title: Confrontation of fibroblasts with cancer cells in vitro: gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth.
abstract: BACKGROUND
  There is growing evidence that emerging malignancies in solid tissues might be kept under control by physical intercellular contacts with normal fibroblasts.
  
  
  METHODS
  Here we characterize transcriptional landscapes of fibroblasts that confronted cancer cells. We studied four pairs of in vitro and ex vivo fibroblast lines which, within each pair, differed in their capacity to inhibit cancer cells. The natural process was modeled in vitro by confronting the fibroblasts with PC-3 cancer cells. Fibroblast transcriptomes were recorded by Affymetrix microarrays and then investigated using network analysis.
  
  
  RESULTS
  The network enrichment analysis allowed us to separate confrontation- and inhibition-specific components of the fibroblast transcriptional response. Confrontation-specific differences were stronger and were characterized by changes in a number of pathways, including Rho, the YAP/TAZ cascade, NF-kB, and TGF-beta signaling, as well as the transcription factor RELA. Inhibition-specific differences were more subtle and characterized by involvement of Rho signaling at the pathway level and by potential individual regulators such as IL6, MAPK8, MAP2K4, PRKCA, JUN, STAT3, and STAT5A.
  
  
  CONCLUSIONS
  We investigated the interaction between cancer cells and fibroblasts in order to shed light on the potential mechanisms and explain the differential inhibitory capacity of the latter, which enabled both a holistic view on the process and details at the gene/protein level. The combination of our methods pointed to proteins, such as members of the Rho pathway, pro-inflammatory signature and the YAP1/TAZ cascade, that warrant further investigation via tools of experimental perturbation. We also demonstrated functional congruence between the in vitro and ex vivo models. The microarray data are made available via the Gene Expression Omnibus as GSE57199.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. andrej.alekseenko@scilifelab.se.|Bioinformatics Infrastructure for Life Sciences, Science for Life Laboratory, Karolinska Institutet, Box 1031, 171 21, Solna, Sweden. andrej.alekseenko@scilifelab.se.
authors.forename: Andrey
authors.initials: A
authors.lastname: Alexeyenko
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. twana.alkasalias@ki.se.|College of Science, Department of Biology, Salahaddin University, Erbil, Kurdistan-Iraq. twana.alkasalias@ki.se.
authors.forename: Twana
authors.initials: T
authors.lastname: Alkasalias
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. tatiana.pavlova@ki.se.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pavlova
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Laszlo.Szekely@ki.se.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Szekely
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Vladimir.Kashuba@ki.se.|Institute of Molecular Biology and Genetics, UNAS, Kiev, Ukraine. Vladimir.Kashuba@ki.se.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kashuba
authors.affiliation: Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden. Helene.Rundqvist@ki.se.
authors.forename: Helene
authors.initials: H
authors.lastname: Rundqvist
authors.affiliation: Department of Molecular Medicine and Surgery, section of Urology, Karolinska Institutet, Stockholm, Sweden. Peter.Wiklund@ki.se.
authors.forename: Peter
authors.initials: P
authors.lastname: Wiklund
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Lars.Egevad@ki.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.affiliation: Department of Medical Chemistry, Semmelweis University, P.O. Box 260, H-1444, Budapest 8, Hungary. csermelynet@gmail.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Csermely
authors.affiliation: TGAC, The Genome Analysis Centre, Norwich Research Park, Norwich, UK. korcsmaros@gmail.com.|Gut Health and Food Safety Programme, Institute of Food Research, Norwich Research Park, Norwich, UK. korcsmaros@gmail.com.
authors.forename: Tamas
authors.initials: T
authors.lastname: Korcsmaros
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Hayrettin.Guven@ki.se.
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Guven
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Georg.Klein@ki.se.
authors.forename: George
authors.initials: G
authors.lastname: Klein
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics*