A novel GPCR mediates pancreatic cancer associated fibroblast-cancer cell interaction

作     者：Shu Z WILEY Krishna SRIRAM Wen-jing LIANG Sarah E CHANG Randall FRENCH Thalia MCCANN Hiroshi NISHIHARA Andrew M LOWY Paul A INSEL 

作者机构：Departments of PharmacologyMedicine and Surgery and Moores Cancer CenterUniversity of California Division of Clinical Cancer GenomicsHokkaido Cancer Center 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2017年第31卷第10期

页      面：953-953页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：pancreatic ductal adenocarcinoma pancreatic cancer-associated fibroblasts G proteincoupled receptors 

摘      要：OBJECTIVE Pancreatic ductal adenocarcinoma(PDAC),a lethal cancer in need of new,effective therapies,has a unique tumor microenvironment characterized by a dense fibrotic stroma(desmoplasia)that is generated by pancreatic cancer-associated fibroblasts(PCAFs)derived from pancreatic stellate cells(PSCs)and pancreatic fibroblasts(PFs).METHEDS and RESULTS Hypothesizing that G protein-coupled receptors(GPCRs)may regulate PCAFs,we used an unbiased GPCRomic array approach to compare GPCR expression in PCAFs,PFs and PSCs and identified 82 GPCRs commonly expressed by PCAFs derived from primary tumors of five PDAC *** discovered that PCAFs have increased expression of numerous GPCRs,in particular a GPCR with much higher expression in PCAFs compared to both PFs and *** revealed increased expression of this GPCR in PDAC ***-culture of PSCs with PDAC cells or incubation with TNFαinduced its *** of the GPCR in PCAF sincreased expression of interleukin-6(IL-6)via a cA MP/PKA/CREB signaling *** knockdown with siR NA diminished IL-6 production and secretionby PCAFs and ability of PCAF conditioned media to enhance proliferation of PDAC *** We conclude that PDAC cells induce expression by PCAFs of a novel GPCR,resulting in increased IL-6 production by PCAFs and promotion of PDAC cell *** PCAF-expressed GPCR thus contributes to PDAC cell-PCAF interaction and as such,may be a novel therapeutic target for PDAC tumors.