RRC ID 59837
Author Mitsui Y, Tomonobu N, Watanabe M, Kinoshita R, Sumardika IW, Youyi C, Murata H, Yamamoto KI, Sadahira T, Rodrigo AGH, Takamatsu H, Araki K, Yamauchi A, Yamamura M, Fujiwara H, Inoue Y, Futami J, Saito K, Iioka H, Kondo E, Nishibori M, Toyooka S, Yamamoto Y, Nasu Y, Sakaguchi M.
Title Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts.
Journal Oncol Res
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.
Volume 27(8)
Pages 945-956
Published 2019-8-8
DOI 10.3727/096504019X15555408784978
PMID 31046874
PMC PMC7848232
MeSH Adenocarcinoma / blood Adenocarcinoma / genetics* Adenocarcinoma / pathology Antigens, Neoplasm / genetics Cancer-Associated Fibroblasts / metabolism Cancer-Associated Fibroblasts / pathology Carcinoma, Pancreatic Ductal / blood Carcinoma, Pancreatic Ductal / genetics* Carcinoma, Pancreatic Ductal / pathology Cell Line, Tumor Cell Movement / genetics Cell Proliferation / genetics Coculture Techniques Cyclooxygenase 2 / genetics Dinoprostone / genetics Gene Expression Regulation, Neoplastic / genetics Humans MAP Kinase Kinase Kinases / genetics* Mitogen-Activated Protein Kinase Kinases / genetics Mitogen-Activated Protein Kinases / genetics Neoplastic Cells, Circulating / metabolism Proto-Oncogene Proteins / genetics* S100 Proteins / blood S100 Proteins / genetics*
IF 4.634
Times Cited 1
Human and Animal Cells 293T(RCB2202) PK-8(RCB2700)