System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity

Rajaram, M., Li, J., Egeblad, M., Powers, R. S. (September 2013) System-wide analysis reveals a complex network of tumor-fibroblast interactions involved in tumorigenicity. PLoS Genetics, 9 (9). e1003789. ISSN 1553-7404 (Electronic)1553-7390 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/24068959
DOI: 10.1371/journal.pgen.1003789

Abstract

Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Program > Signal Transduction
CSHL labs > Egeblad lab
CSHL labs > Powers lab
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
Depositing User: Matt Covey
Date: September 2013
Date Deposited: 15 Oct 2013 20:17
Last Modified: 29 Oct 2015 20:44
PMCID: PMC3778011
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28649

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