Essential Roles of IL-6 <i>Trans</i>-Signaling in Colonic Epithelial Cells, Induced by the IL-6/Soluble–IL-6 Receptor Derived from Lamina Propria Macrophages, on the Development of Colitis-Associated Premalignant Cancer in a Murine Model

Matsumoto, Satoshi; Hara, Takeo; Mitsuyama, Keiichi; Yamamoto, Mayuko; Takahashi, Osamu; Sata, Michio; Scheller, Jürgen; Rose-John, Stefan; Kado, Shoichi; Takada, Toshihiko

doi:10.4049/jimmunol.0801217

Cited by 194 publications

(143 citation statements)

References 49 publications

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“…SPINK1 protein is secreted from the liver in the systemic circulation as one of the acute-phase proteins to inhibit trypsin activity in tissues. In addition, it has already been reported that IL6 is induced in DSS colitis mice (35). In the current study, we showed that Spink3 was overexpressed at the regenerative stage in DSS colitis and that it may have contributed to the proliferation and repair of the colonic cells.…”

Section: Discussionsupporting

confidence: 50%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression.Implications: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.

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Section: Discussionsupporting

confidence: 50%

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Ida

Ozaki

Araki

et al. 2015

Molecular Cancer Research

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“…The amounts administered were sufficient to block IL-6 trans-signaling mediated processes in other mouse models. 25,26 In summary, IL-6 trans-signaling does not seem to play a role in this model of plasmacytoma development, however, it could be of importance in addressing other gp130 positive cells in the bone marrow, such as stromal cells and osteoclasts. 27 The activation of gp130 is a major event in controlling the growth and survival of malignant plasma cells.…”

Section: Discussionmentioning

confidence: 99%

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

et al. 2016

Self Cite

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IntroductionMultiple myeloma (MM) is characterized by the expansion of clonal plasma cells within the bone marrow (BM), leading to an M-protein in serum, antibody deficiency, and skeletal destruction. Despite stem cell transplantation and novel therapies, the vast majority of patients with MM will eventually relapse and become refractory to standard therapy. Treatment strategies specifically targeting mechanisms of tumor growth and survival are being intensely explored in MM in order to improve © Ferrata Storti Foundation patient outcome. 1In the pathogenesis of MM, genetic changes drive the development of the malignant clone, but the interaction between the malignant plasma cells and the BM microenvironment has been shown to be equally important in mediating myeloma cell survival and progression.2 One of the established pathogenic key factors produced in the BM milieu is interleukin(IL)-6, which promotes the growth and survival of the malignant plasma cells and mediates drug resistance.3 While some myeloma cells produce their own IL-6, 4 bone marrow stromal cells (BMSCs) are the main source, establishing a strong paracrine growth stimulation. 5 Other sources of IL-6 in MM are macrophages, osteoblasts and osteoclasts; 2 eosinophils and megakaryocytes may also contribute. 6The receptor for IL-6 comprises a specific α-receptor, glycoprotein (gp) 80 (CD126), which, after ligand binding, recruits the gp130 receptor (IL6ST, CD130). Gp130 is the common signal transducer for a family of cytokines with pleiotropic and partly redundant activities.7 While signaling via IL-6 and IL-11 is initiated via gp130 homodimerization, the receptor complexes of other family members consist of heterodimers of gp130 with a second signaling molecule, most of which use the leukemia inhibitory factor receptor (LIFR). Leukemia inhibitory factor (LIF) and oncostatin M (OSM) directly induce gp130/LIFR heterodimerization without the involvement of other receptor components. Upon dimerization, associated Janus kinases (JAKs) become activated and phosphorylate specific tyrosine residues on the receptors, which serve as docking sites for transcription factors and adaptor proteins. The main signaling pathways induced by gp130 are the activation of STAT (signal transducer and activator of transcription)-3, the Ras-dependent mitogen-activated protein kinase (MAPK) cascade, and the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway. 7,8The human plasma cell line INA-6 was generated in our laboratory from the pleural effusion of a patient with advanced plasma cell disease. 9 The survival of INA-6 cells in vitro is strictly dependent on exogenous IL-6 without growth response to other gp130 cytokines. With the establishment of a xenograft model in severe combined immune deficiency (SCID) mice using INA-6, a non-optimal environment devoid of human IL-6 was provided. Despite the fact that murine IL-6 is not active on human cells, plasma cell tumors developed over a period of up to five months. In serum and ascites of tumor-beari...

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“…sIL-6Ra can also bind IL-6, to form the IL-6/sIL-6Ra complex that interact with membrane gp130 to induce signal transduction. The importance of IL-6 trans-signaling in chronic colitis and CAC development has been well demonstrated (6,22). TACE plays a major role in the inflammatory processes by promoting the shedding of the extracellular domain of several transmembrane proteins such as receptors and adhesion molecules (26,27).…”

Section: Discussionmentioning

confidence: 99%

“…TACE plays a major role in the inflammatory processes by promoting the shedding of the extracellular domain of several transmembrane proteins such as receptors and adhesion molecules (26,27). In the CAC model, tumor epithelial cells express high level of TACE, which control IL-6R shedding and thus IL-6 trans-signaling (6,22). The specific inhibition of this signaling by the antibody against IL-6Ra or the blockade of sIL-6Ra using gp130-Fc prevented CAC tumorigenesis (6).…”

Section: Discussionmentioning

confidence: 99%

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

Dai

Jiao

Teng

et al. 2014

Molecular Cancer Therapeutics

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The interleukin-6 (IL-6)/STAT3 signaling regulates survival and proliferation of intestinal epithelial cells and plays an important role in the pathogenesis of inflammatory bowel disease and colorectal cancer. Embelin is a small molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), with antioxidant, anti-inflammatory, and antitumor activities. We previously showed that embelin inhibits the growth of colon cancer cells in vitro, and effectively suppresses 1,2-dimethylhydrazine dihydrochloride-induced colon carcinogenesis in mice. Here, we explored the antitumor effects and mechanisms of embelin on colitis-associated cancer (CAC) using the azoxymethane/dextran sulfate sodium (AOM/DSS) model, with a particular focus on whether embelin exerts its effect through the IL-6/STAT3 pathway. We found that embelin significantly reduced incidence and tumor size in CAC-bearing mice. In addition to inhibiting proliferation of tumor epithelial cells, embelin suppressed colonic IL-6 expression and secretion, and subsequently STAT3 activation in vivo. Importantly, in vitro studies have revealed that in colon cancer cells, embelin diminished both the constitutive and IL-6-induced STAT3 activation by stimulating Src homology domain 2-containing protein tyrosine phosphatase (SHP2) activity. Moreover, embelin protected mice from AOM/DSS-induced colitis before tumor development. Embelin decreased IL-1b, IL-17a, and IL-23a expression as well as the number of CD4 þ T cells and macrophages infiltrating the colonic tissues. Thus, our findings demonstrated that embelin suppresses CAC tumorigenesis, and its antitumor effect is partly mediated by limiting IL-6/STAT3 activation and Th17 immune response. Embelin may be a potential agent in the prevention and treatment of CAC. Mol Cancer Ther; 13(5); 1206-16. Ó2014 AACR.

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Essential Roles of IL-6 Trans-Signaling in Colonic Epithelial Cells, Induced by the IL-6/Soluble–IL-6 Receptor Derived from Lamina Propria Macrophages, on the Development of Colitis-Associated Premalignant Cancer in a Murine Model

Cited by 194 publications

References 49 publications

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

Embelin Reduces Colitis-Associated Tumorigenesis through Limiting IL-6/STAT3 Signaling

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