Prostaglandin E2 Signaling and Bacterial Infection Recruit Tumor-Promoting Macrophages to Mouse Gastric Tumors

Oshima, Hiroko; Hioki, Kyoji; Popivanova, Boryana Konstantinova; Oguma, Koichi; Rooijen, Nico van; Ishikawa, Tomo-o; Oshima, Masanobu

doi:10.1053/j.gastro.2010.11.007

Cited by 114 publications

(106 citation statements)

References 32 publications

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“…We recently showed that inflammatory responses and macrophage infiltration were suppressed in K19-C2mE mouse gastritis and Gan mouse tumors when mice were maintained under germfree conditions (Figure 5d and Oshima et al, 2011). Notably, miR-7 expression levels were increased significantly in germfree K19-C2mE and Gan mice compared with the levels of mice maintained in a specific pathogen free (SPF) facility (Figure 5e).…”

Section: Downregulation Of Mir-7 In the Stomach By Inflammatory Respomentioning

confidence: 91%

“…Moreover, the genomic region including miR-7-1 was not deleted in human gastric cancer cells (Supplementary Figure 3b), suggesting that miR-7 downregulation in gastric cancer is not caused by genomic deletion. We next examined whether activated macrophages have a role in the downregulation of miR-7, because the major source of proinflammatory cytokines in gastric tumors are macrophages (Oshima et al, 2004(Oshima et al, , 2011. To monitor miR-7 activity, reporter vector-transfected cells were used.…”

Section: Repression Of Mir-7 In Gastric Cancer Cells By Macrophage-dementioning

confidence: 99%

“…For expression analyses, K19-C2mE mouse gastritis and Gan mouse gastric tumor samples, and wild-type mouse stomach tissues were obtained at 30-40 weeks of age. Germfree mouse colonies were constructed as described previously (Oshima et al, 2011), and the histology and miR-7 expression were examined at 55 weeks of age (n ¼ 5). H. felis (American Type Culture Collection 49179, ATCC, Manassas, VA, USA) were inoculated at 10 8 per mouse into wild-type mice at 6-8 weeks of age, and the histology and miRNA expression were examined at 20 weeks after infection (n ¼ 6).…”

Section: Mouse Modelsmentioning

confidence: 99%

“…Using genetic mouse models, we previously demonstrated that induction of COX-2 and its downstream product, prostaglandin E 2 (PGE 2 ), is required for gastrointestinal tumorigenesis (Sonoshita et al, 2001;Oshima et al, 2006). The COX-2/PGE 2 pathway, together with a bacterial infection, induces inflammatory responses in the stomach through the recruitment of macrophages, which promotes gastric tumorigenesis (Oshima et al, 2011). However, it remains to be fully elucidated precisely how such inflammatory responses contribute to the promotion of gastric tumors.…”

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confidence: 99%

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Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells

Kong

Piao

Yamashita³

et al. 2011

Oncogene

102

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Inflammation has an important role in cancer development through various mechanisms. It has been shown that dysregulation of microRNAs (miRNAs) that function as oncogenes or tumor suppressors contributes to tumorigenesis. However, the relationship between inflammation and cancer-related miRNA expression in tumorigenesis has not yet been fully understood. Using K19-C2mE and Gan mouse models that develop gastritis and gastritis-associated tumors, respectively, we found that 21 miRNAs were upregulated, and that 29 miRNAs were downregulated in gastric tumors in an inflammation-dependent manner. Among these miRNAs, the expression of miR-7, a possible tumor suppressor, significantly decreased in both gastritis and gastric tumors. Moreover, the expression of miR-7 in human gastric cancer was inversely correlated with the levels of interleukin-1b and tumor necrosis factor-a, suggesting that miR-7 downregulation is related to the severity of inflammatory responses. In the normal mouse stomach, miR-7 expression was at a basal level in undifferentiated gastric epithelial cells, and was induced during differentiation. Moreover, transfection of a miR-7 precursor into gastric cancer cells suppressed cell proliferation and soft agar colony formation. These results suggest that suppression of miR-7 expression is important for maintaining the undifferentiated status of gastric epithelial cells, and thus contributes to gastric tumorigenesis. Although epigenetic changes were not found in the CpG islands around miR-7-1 of gastritis and gastric tumor cells, we found that activated macrophage-derived small molecule(s) (o3 kDa) are responsible for miR-7 repression in gastric cancer cells. Furthermore, the miR-7 expression level significantly decreased in the inflamed gastric mucosa of Helicobacter-infected mice, whereas it increased in the stomach of germfree K19-C2mE and Gan mice wherein inflammatory responses were suppressed.Taken together, these results indicate that downregulation of tumor suppressor miR-7 is a novel mechanism by which the inflammatory response promotes gastric tumorigenesis.

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Section: Downregulation Of Mir-7 In the Stomach By Inflammatory Respomentioning

confidence: 91%

Section: Repression Of Mir-7 In Gastric Cancer Cells By Macrophage-dementioning

confidence: 99%

Section: Mouse Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

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Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells

Kong

Piao

Yamashita³

et al. 2011

Oncogene

102

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“…In the gastric tumors of Gan mice, macrophages infiltrate into the tumor stroma, and they are activated to express proinflammatory cytokines, chemokines, growth factors and proteases (Oshima et al 2011a). We found that the expression of EGFR ligands, including amphiregulin and epiregulin, and ADAM family proteases, is upregulated in Gan mouse tumors by an inflammation-dependent mechanism (Oshima et al 2011b).…”

Section: Tnf-α Signaling In Gan Mouse Gastric Tumorigenesismentioning

confidence: 81%

PGE2-Associated Inflammation and Gastrointestinal Tumorigenesis

Oshima

2015

Inflammation and Immunity in Cancer

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SummaryAccumulating evidence has indicated that chronic inflammation is associated with a variety of diseases, including cancer, heart attacks, Alzheimer's and other diseases. In the cancer research field, the association of inflammatory infiltration with cancer has been known histologically for a long time. Recent studies have indicated that macrophages and other immune cells infiltrate cancer tissues, expressing cytokines, chemokines and growth factors, thereby constructing an inflammatory microenvironment. In such microenvironment, NF-κB is activated, which contributes to the growth and survival of cancer cells. Moreover, it has also been shown that NF-κB activation is associated with the acquisition of stem cell properties by cancer cells. Using inflammation-associated gastric cancer model mice, Gan mice, we have shown that TNF-α signaling is activated in inflammatory microenvironment, 2 and plays a tumor promoting role by inducing Noxo1 in tumor cells. Taken together, these results indicate that regulation of chronic inflammation in tumor tissues would be an effective preventive and/or therapeutic strategy against cancer development and malignant progression.3

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