Nov 3, 2017

GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Shu Z WileyPaul A Insel

Abstract

The microenvironment of pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) generated by pancreatic cancer-associated fibroblasts (CAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach, we identified 82 G-protein-coupled receptors (GPCRs) commonly expressed by CAFs derived from 5 primary PDAC tumors. Compared with PSCs and PFs, CAFs have increased expression of GPR68 (a proton-sensing GPCR), with the results confirmed by immunoblotting, The Cancer Genome Atlas data, and immunohistochemistry of PDAC tumors. Co-culture of PSCs with PDAC cells, or incubation with TNF-α, induced GPR68 expression. GPR68 activation (by decreasing the extracellular pH) enhanced IL-6 expression via a cAMP/PKA/cAMP response element binding protein signaling pathway. Knockdown of GPR68 by short interfering RNA diminished low pH-induced production of IL-6 and enhancement of PDAC cell proliferation by CAF conditioned media. CAFs from other gastrointestinal cancers also express GPR68. PDAC cells thus induce expression by CAFs of GPR68, which senses the acidic microenvironment, thereby increasing production of fibrotic markers and IL-6 and ...Continue Reading

  • References62
  • Citations15

References

Mentioned in this Paper

Biological Markers
GPR68 protein, human
GPR68 gene
Cyclic AMP-Responsive DNA-Binding Protein
Gene Expression Regulation, Neoplastic
Immunohistochemistry
TBX1 wt Allele
Tumor Necrosis Factor-alpha
Specimen Type - Fibroblasts
Gene Knockdown Techniques

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