The Hedgehog inhibitor suppresses the function of monocyte-derived dendritic cells from patients with advanced cancer under hypoxia

•Activation of Hh signaling is observed in monocyte derived dendritic cells (Mo-DCs).•Hh signaling inhibitor decreased the function of Mo-DCs under hypoxic condition.•Hh signaling plays a pivotal role for the maintenance and function of Mo-DCs.•Combination of Hh inhibitors and immunotherapy with Mo-...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2013-06, Vol.436 (1), p.53-59
Main Authors: Onishi, Hideya, Morisaki, Takashi, Kiyota, Akifumi, Koya, Norihiro, Tanaka, Hiroto, Umebayashi, Masayo, Katano, Mitsuo
Format: Article
Language:English
Subjects:
Adult
Advanced cancer
Aged
Antigen Presentation
Cell Hypoxia
Cell Movement
Cell Proliferation
Cyclopamine
Dendritic cells
Dendritic Cells - cytology
Female
Gene Expression Regulation, Neoplastic
Hedgehog Proteins - antagonists & inhibitors
Hedgehog Proteins - metabolism
Hedgehog signaling
Humans
Hypoxia
Interleukin-12 - metabolism
Interleukin-12 Subunit p40 - metabolism
Male
Middle Aged
Monocytes - cytology
Neoplasms - genetics
Neoplasms - metabolism
Signal Transduction
Tumor Cells, Cultured
Veratrum Alkaloids - pharmacology
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Summary:•Activation of Hh signaling is observed in monocyte derived dendritic cells (Mo-DCs).•Hh signaling inhibitor decreased the function of Mo-DCs under hypoxic condition.•Hh signaling plays a pivotal role for the maintenance and function of Mo-DCs.•Combination of Hh inhibitors and immunotherapy with Mo-DCs may be disadvantageous. Immunotherapy using monocyte derived dendritic cells (Mo-DCs) from cancer patients has been developed; however, the Mo-DCs regularly studied have been derived from non-cancer bearing donors or mice, and evaluated in normoxic conditions. In the present study, we investigated the effects of Hedgehog (Hh) inhibitors which are being developed as molecular target drugs for cancer on the functions of Mo-DCs derived from patients with advanced cancer when cultured in a tumor-like hypoxic environment. Mo-DC induction, migration, chemotaxis, phagocytosis, maturation, IL-12 p40 or p70 secretion and the allogeneic lymphocyte stimulation activity of Mo-DCs from patients with advanced cancer were all significantly inhibited by the Hh inhibitor, cyclopamine under hypoxic conditions. Our results suggest that Hh signaling plays an important role in the maintenance and function of Mo-DCs derived from patients with advanced cancer when cultured under hypoxic conditions.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2013.05.057