Confrontation of fibroblasts with cancer cells in vitro: Gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth

Andrey Alexeyenko, Twana Alkasalias, Tatiana Pavlova, Laszlo Szekely, Vladimir Kashuba, Helene Rundqvist, Peter Wiklund, Lars Egevad, Peter Csermely, Tamas Korcsmaros, Hayrettin Guven, George Klein

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Article number62
JournalJournal of Experimental and Clinical Cancer Research
Volume34
Issue number1
DOIs
Publication statusPublished - Jun 18 2015

Keywords

  • Cancer associated fibroblasts (CAFs)
  • Cancer cell growth
  • Differential expression
  • Fibroblast
  • Stroma
  • Systems biology
  • Transcriptome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Confrontation of fibroblasts with cancer cells in vitro: Gene network analysis of transcriptome changes and differential capacity to inhibit tumor growth'. Together they form a unique fingerprint.

  • Cite this