Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells

K. E. Richards, A. E. Zeleniak, Melissa Fishel, J. Wu, L. E. Littlepage, R. Hill

Research output: Contribution to journalArticle

141 Citations (Scopus)

Abstract

Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.Oncogene advance online publication, 26 September 2016; doi:10.1038/onc.2016.353.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Sep 26 2016

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Exosomes
Pancreatic Neoplasms
gemcitabine
Adenocarcinoma
Drug Resistance
Drug Therapy
Neoplasms
Epithelial Cells
Cell Proliferation
Cancer-Associated Fibroblasts
Standard of Care
Oncogenes
Publications
Cultured Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. / Richards, K. E.; Zeleniak, A. E.; Fishel, Melissa; Wu, J.; Littlepage, L. E.; Hill, R.

In: Oncogene, 26.09.2016.

Research output: Contribution to journalArticle

Richards, K. E. ; Zeleniak, A. E. ; Fishel, Melissa ; Wu, J. ; Littlepage, L. E. ; Hill, R. / Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. In: Oncogene. 2016.
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