Cheng N, Bhowmick NA, Chytil A, Gorksa AE, Brown KA, Muraoka R et al.Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. Oncogene 24:5053-5068

Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-6838, USA.
Oncogene (Impact Factor: 8.46). 08/2005; 24(32):5053-68. DOI: 10.1038/sj.onc.1208685
Source: PubMed


Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary fibroblasts (Tgfbr2(fspKO)). Tgfbr2(fspKO) mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2(fspKO) 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 Tgfbr2(fspKO) 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-alpha signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-beta signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-alpha, MSP, and HGF signaling pathways.

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Available from: Simon W Hayward, Mar 17, 2014
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    • "Additionally, cooperation between normal fibroblast and immune system preventing tumorigenesis has been described. This anti-tumoral mechanism might be the CAF loss (Cheng et al., 2005). Finally, recent reports have indicated a relevant role for CAF in the modulation of cancer stem cells (Malanchi et al., 2012). "
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    ABSTRACT: The process of malignancy emergence is associated with the acquisition of the capacity to invade other tissues. Several different biological processes have been described as involved in this process. Specifically, epithelial mesenchymal transition (EMT), a mechanism associated with embryogenesis and wound repair but also with mobility acquisition, is one of the concerned processes. In EMT an epithelial cell loses its epithelial characteristics, its junctions with neighbor cells and with the basal lamina and acquires mobility and mesenchymal characteristics. Also, factors of the tumor microenvironment have been described as involved. Tumor presence triggers a response in the surrounding tissue known as reactive stromal. It shows particular characteristics similar to those found in wound healing stroma: an increase of the fibroblast number and enhancing of the capillary density. The notable difference is the chronicity in the tumoral process. Of a high relevance seems to be the role of activated macrophages with a characteristic phenotype. Finally, cancer associated fibroblasts (CAF) are a type of cells found in tumors, developed from local tissue or possibly from bone marrow. CAF characteristically show a distinct morphology and secrete a high number of metalloproteases allowing tumoral cells advance through the tissue. Additionally, CAF have a direct effect on the survival of the epithelial cells. The three processes are interrelated and metastasis is probably caused by the effect of all of them and probably by other additional factors.
    International Journal of Morphology 09/2014; 32(3):986-992. DOI:10.4067/S0717-95022014000300031 · 0.32 Impact Factor
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    • "These cells are typically myofibroblast-like cells that express α-Smooth muscle actin (α-SMA), vimentin, and fibroblast specific protein-1 (FSP1) [105]. Some of the early studies showed that these fibroblasts could be recruited from the bone marrow to the tumor [106] and that they could stimulate malignant transformation [7], tumor cell growth, and invasion [107]. These effects on tumor cell growth are thought to be mediated through CXCL12 [108] and TGF-β [109]. "
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    • "Metastasis is a multistep cascade process, including EMT, cell migration, invasion, intravasation, and extravasation from the circulation [23, 26, 52, 57]. Cheng et al. [58] demonstrated using an in vitro assay that cancer cells cultured under fibroblast-conditioned medium showed increased proliferation and motility, indicating the role of stromal TGF-β1 signaling in neoplastic progression. Conversely, attenuation of carcinoma cell response to TGF-β1 by a dominant-negative type II receptor transgene (dnTβRII) significantly reduced tumor latency in the presence of TGF-α expression in mammary epithelium [52]. "
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