Tumor Necrosis Factor-α Is a Potent Endogenous Mutagen that Promotes Cellular Transformation

Yan, Bin; Wang, Huili; Rabbani, Zahid N.; Zhao, Yulin; Li, Wenrong; Yuan, Yeqing; Li, Fang; Dewhirst, Mark W.; Li, Chuan-Yuan

doi:10.1158/0008-5472.can-06-2540

Cited by 142 publications

(110 citation statements)

References 19 publications

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“…37,38 For example, TNF-␣ may stimulate the production of genotoxic molecules such as reactive oxygen species, leading to DNA damage and tumor initiation. 39 In humans, genetic polymorphisms in the TNF-␣ locus are associated with increased incidence of many cancers including gastric, breast, prostate, colon, and some hematological malignancies. 40 -44 Mice deficient in the TNF-␣ receptors TNFR1 and TNFR2 have reduced tumorigenesis, 45 and anti-TNF-␣ neutralizing antibody protects against inflammation-induced liver cancer in MDR2-null mice.…”

Section: Discussionmentioning

confidence: 99%

Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Maggio‐Price

Treuting

Bielefeldt‐Ohmann

et al. 2009

The American Journal of Pathology

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Alterations in genes encoding transforming growth factor-␤-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-␤ signaling molecule, Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3-null mice with mice deficient in both B and T lymphocytes (Rag2 ؊/؊ mice). Helicobacter-infected Smad3/Rag2-double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter-infected

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Section: Discussionmentioning

confidence: 99%

Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Maggio‐Price

Treuting

Bielefeldt‐Ohmann

et al. 2009

The American Journal of Pathology

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“…Similar as in replicational stress, linking p53 to NF-kB signaling allows antiapoptotic gene expression in cells where the tumor suppressor can execute apoptosis if necessary. Such situations arise, for example, when TNF promotes inflammation-related tumorigenesis by NF-kB activation (Pikarsky et al, 2004;Hayashi et al, 2007) or by TNF-mediated induction of reactive oxygen species bearing mutagenic potential (Yan et al, 2006;Li et al, 2007;Yazdanpanah et al, 2009). Of note, p53-positive cells can protect themselves from such cyto-and genotoxic molecules by inducing MnSOD, an antioxidizing enzyme known to balance TNF signaling (Gilmore and Herscovitch, 2006).…”

Section: Control Of Activated Nf-jb By P53mentioning

confidence: 99%

Cross talk between stimulated NF-κB and the tumor suppressor p53

et al. 2010

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Nuclear factor-jB (NF-jB) and p53 critically determine cancer development and progression. Defining the cross talk between these transcription factors can expand our knowledge on molecular mechanisms of tumorigenesis. Here, we show that induction of replicational stress activates NF-jB p65 and triggers its interaction with p53 in the nucleus. Experiments with knockout cells show that p65 and p53 are both required for enhanced NF-jB activity during S-phase checkpoint activation involving ataxiatelangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factora (TNF-a) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on jB response elements. Gene expression analyses revealed that, independent of NF-jB activation in the cytosol, TNFinduced NF-jB-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-jB-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain-and loss-of function approaches argue that anti-apoptotic NF-jB p65 activity is constitutively evoked by a p53 hot-spot mutant frequently found in tumors. Our observations suggest explanations for the outstanding question why p53 mutations rather than p53 deletions arise in tumors of various origins.

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“…In these models and in human cancers, TNF-α is produced by malignant and/or host cells within the tumor microenvironment (11,14,(17)(18)(19)(20)(21)(22)(23). The mechanisms of action of TNF-α in the tumor microenvironment are not fully elucidated but may include a central role in a cancer-cell autonomous tumor-promoting network of other cytokines and chemokines (20), stimulation of epithelial to mesenchymal transition in malignant cells (24), or further DNA damage to malignant cells (25). The actions of TNF-α on other cells in the tumor microenvironment include promotion of angiogenesis (20) that could be via induction of a proangiogenic phenotype in recruited monocytes (26), impairment of immune surveillance through T cell suppression (27), and inhibiting the cytotoxicity of activated macrophages (28).…”

Section: Introductionmentioning

confidence: 99%

The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans

Charles¹,

Kulbe²,

Soper³

et al. 2009

J. Clin. Invest.

290

225

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Cytokines orchestrate the tumor-promoting interplay between malignant cells and the immune system. In many experimental and human cancers, the cytokine TNF-α is an important component of this interplay, but its effects are pleiotropic and therefore remain to be completely defined. Using a mouse model of ovarian cancer in which either TNF receptor 1 (TNFR1) signaling was manipulated in different leukocyte populations or TNF-α was neutralized by antibody treatment, we found that this inflammatory cytokine maintained TNFR1-dependent IL-17 production by CD4 + cells and that this led to myeloid cell recruitment into the tumor microenvironment and enhanced tumor growth. Consistent with this, in patients with advanced cancer, treatment with the TNF-α-specific antibody infliximab substantially reduced plasma IL-17 levels. Furthermore, expression of IL-1R and IL-23R was downregulated in CD4 + CD25 -cells isolated from ascites of ovarian cancer patients treated with infliximab. We have also shown that genes ascribed to the Th17 pathway map closely with the TNF-α signaling pathway in ovarian cancer biopsy samples, showing particularly high levels of expression of genes encoding IL-23, components of the NF-κB system, TGF-β1, and proteins involved in neutrophil activation. We conclude that chronic production of TNF-α in the tumor microenvironment increases myeloid cell recruitment in an IL-17-dependent manner that contributes to the tumor-promoting action of this proinflammatory cytokine.

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Tumor Necrosis Factor-α Is a Potent Endogenous Mutagen that Promotes Cellular Transformation

Cited by 142 publications

References 19 publications

Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Cross talk between stimulated NF-κB and the tumor suppressor p53

The tumor-promoting actions of TNF-α involve TNFR1 and IL-17 in ovarian cancer in mice and humans

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