Journal
PROTEOMICS
Volume 10, Issue 13, Pages 2458-2470Publisher
WILEY
DOI: 10.1002/pmic.200900701
Keywords
Cell biology; Fibroblasts; Secretome; Stable isotope labeling with amino acids in cell culture; TGF-beta type II receptor
Funding
- Vanderbilt Breast Cancer SPORE [P50 CA098131]
- Vanderbilt-Ingram Cancer Center [P30 CA068485]
- Vanderbilt University Tumor Microenvironment Network [1U54 CA126505]
- Robert J. and Helen C. Kleberg Foundation
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Transforming growth factor beta (TGF-beta) is a master regulator of autocrine and paracrine signaling pathways between a tumor and its microenvironment. Decreased expression of TGF-beta type II receptor (T beta RII) in stromal cells is associated with increased tumor metastasis and shorter patient survival. In this study, SILAC quantitative proteomics was used to identify differentially externalized proteins in the conditioned media from the mammary fibroblasts with or without intact T beta RII. Over 1000 proteins were identified and their relative differential levels were quantified. Immunoassays were used to further validate identification and quantification of the proteomic results. Differential expression was detected for various extracellular proteins, including proteases and their inhibitors, growth factors, cytokines, and extracellular matrix proteins. CXCL10, a cytokine found to be up-regulated in the T beta RII knockout mammary fibroblasts, is shown to directly stimulate breast tumor cell proliferation and migration Overall, this study revealed hundreds of specific extracellular protein changes modulated by deletion of T beta RII in mammary fibroblasts, which may play important roles in the tumor microenvironment. These results warrant further investigation into the effects of inhibiting the TGF-beta signaling pathway in fibroblasts because systemic inhibition of TGF-beta signaling pathways is being considered as a potential cancer therapy.
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