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Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.

Abstract
The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.
AuthorsMelanie R Rutkowski, Tom L Stephen, Nikolaos Svoronos, Michael J Allegrezza, Amelia J Tesone, Alfredo Perales-Puchalt, Eva Brencicova, Ximena Escovar-Fadul, Jenny M Nguyen, Mark G Cadungog, Rugang Zhang, Mariana Salatino, Julia Tchou, Gabriel A Rabinovich, Jose R Conejo-Garcia
JournalCancer cell (Cancer Cell) Vol. 27 Issue 1 Pg. 27-40 (Jan 12 2015) ISSN: 1878-3686 [Electronic] United States
PMID25533336 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • Galectin 1
  • Interleukin-17
  • Interleukin-6
  • Toll-Like Receptor 5
Topics
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Galectin 1 (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-17 (metabolism)
  • Interleukin-6 (metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microbiota
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Neoplasms (immunology, pathology)
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • Toll-Like Receptor 5 (genetics, metabolism)

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