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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
- 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.
- Subjects :
- Cancer microenvironment
0301 basic medicine
Cancer Research
endocrine system diseases
Adenocarcinoma
Dinoprostone
Article
03 medical and health sciences
0302 clinical medicine
Circulating tumor cell
Cancer-Associated Fibroblasts
Downregulation and upregulation
Antigens, Neoplasm
Cell Movement
Cell Line, Tumor
Proto-Oncogene Proteins
Pancreatic cancer
medicine
Humans
Protein kinase A
Cell Proliferation
Mitogen-Activated Protein Kinase Kinases
MAP kinase kinase kinase
Chemistry
Kinase
S100 Proteins
Cell migration
General Medicine
Fibroblasts
MAP Kinase Kinase Kinases
Neoplastic Cells, Circulating
medicine.disease
Coculture Techniques
RAGE
digestive system diseases
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
Cyclooxygenase 2
S100A11
030220 oncology & carcinogenesis
Cancer cell
Cancer research
Mitogen-Activated Protein Kinases
Carcinoma, Pancreatic Ductal
Subjects
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