Article

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.

Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-6838, USA.
Oncogene (Impact Factor: 8.56). 08/2005; 24(32):5053-68. DOI: 10.1038/sj.onc.1208685
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
70 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastasis is the most devastating aspect of cancer, however we know very little about the mechanisms of local invasion, the earliest step of metastasis. During tumor growth CD11b+Gr1+ cells, known also as MDSCs, have been shown to promote tumor progression by a wide spectrum of effects that suppress the anti-tumor immune response. In addition to immunosuppression, CD11b+Gr1+ cells promote metastasis by mechanisms that are currently unknown. CD11b+Gr1+ cells localize near fibroblasts, which remodel the ECM and leave tracks for collective cell migration of carcinoma cells. In this study we discovered that CD11b+Gr1+ cells promote invasion of mammary carcinoma cells by increasing fibroblast migration. This effect was directed by secreted factors derived from CD11b+Gr1+ cells. We have identified several CD11b+Gr1+ cell secreted proteins that activate fibroblast migration, including CXCL11, CXCL15, FGF2, IGF-I, IL1Ra, Resistin, and Shh. The combination of CXCL11 and FGF2 had the strongest effect on fibroblast migration that is associated with Akt1 and ERK1/2 phosphorylation. Analysis of subsets of CD11b+Gr1+ cells identified that CD11b+Ly6ChighLy6Glow cells increase fibroblast migration more than other myeloid cell populations. Additionally, tumor-derived CD11b+Gr1+ cells promote fibroblast migration more than splenic CD11b+Gr1+ cells of tumor-bearing mice. While TGFβ signaling in fibroblasts does not regulate their migration toward CD11b+Gr1+ cells, however deletion of TGFβ receptor II on CD11b+Gr1+ cells downregulates CXCL11, Shh, IGF1 and FGF2 resulting in reduced fibroblast migration. These studies show that TGFβ signaling in CD11b+Gr1+ cells promotes fibroblast directed carcinoma invasion and suggests that perivascular CD11b+Ly6ChighLy6Glow cells may be the stimulus for localized invasion leading to metastasis.
    PLoS ONE 01/2015; 10(1):e0117908. DOI:10.1371/journal.pone.0117908 · 3.53 Impact Factor
  • Frontiers in Bioscience 01/2007; 12(8-12):3468. DOI:10.2741/2327 · 4.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-beta-induced (TGFBI) serves as a linker protein and plays a role in the activation of morphogenesis, cell proliferation, adhesion, migration, differentiation and inflammation. High expression levels of the human TGFBI gene are correlated with numerous human malignancies. In order to explore the roles of TGFBI in the tumor progression of colorectal cancer, colorectal cancer specimens from 115 patients with strict follow-up were selected for the analysis of TGFBI by immunohistochemistry. The correlations between TGFBI expression and the clinicopathological features of colorectal cancers were evaluated. In the colorectal cancer tissues, TGFBI was mainly localized in the cytoplasm and stroma and scarcely in the nucleus. TGFBI expression in the cytoplasm and stroma was not found to be associated with age, gender, tumor histopathological grading, PT category and tumor location (P > 0.05 for each). However, high TGFBI expression in the cytoplasm and stroma correlated with lymph node metastasis, distant metastasis and Dukes stage (P < 0.05 for each). The survival rate was significantly lower in patients with high TGFBI expression than in those with low TGFBI expression. Furthermore, we found that tumor node metastasis (TNM) staging (HR: 2.963; 95% CI: 1.573-1.664; P = 0.000), differentiation (HR: 1.574; 95% CI: 1.001-2.476; P = 0.049) and high TGFBI cytoplasmic expression (HR: 3.332; 95% CI: 1.410-7.873; P = 0.000) proved to be independent prognostic factors for survival in colorectal cancer. In conclusion, TGFBI plays an important role in the progression of colorectal cancers and it is an independent poor prognostic factor for colorectal cancer patients.

Full-text (2 Sources)

Download
20 Downloads
Available from
Jun 1, 2014