Characterization of heterotypic interaction effects in vitro to deconvolute global gene expression profiles in cancerReport as inadecuate




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Genome Biology

, 8:R191

First Online: 14 September 2007Received: 26 March 2007Revised: 14 June 2007Accepted: 14 September 2007

Abstract

BackgroundPerturbations in cell-cell interactions are a key feature of cancer. However, little is known about the systematic effects of cell-cell interaction on global gene expression in cancer.

ResultsWe used an ex vivo model to simulate tumor-stroma interaction by systematically co-cultivating breast cancer cells with stromal fibroblasts and determined associated gene expression changes with cDNA microarrays. In the complex picture of epithelial-mesenchymal interaction effects, a prominent characteristic was an induction of interferon-response genes IRGs in a subset of cancer cells. In close proximity to these cancer cells, the fibroblasts secreted type I interferons, which, in turn, induced expression of the IRGs in the tumor cells. Paralleling this model, immunohistochemical analysis of human breast cancer tissues showed that STAT1, the key transcriptional activator of the IRGs, and itself an IRG, was expressed in a subset of the cancers, with a striking pattern of elevated expression in the cancer cells in close proximity to the stroma. In vivo, expression of the IRGs was remarkably coherent, providing a basis for segregation of 295 early-stage breast cancers into two groups. Tumors with high compared to low expression levels of IRGs were associated with significantly shorter overall survival; 59% versus 80% at 10 years log-rank p = 0.001.

ConclusionIn an effort to deconvolute global gene expression profiles of breast cancer by systematic characterization of heterotypic interaction effects in vitro, we found that an interaction between some breast cancer cells and stromal fibroblasts can induce an interferon-response, and that this response may be associated with a greater propensity for tumor progression.

AbbreviationsDMEMDulbecco-s modified Eagle-s medium

EIF2AK2eukaryotic translation initiation factor 2-alpha kinase

FACSfluorescent assisted cell sorting

FBSfetal bovine serum

FDRfalse discovery rate

HMEChuman mammary epithelial cell

IFITinterferon-induced protein with tetratricopeptide repeats

IFNinterferon

OAS2-,5-oligoadenylate synthetase

NKINetherlands Cancer Institute

PBSphosphate-buffered saline

SAMsignificance analysis of microarray data

STATsignal transducer and activator of transcription

TGFtransforming growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-gb-2007-8-9-r191 contains supplementary material, which is available to authorized users.

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Author: Martin Buess - Dimitry SA Nuyten - Trevor Hastie - Torsten Nielsen - Robert Pesich - Patrick O Brown

Source: https://link.springer.com/



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