Abstract
Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.
Highlights
The microenvironment of normal tissue can inhibit tumor growth, changes induced by tumor cells influence this microenvironment to promote tumor progression and metastasis [1,2,3]
Initial experiments indicated that deletion of both alleles in homozygous Ets2loxP/loxP mice was inefficient with several different Cre-driver lines [14,15], including Fibroblast Specific Protein promoter-Cre (Fsp-Cre)
No difference was observed in tumor initiation; tumor progression was significantly impeded by the ablation of Ets2 in mammary fibroblasts
Summary
The microenvironment of normal tissue can inhibit tumor growth, changes induced by tumor cells influence this microenvironment to promote tumor progression and metastasis [1,2,3]. Cancer associated fibroblasts (CAFs) were shown to mediate immune cell recruitment in an NF-kB dependent manner in a mouse model of squamous cell carcinoma [5]. Stromal fibroblasts are one of the major components within the tumor microenvironment that drive a number of characteristics associated with tumor malignancy, including remodeling of the extracellular matrix, immune cell recruitment and modulation, angiogenesis and tumor cell proliferation and invasion [7,8]. Identification of specific molecules and signaling pathways within this stroma which promote tumor initiation and progression is essential for the potential development of novel therapeutics to be used independently or in combination with other tumor cellspecific treatments [9]
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