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Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

Authors :
Ken Saito
Akira Yamauchi
Hidekazu Iioka
Hitoshi Murata
Rie Kinoshita
Takuya Sadahira
Junichiro Futami
Shinichi Toyooka
Acosta Gonzalez Herik Rodrigo
Chen Youyi
I. Wayan Sumardika
Nahoko Tomonobu
Ken Ichi Yamamoto
Masakiyo Sakaguchi
Eisaku Kondo
Hideyo Fujiwara
Yasutomo Nasu
Masahiro Nishibori
Yusuke Inoue
Masahiro Yamamura
Yosuke Mitsui
Hitoshi Takamatsu
Masami Watanabe
Kota Araki
Yasuhiko Yamamoto
Source :
Oncology Research
Publication Year :
2019
Publisher :
Computers, Materials and Continua (Tech Science Press), 2019.

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.

Details

ISSN :
09650407
Volume :
27
Database :
OpenAIRE
Journal :
Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics
Accession number :
edsair.doi.dedup.....c819ef11cef47a658672a5aeea2fae65
Full Text :
https://doi.org/10.3727/096504019x15555408784978