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

Journal of Experimental & Clinical Cancer Research

George Klein³  Hayrettin Guven³  Tamas Korcsmaros⁷  Peter Csermely⁵  Lars Egevad²  Peter Wiklund⁹  Helene Rundqvist⁶  Vladimir Kashuba⁸  Laszlo Szekely³  Tatiana Pavlova³  Twana Alkasalias⁴  Andrey Alexeyenko¹ 

[1] Bioinformatics Infrastructure for Life Sciences, Science for Life Laboratory, Karolinska Institutet, Solna, 171 21, Sweden;Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden;Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden;College of Science, Department of Biology, Salahaddin University, Erbil, Kurdistan-Iraq;Department of Medical Chemistry, Semmelweis University, Budapest 8, H-1444, Hungary;Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden;TGAC, The Genome Analysis Centre, Norwich Research Park, Norwich, UK;Institute of Molecular Biology and Genetics, UNAS, Kiev, Ukraine;Department of Molecular Medicine and Surgery, section of Urology, Karolinska Institutet, Stockholm, Sweden

关键词: Cancer cell growth;    Cancer associated fibroblasts (CAFs);    Differential expression;    Systems biology;    Transcriptome;    Stroma;    Fibroblast;   

Others  :  1220676
DOI  :  10.1186/s13046-015-0178-x

 received in 2015-03-04, accepted in 2015-06-02,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Alexeyenko et al.

【 图 表 】

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