title: Esophageal Squamous Cell Carcinoma Cells Modulate Chemokine Expression and Hyaluronan Synthesis in Fibroblasts.
abstract: The aim of this study was to characterize the interaction of KYSE-410, an esophageal squamous cell carcinoma cell line, and fibroblasts with respect to the extracellular matrix component hyaluronan (HA) and chemokine expression. KYSE-410 cells induced the mRNA expression of HA synthase 2 (Has2) in normal skin fibroblasts (SF) only in direct co-cultures. Parallel to Has2 mRNA, Has2 antisense RNA (Has2os2) was up-regulated in co-cultures. Knockdown of LEF1, a downstream target of Wnt signaling, abrogated Has2 and Has2os2 induction. After knockdown of Has2 in SF, significantly less α-smooth muscle actin expression was detected in co-cultures. Moreover, it was investigated whether the phenotype of KYSE-410 was affected in co-culture with SF and whether Has2 knockdown in SF had an impact on KYSE-410 cells in co-culture. However, no effects on epithelial-mesenchymal transition markers, proliferation, and migration were detected. In addition to Has2 mRNA, the chemokine CCL5 was up-regulated and CCL11 was down-regulated in SF in co-culture. Furthermore, co-cultures of KYSE-410 cells and cancer-associated fibroblasts (CAF) were investigated. Similar to SF, Has2 and Ccl5 were up-regulated and Ccl11 was down-regulated in CAF in co-culture. Importantly and in contrast to SF, inhibiting HA synthesis by 4-methylumbelliferone abrogated the effect of co-culture on Ccl5 in CAF. Moreover, HA was found to promote adhesion of CD4(+) but not CD8(+) cells to xenogaft tumor tissues. In conclusion, direct co-culture of esophageal squamous cell carcinoma and fibroblasts induced stromal HA synthesis via Wnt/LEF1 and altered the chemokine profile of stromal fibroblasts, which in turn may affect the tumor immune response.
authors.affiliation: From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany and jens.fischer@uni-duesseldorf.de.
authors.forename: Inga
authors.initials: I
authors.lastname: Kretschmer
authors.affiliation: From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany and.
authors.forename: Till
authors.initials: T
authors.lastname: Freudenberger
authors.affiliation: From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany and.
authors.forename: Sören
authors.initials: S
authors.lastname: Twarock
authors.affiliation: the Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany and.
authors.forename: Maria
authors.initials: M
authors.lastname: Grandoch
authors.affiliation: From the Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität, Moorenstrasse 5, 40225 Düsseldorf, Germany and jens.fischer@uni-duesseldorf.de.
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054413:Chemokine CCL11 / Q000096:biosynthesis* / Q000235:genetics; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D018920:Coculture Techniques; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis* / Q000235:genetics; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C515456:CCL11 protein, human; C483024:CCL5 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases
keywords: CCL11; CCL5; cancer; cell-cell interaction; chemokine; fibroblast; hyaluronan