Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancerReport as inadecuate




Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer - Download this document for free, or read online. Document in PDF available to download.

Cancer Immunology, Immunotherapy

, Volume 63, Issue 5, pp 513–528

First Online: 21 March 2014Received: 12 October 2013Accepted: 22 February 2014DOI: 10.1007-s00262-014-1527-x

Cite this article as: Panni, R.Z., Sanford, D.E., Belt, B.A. et al. Cancer Immunol Immunother 2014 63: 513. doi:10.1007-s00262-014-1527-x

Abstract

Pancreatic cancer PC mobilizes myeloid cells from the bone marrow to the tumor where they promote tumor growth and proliferation. Cancer stem cells CSCs are a population of tumor cells that are responsible for tumor initiation. Aldehyde dehydrogenase-1 activity in PC identifies CSCs, and its activity has been correlated with poor overall prognosis in human PC. Myeloid cells have been shown to impact tumor stemness, but the impact of immunosuppressive tumor-infiltrating granulocytic and monocytic myeloid-derived suppressor cells Mo-MDSC on ALDH1 CSCs and epithelial to mesenchymal transition is not well understood. In this study, we demonstrate that Mo-MDSC CD11b-Gr1-Ly6G-Ly6C significantly increase the frequency of ALDH1 CSCs in a mouse model of PC. Additionally, there was significant upregulation of genes associated with epithelial to mesenchymal transition. We also found that human PC converts CD14 peripheral blood monocytes into Mo-MDSC CD14-HLA-DR in vitro, and this transformation is dependent on the activation of the STAT3 pathway. In turn, these Mo-MDSC increase the frequency of ALDH1 CSCs and promote mesenchymal features of tumor cells. Finally, blockade of STAT3 activation reversed the increase in ALDH1 CSCs. These data suggest that the PC tumor microenvironment transforms monocytes to Mo-MDSC by STAT3 activation, and these cells increase the frequency of ALDH1 CSCs. Therefore, targeting STAT3 activation may be an effective therapeutic strategy in targeting CSCs in PC.

KeywordsMonocytic MDSC Stem cell Epithelial to mesenchymal transition Pancreatic cancer STAT3 activity AbbreviationsCCR2Chemokine C–C motif receptor 2

CSCCancer stem cell

G-CSFGranulocyte colony-stimulating factor CSF-3

G-MDSCGranulocytic myeloid-derived suppressor cell

Mo-MDSCMonocytic myeloid-derived suppressor cell

PCPancreatic cancer

STAT3Signal transducer and activator of transcription 3

TAMTumor-associated macrophage

Electronic supplementary materialThe online version of this article doi:10.1007-s00262-014-1527-x contains supplementary material, which is available to authorized users.

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