
  7. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts.
    J Biol Chem. 1999 Dec 17;274(51):36505-12 PMID: 10593948
  8. Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10356-61 PMID: 11526241
  9. A role for Wnt signalling in self-renewal of haematopoietic stem cells.
    Nature. 2003 May 22;423(6938):409-14 PMID: 12717450
  10. CD44 promotes resistance to apoptosis in human colon cancer cells.
    Exp Mol Pathol. 2004 Aug;77(1):18-25 PMID: 15215046
  11. Biogenesis and secretion of exosomes.
    Curr Opin Cell Biol. 2014 Aug;29:116-25 PMID: 24959705
  12. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.
    Cell. 2014 Oct 23;159(3):499-513 PMID: 25417103
  13. The requirement for freshly isolated human colorectal cancer (CRC) cells in isolating CRC stem cells.
    Br J Cancer. 2015 Feb 3;112(3):539-46 PMID: 25535733
  14. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake.
    J Clin Invest. 2006 Jul;116(7):1955-62 PMID: 16794736
  15. Identification and expansion of human colon-cancer-initiating cells.
    Nature. 2007 Jan 4;445(7123):111-5 PMID: 17122771
  16. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.
    Nature. 2007 Jan 4;445(7123):106-10 PMID: 17122772
  17. Wnt/beta-catenin signaling in cancer stemness and malignant behavior.
    Curr Opin Cell Biol. 2007 Apr;19(2):150-8 PMID: 17306971
  18. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy.
    PLoS One. 2008;3(6):e2428 PMID: 18560594
  19. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition.
    Cancer Res. 2009 Mar 1;69(5):1951-7 PMID: 19244128
  20. Environment-mediated drug resistance: a major contributor to minimal residual disease.
    Nat Rev Cancer. 2009 Sep;9(9):665-74 PMID: 19693095
  21. Heterogeneity in cancer: cancer stem cells versus clonal evolution.
    Cell. 2009 Sep 4;138(5):822-9 PMID: 19737509
  22. Molecular biology of cancer-associated fibroblasts: can these cells be targeted in anti-cancer therapy?
    Semin Cell Dev Biol. 2010 Feb;21(1):2-10 PMID: 19840860
  23. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
    Nat Cell Biol. 2010 May;12(5):468-76 PMID: 20418870
  24. Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling.
    J Cell Biol. 2010 Sep 20;190(6):1079-91 PMID: 20837771
  25. Global cancer statistics.
    CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90 PMID: 21296855
  26. ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients.
    Cancer Res. 2011 Aug 1;71(15):5307-16 PMID: 21652540
  27. Intercellular communication: diverse structures for exchange of genetic information.
    Nat Rev Mol Cell Biol. 2012 May;13(5):328-35 PMID: 22510790
  28. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration.
    Cell Stem Cell. 2012 May 4;10(5):556-69 PMID: 22560078
  29. Cancer stem cells: current status and evolving complexities.
    Cell Stem Cell. 2012 Jun 14;10(6):717-28 PMID: 22704512
  30. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.
    Nat Med. 2012 Jun;18(6):883-91 PMID: 22635005
  31. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug.
    J Natl Cancer Inst. 2012 Sep 5;104(17):1320-34 PMID: 22911669
  32. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration.
    Cell. 2012 Dec 21;151(7):1542-56 PMID: 23260141
  33. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma.
    Cancer Res. 2013 Jan 15;73(2):897-907 PMID: 23221385
  34. Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment.
    Cancer Res. 2013 Apr 15;73(8):2480-92 PMID: 23436796
  35. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.
    J Exp Med. 2013 Dec 16;210(13):2851-72 PMID: 24323355
  36. CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment.
    Stem Cells. 2014 Jan;32(1):145-56 PMID: 24395741
  37. Synergism between upregulation of Rab7 and inhibition of autophagic degradation caused by mycoplasma facilitates intracellular mycoplasma infection.
    Mol Med Rep. 2014 Mar;9(3):793-800 PMID: 24452847
  38. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis.
    Cancer Cell. 2014 Apr 14;25(4):501-15 PMID: 24735924
  39. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
    Nat Cell Biol. 2007 Jun;9(6):654-9 PMID: 17486113
  40. The gastrointestinal tract stem cell niche.
    Stem Cell Rev. 2006;2(3):203-12 PMID: 17625256
  41. Ceramide triggers budding of exosome vesicles into multivesicular endosomes.
    Science. 2008 Feb 29;319(5867):1244-7 PMID: 18309083
  42. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells.
    Nature. 1999 Apr 1;398(6726):422-6 PMID: 10201372
  43. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4.
    Cell Stem Cell. 2007 Oct 11;1(4):389-402 PMID: 18371377
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0125625
Published
2015-00-00
Epub
2015-00-04
Pages
e0125625
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC4418721
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0125625 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2