TY - JOUR
T1 - Extracellular S100A11 plays a critical role in spread of the fibroblast population in pancreatic cancers
AU - Takamatsu, Hitoshi
AU - Yamamoto, Ken ichi
AU - Tomonobu, Nahoko
AU - Murata, Hitoshi
AU - Inoue, Yusuke
AU - Yamauchi, Akira
AU - Wayan Sumardika, I.
AU - Chen, Youyi
AU - Kinoshita, Rie
AU - Yamamura, Masahiro
AU - Fujiwara, Hideyo
AU - Mitsui, Yosuke
AU - Araki, Kota
AU - Futami, Junichiro
AU - Saito, Ken
AU - Iioka, Hidekazu
AU - Made Winarsa Ruma, I.
AU - Putranto, Endy Widya
AU - Nishibori, Masahiro
AU - Kondo, Eisaku
AU - Yamamoto, Yasuhiko
AU - Toyooka, Shinichi
AU - Sakaguchi, Masakiyo
N1 - Funding Information:
ACKNOWLEDGMENTS: We thank the central research center for Kawasaki Medical School for technical support. This work was supported by the Foundation for Promotion of Cancer Research (M. Sakaguchi) and in part by grants from the JSPS KAKENHI Grant (No. 17H03577) (M. Sakaguchi), JSPS KAKENHI Grant (No. 15K10201) (A. Yamauchi), and Takeda Science Foundation (M. Sakaguchi). The authors declare no conflicts of interest.
Publisher Copyright:
Copyright © 2019 Cognizant, LLC.
PY - 2019
Y1 - 2019
N2 - The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11–RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE–MyD88–mTOR–p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.
AB - The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11–RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE–MyD88–mTOR–p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.
KW - Cancer microenvironment
KW - Fibroblasts
KW - Pancreatic cancer
KW - RAGE
KW - S100A11
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UR - http://www.scopus.com/inward/citedby.url?scp=85068490977&partnerID=8YFLogxK
U2 - 10.3727/096504018X15433161908259
DO - 10.3727/096504018X15433161908259
M3 - Article
C2 - 30850029
AN - SCOPUS:85068490977
VL - 27
SP - 713
EP - 727
JO - Cancer Communications
JF - Cancer Communications
SN - 0965-0407
IS - 6
ER -