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

Abstract

Hepatic stem cells (oval cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct cells. Oval cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatocellular growth. The experiments reported here explore the relationship among the TNF inflammatory pathway, liver stem cell activation, and tumorigenesis. We demonstrate that TNF is upregulated during oval cell proliferation induced by a choline-deficient, ethionine-supplemented diet and that it is expressed by oval cells. In TNF receptor type 1 knockout mice, oval cell proliferation is substantially impaired and tumorigenesis is reduced. Oval cell proliferation is impaired to a lesser extent in interleukin 6 knockout mice and is unchanged in TNF receptor type 2 knockout mice. These findings demonstrate that TNF signaling participates in the proliferation of oval cells during the preneoplastic phase of liver carcinogenesis and that loss of signaling through the TNF receptor type 1 reduces the incidence of tumor formation. The TNF inflammatory pathway may be a target for therapeutic intervention during the early stages of liver carcinogenesis.

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

“…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).…”

Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells

“…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.…”

“…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).…”

“…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.…”

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

“…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.…”