Open Accessc‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice
Author(s) -
Sato Takeshi,
Shibata Wataru,
Hikiba Yohko,
Kaneta Yoshihiro,
Suzuki Nobumi,
Ihara Sozaburo,
Ishii Yasuaki,
Sue Soichiro,
Kameta Eri,
Sugimori Makoto,
Yamada Hiroaki,
Kaneko Hiroaki,
Sasaki Tomohiko,
Ishii Tomohiro,
Tamura Toshihide,
Kondo Masaaki,
Maeda Shin
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13382
Subject(s) - kras , stroma , ccl20 , kinase , cancer research , c jun , pancreatic cancer , chemokine , chemistry , biology , medicine , microbiology and biotechnology , immunology , cancer , inflammation , immunohistochemistry , chemokine receptor , colorectal cancer , biochemistry , gene , transcription factor
Pancreatic ductal adenocarcinoma ( PDAC ) is a life‐threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c‐Jun N‐terminal kinase ( JNK ) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a Cre/+ ; Kras G12D/+ mice with JNK 1 −/− mice to generate Ptf1a Cre/+ ;Kras G12D/+ ; JNK 1 −/− (Kras; JNK 1 −/− ) mice. Tumor weight was significantly lower in Kras; JNK 1 −/− mice than in Kras; JNK 1 +/− mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line ( mPC ) with intact JNK 1 s.c. into WT and JNK 1 −/− mice. Tumor diameters were significantly smaller in JNK 1 −/− mice. Phosphorylated JNK (p‐ JNK ) was activated in α‐smooth muscle actin ( SMA )‐positive cells in tumor stroma, and mPC ‐conditioned medium activated p‐ JNK in tumor‐associated fibroblasts ( TAF ) in vitro . Relative expression of Ccl20 was downregulated in stimulated TAF . Ccl20 is an important chemokine that promotes CD 8 + T‐cell infiltration by recruitment of dendritic cells, and the number of CD 8 + T cells was decreased in Kras; JNK 1 +/− mice compared with Kras; JNK 1 −/− mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK , and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD 8 + T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD 8 + T cells, which would be expected to enhance antitumor immunity.