Molecular analysis of lipid‐depleting factor in a colon‐26‐inoculated cancer cachexia model

Inadera, Hidekuni; Nagai, Shigenori; Dai, Hong; Matsushima, Kouji

doi:10.1002/ijc.10578

Cited by 18 publications

(46 citation statements)

References 52 publications

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“…[12][13][14][15][16] Tumor cell-and host-produced cytokines such as IL-6, TNF-␣ and IFN-␥ are thought to play an important role in the catabolism and weight loss associated with several malignant and nonmalignant conditions. 10,11,[17][18][19] However, the specific contribution of human tumor cell-secreted IL-6 to body weight loss has not been described. We hypothesized that neutralization of tumor cell-secreted IL-6 could inhibit body weight loss.…”

Section: Discussionmentioning

confidence: 43%

CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice

Zaki¹,

Nemeth²,

Trikha³

2004

Intl Journal of Cancer

105

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IL-6 is a multifunctional cytokine implicated in several cancers. IL-6 is a growth factor for certain tumors and contributes to drug resistance, cachexia and bone resorption. Cachexia is characterized by progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle. We have developed CNTO 328 (cCLB8), a humanmouse chimeric MAb to IL-6 (K d approx. 10 ؊12 M) that inhibits IL-6 function. A phase I study with CNTO 328 in multiple myeloma patients demonstrated that the antibody was safe and had a circulating half-life of approximately 17 days. Since IL-6 is implicated in cachexia, we hypothesized that CNTO 328 could inhibit tumor-induced cachexia. We used 2 human tumor-induced cachexia models in nude mice. In the first model, human melanoma cells were inoculated in female nude mice. Control treated animals lost 19% (؎7.7%) body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)-treated animals lost only 1.5% (؎1.3%) body weight from day 0 to day 31 (p ‫؍‬ 0.023). Cachexia (wasting syndrome) is a debilitating state of involuntary weight loss that is characterized by hypercatabolism of the body's carbon sources, proteins and lipids, for conversion into energy. 1 Cachexia is induced by a variety of pathologic conditions, including cancer, where an estimated 30% of cancer deaths are attributed to cachexia. Tumor necrosis factor (TNF)-␣, IL-1, IFN-␥ and IL-6 contribute to many of the host changes seen in cancer cachexia, including loss of appetite, loss of body weight and induction of acute-phase proteins. 2 These cytokines induce cachexia by altering the metabolism of lipids and proteins. IL-6 is a 26 kDa protein with a broad range of activities, involving not only immunomodulation but also hemostatic, neuroendocrine and cancer-associated disorders. 3 IL-6 is an acute phase-inducing cytokine that is secreted to a large extent by human adipose tissue under noninflammatory conditions. 4 It also influences atrophy and increases catabolism of muscle protein. IL-6 is expressed together with its receptor in neurons of hypothalamic nuclei that regulate body composition. IL-6 levels in serum correlate with body mass index (BMI), and IL-6-deficient mice developed mature-onset obesity. 4 Although several studies have suggested that host-derived IL-6 contributes to cachexia, the role for tumor cell-secreted IL-6 in cachexia is less clear.IL-6 is also implicated in regulating the growth and differentiation of several malignant diseases. The ability of IL-6 to mediate tumor cell survival and disease progression has been demonstrated by the inhibitory effects of an anti-IL-6 MAb on tumor growth both in vitro and in vivo. Blockade of IL-6 can inhibit growth of human glioblastoma cells in vitro. 5 Using the same approach, it was shown that injection of an antihuman IL-6 MAb prolonged the survival of human lymphoma-bearing mice. 6 Several clinical trials using monoclonal antibodies (MAbs) against IL-6 have been conducted on various diseases, including plasma cell leukemia, multiple myeloma, B-lymphop...

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Section: Discussionmentioning

confidence: 43%

CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice

Zaki¹,

Nemeth²,

Trikha³

2004

Intl Journal of Cancer

105

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“…The BALB/c mouse-derived cancer cell line Colon-26 (13,39) was obtained from the Cell Resource Center for Biomedical Research of Tohoku University. Colon-26 is an undifferentiated carcinoma induced by the carcinogen N-nitroso-N-methylurethane (13). The human colon cancer cell line HT29 was obtained from the American Type Culture Collection (Manassas, VA).…”

Section: Methodsmentioning

confidence: 48%

Epithelial Toll-Like Receptor 5 Is Constitutively Localized in the Mouse Cecum and Exhibits Distinctive Down-Regulation during Experimental Colitis

Ortega-Cava

Ishihara

Rumi

et al. 2006

Clin Vaccine Immunol

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We recently demonstrated that the pattern recognition receptors (PRRs) toll-like receptor 2 (TLR2), TLR4, and CD14 are expressed in mouse colonic epithelium in a compartmentalized manner. Here we report the localization of TLR5, the receptor for bacterial flagellin, and its distinctive down-regulation during experimental colitis. Guts from normal BALB/c mice and those with dextran sodium sulfate (DSS)-induced colitis were compared. Each gut was divided into seven segments (stomach, small intestine [three parts], and colon [three parts]), and epithelial cells and crypt units were collected by scraping and EDTA treatment, respectively. Northern blotting showed that TLR5 mRNA was preferentially expressed in the epithelium of the proximal colon in normal mice. Laser capture microdissection coupled to reverse transcriptase PCR confirmed this localization. TLR5 protein expression reflected mRNA expression, as evidenced by Western blotting. In mice with acute colitis, inflammation occurred mainly in the distal colon. Interestingly, while TLR2, TLR4, and CD14 were up-regulated in the inflamed colon, TLR5 was down-regulated at both the mRNA and protein levels. Decreased TLR5 expression was more evident during chronic colitis. Additional in vitro studies using a mouse cell line, Colon-26, showed that gamma interferon (IFN-␥) time-and dose-dependently down-regulates TLR5. In conclusion, epithelial cells, mainly in the proximal colon, constitutively express TLR5. TLR5 expression is down-regulated in vivo during acute and chronic DSS-induced colitis, in contrast to the expression of TLR2, TLR4, and CD14. The mechanism governing TLR5 regulation may therefore differ from that controlling other PRRs. Finally, IFN-␥ may be involved in down-regulating TLR5 expression.The concept of a highly efficient innate immune system that recognizes potential pathogens by detecting lipopolysaccharides (LPSs), peptidoglycans, lipopeptides, flagellin, or many other highly preserved and unvarying structural molecules (27) is now widely accepted, and innate immunity acts as the firstline defense against pathogenic microorganisms in mammals. Although the innate immune system is basically activated by pathogen-related molecules, this activation seems to be driven by several kinds of strategically regulated pattern recognition receptors (PRRs). Because of the variety of PRRs and their sophisticated intracellular signal transduction systems, the innate immune system is increasingly regarded as highly complex.Since the discovery of human toll (22), several new receptors and ligands have been recognized, and more are constantly being added to the arena. Toll-like receptors (TLRs) are transmembrane proteins that share a leucine-rich repeat ectodomain, which confers high specificity for particular ligands (4). TLRs also share an intracellular domain which contains a toll-interleukin-1 (IL-1) receptor homology domain common to the IL-1 receptor family and the IL-18 receptor (36). Ligand binding to TLRs triggers activation of the IL-1 receptor-associated k...

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“…Soda et al reported that a C-26 clone which did not induce cachexia also enhanced IL-6 to the same level as the C-26 clone that induced severe cachexia [82]. In agreement, Inadara et al reported that the factor causing depletion of adipose tissue in C-26 tumor bearing mice is different from IL-6 or TNF-α [83], suggesting that IL-6 cannot be the only factor causing cachexia in tumor bearing mice.…”

Section: Modulators and Regulators Of Triglyceride Lipases In Cancer mentioning

confidence: 70%

The role of triglyceride lipases in cancer associated cachexia

Das

Höefler

2013

Trends in Molecular Medicine

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Molecular analysis of lipid‐depleting factor in a colon‐26‐inoculated cancer cachexia model

Cited by 18 publications

References 52 publications

CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice

CNTO 328, a monoclonal antibody to IL‐6, inhibits human tumor‐induced cachexia in nude mice

Epithelial Toll-Like Receptor 5 Is Constitutively Localized in the Mouse Cecum and Exhibits Distinctive Down-Regulation during Experimental Colitis

The role of triglyceride lipases in cancer associated cachexia

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