title: Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts.
abstract: Knowledge of tumor-stromal interactions is essential for understanding tumor development. We focused on the interaction between cholangiocarcinoma and cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma and reported their positive interaction in vitro and in vivo. The aim of this study is to identify the key protein involved in the interaction between cholangiocarcinoma cells and CAFs and its role on cholangiocarcinoma progression. Using the conditioning medium from cholangiocarcinoma cells, hepatic stellate cells and coculture of them, Protein-Chip analysis with SELDI-TOF-MS showed that the peak of an 8,360-Da protein remarkably increased in the coculture medium. This protein was identified as CXCL5/ENA78, epithelial cell-derived neutrophil-activating peptide-78, by q-TOF/MS/MS analysis. Two cholangiocarcinoma cell lines, HuCCT1 and RBE, produced CXCL5 that promoted their invasion and migration in an autocrine fashion. These effects of CXCL5 significantly decreased by inhibition of CXC-receptor 2, which is the receptor for CXCL5. In addition, IL-1β produced by hepatic stellate cells induced the expression of CXCL5 in cholangiocarcinoma cells. In human tissue samples, a significant correlation was observed between CAFs and CXCL5 produced by cholangiocarcinoma cells in intrahepatic cholangiocarcinoma (p = 0.0044). Furthermore, the high-CXCL5-expression group exhibited poor overall survival after curative hepatic resection (p = 0.027). The presence of tumor-infiltrating neutrophils expressing CD66b was associated with CXCL5 expression in tumor cells (p < 0.0001). These data suggest that CXCL5 is important for the interaction between cholangiocarcinoma and CAFs, and inhibition of tumor-stromal interactions may be a useful therapeutic approach for cholangiocarcinoma.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Okabe
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hayashi
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Ishiko
authors.forename: Toshiro
authors.initials: T
authors.lastname: Masuda
authors.forename: Ryu
authors.initials: R
authors.lastname: Otao
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takamori
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020556:Neutrophil Infiltration; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015703:Antigens, CD; C504120:CEACAM8 protein, human; C486263:CXCL5 protein, human; D015815:Cell Adhesion Molecules; D054365:Chemokine CXCL5; D017077:Culture Media, Conditioned; D058851:GPI-Linked Proteins; D053583:Interleukin-1beta; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3