Abstract
Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell–cell interactions. To clarify the role of TGF-β signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-β type II receptor gene in mouse mammary fibroblasts (Tgfbr2fspKO). Tgfbr2fspKO mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2fspKO mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2fspKO fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-α signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-β signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-α, MSP, and HGF signaling pathways.
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Abbreviations
- TβRII:
-
TGF-β type II receptor
- PyVmT:
-
polyomavirus middle T antigen
- MSP:
-
macrophage-stimulating protein
- FSP1:
-
fibroblast-specific protein 1
- GFP:
-
green fluorescent protein
- ABS:
-
adult bovine serum
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Acknowledgements
This work was supported by grants number CA102162 and CA85492 (to HLM) from the National Cancer Institute DHHS, and by the TJ Martell Foundation. The following Shared Resources of the Vanderbilt-Ingram Cancer Center provided outstanding assistance and are supported by grant number P30 CA68485: Statistics and Human Acquisition and Pathology Cores. The Mouse Pathology Core is supported by the NIH grant AR41943. We thank Bonnie LaFleur for biostatistical assistance, Dana Brantley-Sieders, and Jin Chen for critical reading of this manuscript.
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Cheng, N., Bhowmick, N., Chytil, A. et al. Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks. Oncogene 24, 5053–5068 (2005). https://doi.org/10.1038/sj.onc.1208685
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DOI: https://doi.org/10.1038/sj.onc.1208685
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