The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

Accumulating evidence has indicated that inflammatory responses are important for cancer development. Epidemiological studies have shown that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colon cancer development. Subsequently, mouse genetic studies have shown that cyclooxygenase (COX)-2, one of the target molecules of NSAIDs, and its downstream product, prostaglandin E 2 (PGE 2), play an important role in gastrointestinal tumorigenesis. Bacterial infection stimulates the Toll-like receptor (TLR)/MyD88 pathway in tumor tissues, which leads to the induction of COX-2 in stromal cells, including macrophages. Induction of the COX-2/PGE 2 pathway in tumor stroma is important for the development and maintenance of an inflammatory microenvironment in gastrointestinal tumors. In such a microenvironment, tumor-associated macrophages express proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, and these cytokines, respectively, activate the nuclear factor (NF)-κB and Stat3 transcription factors in epithelial cells, as well as in stromal cells. Recent mouse studies have uncovered the role of such an inflammatory network in the promotion of gastrointestinal tumor development. Genetically engineered and chemically induced mouse tumor models which mimic sporadic or inflammation-associated tumorigenesis were used in these studies. In this review article, we focus on mouse genetic studies using these tumor models, which have contributed to the elucidation of the molecular mechanisms associated with the inflammatory network in gastrointestinal tumors, and we also discuss the role of each pathway in cancer development. The involvement of immune cells such as macrophages, mast cells, and regulatory T cells in tumor promotion is also discussed. © 2011 Springer

Mouse models of gastric tumors: Wnt activation and PGE₂ induction

金沢大学がん研究所Accumulating evidence has suggested that cooperation of oncogenic activation and the host responses is important for cancer development. In gastric cancer, activation of Wnt signaling appears to be a major oncogenic pathway that causes tumorigenesis. In the chronic gastritis caused by Helicobacter pylori infection, cyclooxigenase-2 induces prostaglandin E 2 (PGE2) biosythesis, which plays an important role in tumorigenesis. We constructed a series of mouse models and investigated the role of each pathway in the gastric tumorigenesis. Wnt activation in gastric epithelial cells suppresses differentiation, and induces development of preneoplastic lesions. On the other hand, induction of the PGE2 pathway in gastric mucosa induces development of spasmolytic polypeptide-expressing metaplasia (SPEM), which is a possible preneoplastic metaplasia. Importantly, simultaneous activation of Wnt and PGE2 pathways leads to dysplastic gastric tumor development. Moreover, induction of the PGE2 pathway also promotes gastric hamartoma development when bone morphogenetic protein (BMP) signaling is suppressed. These results indicate that alteration in the Wnt or BMP signaling impairs epithelial differentiation, and the PGE2 pathway accelerates tumor formation regardless of the types of oncogenic pathways. We review the phenotypes and gene expression profiles of the respective models, and discuss the cooperation of oncogenic pathways and host responses in gastric tumorigenesis. Copyright © 2010 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd

PGE2-Associated Inflammation and Gastrointestinal Tumorigenesis

Accumulating 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 a microenvironment, nuclear factor (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 tumor necrosis factor (TNF)-α signaling is activated in the inflammatory microenvironment 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. © 2015, Springer Japan. All rights reserved.[Book Chapter

Prostaglandin E2-associated inflammation and bacterial infection in gastric tumorigenesis

The 3rd International Symposium on Carcinogenic Spiral & International Symposium on Tumor Biology in Kanazawa, [DATE]: January 24(Thu)-25(Fri),2013, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Infection/Inflammation-Assisted Acceleration of the Carcinogenic Spiral and its Alteration through Vector Conversion of the Host Response to Tumors / Scientific Research on Innovative Areas, a MEXT Grant-in Aid Projec

Activated macrophages promote Wnt signaling through TNF-α in gastric tumor cells

Division of Genetic

Destruction of pancreatic β-cells by transgenic induction of prostaglandin e2 in the islets

金沢大学がん研究所附属がん幹細胞研究センター　Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic β-cells. Furthermore, the number of pancreatic β-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E2 (PGE2). To investigate whether high glucose-induced PGE2 has an adverse effect on pancreatic β-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their β-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of β-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because β-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE2 signaling thus contributes to the reduction of the pancreatic β-cell mass through inhibition of proliferation, thereby aggravating diabetes further. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc

Hypergravity induces expression of cyclooxygenase-2 in the heart vessels

金沢大学がん研究所Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin biosynthesis, is induced by various stimuli including mechanical stress and plays important roles in pathophysiological conditions. For example, gravitational stress has been shown to induce expression of COX-2 in bone tissues, which is essential for bone homeostasis. To investigate whether COX-2 is induced by gravitational loading in other tissues than bone, we exposed mice to hypergravity at 2G and 3G for 4 h. We demonstrate here that COX-2 is induced in the mouse heart vessels by hypergravity. Moreover, hypoxia-inducible factor (HIF)-1α and its downstream genes such as inducible nitric oxide synthase, vascular endothelial growth factor, and heme oxygenase-1 were induced in the heart simultaneously, while none of these genes were induced in the COX-2(−/−) mouse heart. Therefore, COX-2 induced in the heart helps protect the heart function against hypoxia under hypergravity condition through HIF-1α induction

Early Embryonic Lethality Caused by Targeted Disruption of the Mouse Thioredoxin Gene

AbstractThioredoxins belong to a widely distributed group of small proteins with strong reducing activities mediated by a consensus redox-active dithiol (Cys-Gly-Pro-Cys). Thioredoxin was first isolated as a hydrogen donor for enzymatic synthesis of deoxyribonucleotides by ribonucleotide reductase inEscherichia coli.Recent studies have revealed a variety of roles that thioredoxin plays in transcription, growth control, and immune function. In this report, we describe the phenotype of mice carrying a targeted disruption of the thioredoxin gene (Txn). Heterozygotes are viable, fertile, and appear normal. In contrast, homozygous mutants die shortly after implantation, and the concepti were resorbed prior to gastrulation. When preimplantation embryos were placed in culture, the inner cell mass cells of the homozygous embryos failed to proliferate. These results indicate thatTxnexpression is essential for early differentiation and morphogenesis of the mouse embryo