A delicate balance: TGF‐β and the tumor microenvironment

Stover, Daniel G.; Bierie, Brian; Moses, Harold L.

doi:10.1002/jcb.21149

Cited by 125 publications

(116 citation statements)

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“…Using a mouse model for SMO-mediated BCC development, we identified changes in several signaling pathways, particularly TGF␤ signaling. TGF␤ signaling is a known pathway important for tumor development (10,11). Using two biological assays as well as one BCC mouse model, we demonstrated the critical role of TGF␤ signaling in SMO-mediated signaling and cancer development.…”

Section: Discussionmentioning

confidence: 89%

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Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis

Fan

Sheng

et al. 2010

Journal of Biological Chemistry

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Hedgehog (Hh) signaling, via the key signal transducer Smoothened (SMO) and Gli transcription factors, is essential for embryonic development and carcinogenesis. At present, the molecular mechanism of Hh signaling-mediated carcinogenesis is not completely understood. Using a mouse model (K14cre/ R26SmoM2) of SMO-mediated basal cell carcinoma development, we identified TGF␤2 as a major Hh-regulated gene. TGF␤2 expression was high in the keratinocytes, with activated TGF␤ signaling (indicated by elevated expression of phosphorylated SMAD2/3) detected in both tumor and stroma. The significance of TGF␤ signaling for SMO function was demonstrated in two assays. Down-regulation of TGF␤2 expression prevented Hh signaling-dependent osteoblast differentiation and motor neuron differentiation. Furthermore, inhibition of TGF␤ signaling by TGF␤ receptor I inhibitor SD208 significantly reduced tumor area in K14cre/R26SmoM2 mice. Tumor shrinkage in mice was associated with an increased number of lymphocytes, suggesting an immune suppression role of TGF␤ signaling. The relevance of our results to human cancer is reflected by the fact that human basal cell carcinomas, which almost always harbor activated Hh signaling, have activated TGF␤ signaling, as indicated by high levels of phosphorylated SMAD2 and SMAD3 in tumor and stroma. Together, our data indicate that TGF␤ signaling is critical for Hh signaling-mediated carcinogenesis.The Hedgehog pathway plays an important role in cell differentiation, tissue polarity, cell proliferation, and carcinogenesis (1-4). The seven-transmembrane domain-containing protein Smoothened (SMO) 4 serves as the key player for signal transduction of this pathway, whose function is inhibited by another transmembrane protein, Patched (PTC), in the absence of Hh ligands. Binding of Hh to its receptor PTC releases this inhibition, allowing SMO to signal downstream, leading to formation of active forms of Gli transcription factors. As transcription factors, Gli molecules can regulate target gene expression by direct association with a specific consensus sequence located at the promoter region of the target genes (5). In addition to the canonical pathways (ligand overexpression, altered expression of Hh signaling molecules, or gene mutations), recent studies indicate that Hh signaling can also be activated by other signaling pathways, such as K-Ras. Both canonical and non-canonical Hh signaling activation are found in many types of human cancer, including brain tumors, gastrointestinal, prostate, lung, and breast cancers (6 -8).Mounting evidence indicates that Hh signaling activation occurs frequently in a number of human cancers (9), but the underlying molecular basis remains largely elusive. To understand the molecular basis by which Hh signaling regulates carcinogenesis, we analyzed gene expression of a mouse model of basal cell carcinoma in which an activated form of SMO (SmoM2) replaces the wild type SMO allele and is expressed under the control of the keratin 14 promoter. Our results indicated that ...

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Section: Discussionmentioning

confidence: 89%

“…TGF␤ signaling is a known pathway important for tumor development. Depending on the stage of tumor development and cellular context, TGF␤ signaling can function as tumor suppressor, tumor promoter, or modulator for immune surveillance and inflammation (10,11). We investigated the significance of TGF␤ signaling for SMO-mediated signaling.…”

mentioning

confidence: 99%

Requirement of TGFβ Signaling for SMO-mediated Carcinogenesis

Fan

Sheng

et al. 2010

Journal of Biological Chemistry

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“…This concept is best illustrated in the cancer literature. Depending on the combination effects of multiple factors in the tumor microenvironment (eg, the presence of other growth factors), immune cell population dynamics, and ECM composition, TGF-␤ could either promote or suppress cancer progression and metastasis 53,56,57 by altering the proliferative responses in the same cell line. In a previous study, 8 we observed that TGF-␤ expression is up-regulated on mechanical wounding and that, in response to injury, exog- enous TGF-␤ promotes VIC proliferation while it inhibits apoptosis in the early stage of wound repair.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-␤ promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-␤ regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of ␣-smooth muscle actin and vinculin. TGF-␤-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-␤-treated VICs adhered better to substratum and had more vinculin plaques and ␣-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-␤ is context dependent. TGF-␤ prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.

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“…Activated JNK and NFkB in turn induce gene expression of proinvasive factors such as EMMPRIN (extracellular matrix metallo-protease inducer) and MIF (migration inhibitory factor), whose expression enhances MMP-2 and -9 secretion and activity (Hagemann et al 2005). Production of TGFb by alternatively activated macrophages in mammary tumors, mesenchymal support cells, and immature myeloid cells (IMCs) can also enhance the invasive and metastatic programming of malignant cells (Stover et al 2007;Bierie et al 2008;Yang et al 2008) consistent with existence of a TGFb-responsive gene signature that a predicts breast cancer pulmonary metastasis (Arribas et al 1997).…”

Section: Leukocytes In Mammary Development and Cancermentioning

confidence: 99%