Leukemia inhibitory factor via the Toll-like receptor 5 signaling pathway involves aggravation of cachexia induced by human gastric cancer-derived 85As2 cells in rats

Abstract

Cancer cachexia is highly prevalent in gastric cancer patients and characterized by decreased food consumption and body weight. We previously created a rat model of cancer cachexia using MKN45cl85 and 85As2 cells derived from human gastric cancer. The 85As2 cells induced cachexia more potently compared to MKN45cl85 cells. To clarify the mechanism underlying the difference in the cachexia-inducing ability of these cells, we conducted DNA microarray analysis, focusing on cell proliferation and the production of leukemia inhibitory factor (LIF), a cachexia-inducing factor. The plasma human LIF levels of 85As2-induced cachexic rats increased as symptoms worsened, whereas the plasma levels of MKNcl85 were low. 85As2 cells displayed more genetic changes compared to MKN45cl85 cells, which were related to Toll-like receptor (TLR) 4/5 signaling. Stimulation of both cells with TLR4 (lipopolysaccharide) or TLR5 (flagellin) agonists did not affect proliferation. However, in 82As2 cells, LIF production was significantly increased by stimulation with TLR5, which was suppressed by an inhibitor of interleukin-1 receptor-associated kinase-1/4, which are important factors in the TLR5 signaling pathway. The increase in LIF production resulting from activation of the TLR5 signaling pathway may contribute to the cachexia-inducing ability of 85As2 cells.

Management of Cancer Cachexia: Attempting to Develop New Pharmacological Agents for New Effective Therapeutic Options

“…A role in development of cancer cachexia has been recently suggested for TLR5 as well (76). In fact, activation of this receptor, which is expressed on the plasmatic membrane of certain gastric cancer cells, seemed to contribute to the onset of CC, possibly due to TLR5-mediated overexpression of LIF (76).…”

Development and characterization of a cancer cachexia model employing a rare human duodenal neuroendocrine carcinoma-originating cell line

“…We have already established a cachexia-inducing subline, 85As2, from the MKN-45 cell line and developed a mouse model of gastric cancer with high frequency cachexia [19]. Subsequently, 85As2mLuc cells were implanted into nude rats and acclimatized, and the characteristics of this model, drug sensitivity, and efficacy were reported [26–28]. For pancreatic cancer with high frequency cachexia, relatively large numbers of cachexia models are known [14, 15, 17, 29, 30], but few studies have been conducted on cachexia associated with NEC.…”

“…As described above, the cachexia-inducing human gastric cancer subline 85As2 also had a high tumor burden rate in nude mice [19] and was transplanted into nude rats to establish a proper cachexia model and/or for animal welfare [26]. In this rat model, the tumor burden rate was low, and it was able to withstand drug evaluation as a suitable animal model [27, 28]. As such, a similar approach is considered more effective for AkuNEC cells.…”

Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer

“…LIF expression is often either upregulated or downregulated in cancer tissue compared to normal tissue, as can be seen in Figure 2 [ 26 ]. The level of LIF expression can have many regulators that may differ based on cell type or conditions, shown in Figure 3 [ 7 , 16 , 17 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Many of these up-regulators and down-regulators could contribute to the levels of LIF in tissues other than those listed, but conclusions should not be drawn until the interaction is tested in the tissue of interest.…”