Differential role of Interleukin-1 and Interleukin-6 in K-Ras-driven pancreatic carcinoma undergoing mesenchymal transition.

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Version: author
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Serval ID
serval:BIB_E8EDAD175DD1
Type
Article: article from journal or magazin.
Collection
Publications
Title
Differential role of Interleukin-1 and Interleukin-6 in K-Ras-driven pancreatic carcinoma undergoing mesenchymal transition.
Journal
Oncoimmunology
Author(s)
Siddiqui I., Erreni M., Kamal M.A., Porta C., Marchesi F., Pesce S., Pasqualini F., Schiarea S., Chiabrando C., Mantovani A., Allavena P.
ISSN
2162-4011 (Print)
ISSN-L
2162-4011
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
7
Number
2
Pages
e1388485
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
K-Ras mutations are a hallmark of human pancreatic adenocarcinoma (PDAC) and epithelial-mesenchymal-transition (EMT) is a driver of progression. Oncogenic K-Ras causes the constitutive activation of NF-kB and the switch-on of an inflammatory program, which further fuels NF-kB and STAT3 activation. In this study we investigated how inflammatory pathways triggered by oncogenic K-Ras are regulated in human pancreatic cancer cells with distict epithelial or mesenchymal phenotype. Our results demonstrate that in cells with epithelial features, K-Ras driven inflammation is under the control of IL-1, while in cells undergoing EMT, is IL-1 independent. In pancreatic tumor cells with EMT phenotype, treatment with IL-1R antagonist (Anakinra) did not inhibit inflammatory cytokine production and tumor growth in mice. In these cells IL-6 is actively transcribed by the EMT transcription factor TWIST. Targeting of mesenchymal pancreatic tumors in vivo with anti-IL-6RmAb (RoActemra) successfully decreased tumor growth in immunodeficient mice, inhibited the inflammatory stroma and NF-kB-p65 and STAT3 phosphorylation in cancer cells. The results confirm that IL-1 is an important driver of inflammation in epithelial pancreatic tumors; however, tumor cells undergoing EMT will likely escape IL-1R inhibition, as IL-6 is continuously transcribed by TWIST. These findings have implications for the rational targeting of inflammatory pathways in human pancreatic cancer.
Keywords
Cancer Immunotherapy, EMT, Inflammation, Oncogene, Therapeutic Antibodies
Pubmed
Web of science
Create date
22/01/2018 17:26
Last modification date
03/05/2021 16:02
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