期刊
CELLS
卷 10, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/cells10081928
关键词
pancreatic cancer; PDAC; pancreatic stellate cells; IL-6; Tocilizumab; STAT3; fibrosis; eATP
类别
资金
- Danish Council for Independent Research Medical Sciences [8020-00254B]
- Marie Sklodowska-Curie COFUND Doctoral Programme TALENT [H2020-MSCA-COFUND-2017-801199]
- Danish Council for Independent Research Natural Sciences [4002-00162B]
- Novo Nordisk Fonden [100195]
The study reveals an important interaction between PSCs and cancer cells, involving ATP and IL-6 as key players, which activate P2X7 and IL-6 receptors, respectively, potentially serving as therapeutic targets for PDAC.
Pancreatic stellate cells (PSCs) are important pancreatic fibrogenic cells that interact with pancreatic cancer cells to promote the progression of pancreatic ductal adenocarcinoma (PDAC). In the tumor microenvironment (TME), several factors such as cytokines and nucleotides contribute to this interplay. Our aim was to investigate whether there is an interaction between IL-6 and nucleotide signaling, in particular, that mediated by the ATP-sensing P2X7 receptor (P2X7R). Using human cell lines of PSCs and cancer cells, as well as primary PSCs from mice, we show that ATP is released from both PSCs and cancer cells in response to mechanical and metabolic cues that may occur in the TME, and thus activate the P2X7R. Functional studies using P2X7R agonists and inhibitors show that the receptor is involved in PSC proliferation, collagen secretion and IL-6 secretion and it promotes cancer cell migration in a human PSC-cancer cell co-culture. Moreover, conditioned media from P2X7R-stimulated PSCs activated the JAK/STAT3 signaling pathway in cancer cells. The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC.
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