Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice

Knight, Belinda; Yeoh, George; Husk, Kirsten L.; Ly, Tina; Abraham, Lawrence J.; Yu, Changpu; Rhim, Jonathan A.; Fausto, Nelson

doi:10.1084/jem.192.12.1809

Cited by 277 publications

(263 citation statements)

References 49 publications

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“…Furthermore, ovarian tumors from TNF knockdown cells had reduced growth, metastasis, and vascularization in vivo, compared with TNF+/+ or mock-transfected cells (36). Finally, hepatic carcinogenesis induced by a choline-deficient, ethionine-supplemented diet, as well as carcinogen-induced colorectal carcinogenesis, were found to be decreased in TNFR1 null mice (37,38). We suspect that TNFR1 plays a predominant role in TNF-stimulated mammary tumorigenesis as well, based on our previous studies demonstrating that TNFR1, but not TNFR2, mediated the stimulatory effect of TNF on the proliferation of normal mammary epithelial cells (1).…”

Section: Growth Of Several Cancer Types Is Modified By Tnf Statusmentioning

confidence: 83%

Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice

Warren

Shoemaker

Shealy

et al. 2009

Molecular Cancer Therapeutics

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Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that is synthesized and secreted by cells of the immune system, as well as by certain epithelia and stroma. Based on our previous studies demonstrating TNF-stimulated proliferation of normal and malignant mammary epithelial cells, we hypothesized that TNF might promote the growth of breast cancer in vivo. To test this, we generated bigenic mice that overexpressed activated neu/erbB2 in the mammary epithelium and whose TNF status was wild-type, heterozygous, or null. Mammary tumorigenesis was significantly decreased in TNF−/− mice (n = 30) compared with that in TNF+/+ mice (n = 27), with a palpable tumor incidence of 10.0% and 44.4%, and palpable tumors/mouse of 0.10 ± 0.06 and 0.67 ± 0.17, respectively. Tumorigenesis in the heterozygous group fell between that in the TNF +/+ and TNF−/− groups, but was not significantly different from either of the homozygous groups. The decreased tumor development in the TNF−/− mice was associated with a decreased proliferative index in the lobular and ductal mammary epithelium. To further investigate the role of TNF in breast cancer, mammary tumor-bearing mice whose tumors overexpressed wild-type neu/ erbB2 were treated with a TNF-neutralizing antibody or a control antibody for 4 weeks (n = 20/group). Mammary tumor growth was significantly inhibited in mice treated with the anti-TNF antibody compared with the control antibody. Together, these data show a stimulatory role for TNF in the growth of breast tumors and suggest that TNF antagonists may be effective in a subset of patients with breast cancer.

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Section: Growth Of Several Cancer Types Is Modified By Tnf Statusmentioning

confidence: 83%

Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice

Warren

Shoemaker

Shealy

et al. 2009

Molecular Cancer Therapeutics

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“…6,19,29 With respect to the former, it is interesting to note that despite considerable efforts, no LPC-specific growth or differentiation factors have been identified. The characterization of TWEAK as a mitogen for LPCs not only is important for our understanding of how regenerative responses are mediated in chronic damage but also draws us one step closer to achieving selective modulation of LPC behavior for the purposes of cell therapy and regenerative medicine.…”

Section: Discussionmentioning

confidence: 99%

“…Many cytokines orchestrate the LPC response, and it is therefore also not surprising that a deficiency of a single cytokine inhibits but does not fully block LPC proliferation, as has been shown for CDE-fed mice deficient for TNFR1, TNF/ LTa, IFNc, or LTb. 3,5,6 In this respect, it is important to note that Jakubowski et al 8 also used the 14-day time point to examine the response of Fn14 KO mice to 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced injury. Preliminary data detailing the dynamics of the LPC response in this model suggest that rapid growth also occurs between approximately days 5 and 16 (B. Knight, unpublished observations, 2009), with peak Ki67 labeling of LPCs on day 12 (Boulter et al, unpublished data, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…This process, unlike hepatocyte-mediated liver regeneration, is relatively poorly understood. Several factors mediating the LPC response to injury have been identified, including tumor necrosis factor (TNF), lymphotoxin b (LTb), interferon c (IFNc), and transforming growth factor b, among others [3][4][5][6][7] ; however, the mechanisms by which these mediators elicit their effects remain largely unknown. Thus, no definitive LPC growth factor has been described to date.…”

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confidence: 99%

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Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Tirnitz–Parker¹,

Viebahn²,

Jakubowski³

et al. 2010

Hepatology

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160

182

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Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor–like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin–positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFκB subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFκB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (Hepatology 2010)

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“…We have identified impaired oval cell proliferation in TNF receptor 1 (TNFR1) knockout mice, illustrating that TNFR1 downstream signaling events are required for maximal oval cell proliferation. 42 In contrast, TNF receptor 2 (TNFR2) appears to have no involvement, as the number of oval cells induced in TNFR2 knockout mice and controls was similar. Although some TNF production can be attributed to infiltrating inflammatory cells, the majority of hepatic TNF produced during liver regeneration is Kupffer-cell derived.…”

Section: Role Of Inflammatory Cytokinesmentioning

confidence: 99%

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

Lowes

Croager

Olynyk

et al. 2002

J of Gastro and Hepatol

154

123

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In experimental models, which induce liver damage and simultaneously block hepatocyte proliferation, the recruitment of a hepatic progenitor cell population comprised of oval cells is invariably observed. There is a substantial body of evidence to suggest that oval cells are involved in liver regeneration, as they differentiate into hepatocytes and biliary cells. Recently, bone marrow cells were shown to be a source of a stem cells with the capacity to repopulate the liver. Presently, the relationship between bone marrow cells and oval cells is unclear. Investigations will be greatly assisted by the availability of in vitro models based on a knowledge of cytokines that affect oval cells. While the cytokines, which regulate the different hematopoietic lineages, are well characterized, there is relatively little information regarding those that influence oval cells. This review outlines recent developments in the field of oval cell research and focuses on cytokines and growth factors that have been implicated in regulating oval cell proliferation and differentiation.

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Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice

Cited by 277 publications

References 49 publications

Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice

Tumor necrosis factor deficiency inhibits mammary tumorigenesis and a tumor necrosis factor neutralizing antibody decreases mammary tumor growth in neu/erbB2 transgenic mice

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

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