The two faces of transforming growth factor β in carcinogenesis

Roberts, Anita B.; Wakefield, Lalage M.

doi:10.1073/pnas.1633291100

Cited by 701 publications

(631 citation statements)

References 32 publications

(34 reference statements)

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“…Recent data indicate that this may involve Smad activation, and in the case of glioma (Bruna et al, 2007) and breast cancer (Kang et al, 2005), high Smad activity correlates with poor prognosis. It has earlier been proposed that TGF-b-mediated regulation of non-Smad pathways may also contribute to the pro-oncogenic actions of TGF-b (Wakefield and Roberts, 2002;Roberts and Wakefield, 2003). Here, to the best of our knowledge, we provide the first direct evidence in support of this hypothesis.…”

Section: Discussionsupporting

confidence: 76%

TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

et al. 2008

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Transforming growth factor b-1 (TGF-b) acts as both a tumour suppressor and a tumour promoter in a contextdependent manner. The tumour-promoting activities of TGF-b are likely to result from a combination of Smad and non-Smad signalling pathways but remain poorly understood. Here we show that TGF-b-mediated activation of RhoA is dependent on the kinase activity of ALK5 and that continuous ALK5 activity maintains basal RhoA-ROCK signalling, cell morphology and actin dynamics in serum-starved rodent fibroblasts independently of Smad2, Smad3 and Smad4. In immortalized human diploid fibroblasts, we show that oncogenic rewiring by transduction of V12 HaRas instigates regulation of RhoA-ROCK signalling through an autocrine TGFb1-ALK5 pathway. Furthermore, we show that ALK5-mediated activation of RhoA is required for efficient

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Section: Discussionsupporting

confidence: 76%

TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

et al. 2008

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“…In normal epithelial cells, TGF-β1 can induce growth arrest or apoptosis through its ability to increase expression of cyclin-dependent kinase inhibitors, such as p15 INK4b and p21 CIP1 , as well as repress c-myc [21]. In tumors, the TGF-β1 signaling cascade is often dysregulated, such that TGF-β contributes to evasion of immune surveillance, apoptosis resistance, increased proliferation, increased invasion and EMT [21,25]. Hence, TGF-β has both anti-tumor and pro-tumor functions.…”

Section: Introductionmentioning

confidence: 99%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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“…Emerging evidence indicates that some of the genes that under normal conditions would function to eliminate the cancer cells-the tumor suppressors-appear to be co-opted to become oncogenes. One well-known example of this dichotomy is the transforming growth factor (TGF)-b gene, which induces apoptosis or cell cycle arrest in normal or less transformed cells, but facilitates metastasis in advanced tumors (Massague, 2000;Derynck et al, 2001;Roberts and Wakefield, 2003). This 'Jekyll-and-Hyde' conversion is an intriguing but largely unresolved issue in cancer biology.…”

Section: Introductionmentioning

confidence: 99%

A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development

2007

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Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP response element-binding family of transcription factors. We present evidence that ATF3 has a dichotomous role in cancer development. By both gain-and loss-of-function approaches, we found that ATF3 enhances apoptosis in the untransformed MCF10A mammary epithelial cells, but protects the aggressive MCF10CA1a cells and enhances its cell motility. Array analyses indicated that ATF3 upregulates the expression of several genes in the tumor necrosis factor pathway in the MCF10A cells but upregulates the expression of several genes implicated in tumor metastasis, including TWIST1, fibronectin (FN)-1, plasminogen activator inhibitor-1, urokinase-type plasminogen activator, caveolin-1 and Slug, in the MCF10CA1a cells. We present evidence that ATF3 binds to the endogenous promoters and regulates the transcription of the TWIST1, FN-1, Snail and Slug genes. Furthermore, conditioned medium experiments indicated that ATF3 has a paracrine/autocrine effect, consistent with its upregulation of genes encoding secreted factors. Finally, ATF3 gene copy number is >2 in B80% of the breast tumors examined (N ¼ 48) and its protein level is elevated in B50% of the tumors. These results provided a correlative argument that it is advantageous for the malignant cancer cells to express ATF3, consistent with its oncogenic roles suggested by the MCF10CA1a cell data.

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The two faces of transforming growth factor β in carcinogenesis

Cited by 701 publications

References 32 publications

TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

TGF-β-mediated activation of RhoA signalling is required for efficient V12HaRas and V600EBRAF transformation

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development

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