@Article{096504019X15555408784978,
AUTHOR = {Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I Wayan Sumardika, Chen Youyi, 
Hitoshi Murata, Ken-ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, 
Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, 
Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, 
Yasutomo Nasu, Masakiyo Sakaguchi},
TITLE = {Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11  Through Activation of Surrounding Fibroblasts},
JOURNAL = {Oncology Research},
VOLUME = {27},
YEAR = {2019},
NUMBER = {8},
PAGES = {945--956},
URL = {http://www.techscience.com/or/v27n8/48623},
ISSN = {1555-3906},
ABSTRACT = {S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. 
In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells 
and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) 
upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an 
increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of 
RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase 
kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC 
cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin 
E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was 
required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative 
progression through activation of surrounding fibroblasts triggered by the S100A11–RAGE–TPL2–COX2 
pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to 
PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the 
identified pathway.},
DOI = {10.3727/096504019X15555408784978}
}