title: Paracrine SDF-1α signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells.
abstract: Pancreatic cancer exhibits the poorest prognosis among all tumors and is characterized by high resistance to the currently available chemotherapeutic agents. Our previous studies have suggested that stromal components could promote the chemoresistance of pancreatic cancer cells (PCCs). Here, we explored the roles of pancreatic stellate cells (PSCs) and the SDF-1α/CXCR4 axis in pancreatic cancer chemoresitance. Our results showed that primary PSCs typically expressed SDF-1α, whereas its receptor CXCR4 was highly expressed in PCCs. PSC-conditioned medium (PSC-CM) inhibited Gemcitabine (GEM)-induced cytotoxicity and apoptosis in the human PCC line Panc-1, which was antagonized by an SDF-1α neutralizing Ab. Recombinant human SDF-1α (rhSDF-1α) increased IL-6 expression and secretion in Panc-1 cells in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. rhSDF-1α protected Panc-1 cells from GEM-induced apoptosis, and the protective effect was significantly reduced by blocking IL-6 using a neutralizing antibody. Moreover, rhSDF-1α increased FAK, ERK1/2, AKT and P38 phosphorylation in Panc-1 cells, and either FAK or ERK1/2 inhibition suppressed SDF-1α-upregulated IL-6 expression. SDF-1α-induced AKT activation was almost completely blocked by FAK inhibition. In conclusion, we demonstrate for the first time that PSCs promote the chemoresistance of PCCs to GEM, and this effect is mediated by paracrine SDF-1α/CXCR4 signaling-induced activation of the intracellular FAK-AKT and ERK1/2 signaling pathways and a subsequent IL-6 autocrine loop in PCCs. Our findings indicate that blocking the PSC-PCC interaction by inhibiting SDF-1α/CXCR4 signaling may be a promising therapeutic strategy for overcoming chemoresistance in pancreatic cancer.
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Huanwen
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
authors.forename: Tonghua
authors.initials: T
authors.lastname: Liu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; C508600:IL6 protein, human; D015850:Interleukin-6; D019718:Receptors, CXCR4; D003841:Deoxycytidine; D000093542:Gemcitabine