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Updated: May 26, 2026
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models
Hiroko Oshima1, Masanobu Oshima
1Division of Genetics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Abstract:
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.
Insights
Inflammation drives cancer development. Mouse studies reveal how inflammatory pathways, like cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), promote gastrointestinal tumors, highlighting immune cell roles.
Area of Science:
- Oncology
- Immunology
- Gastroenterology
Background:
- Inflammatory responses are increasingly recognized as critical drivers of cancer development.
- Non-steroidal anti-inflammatory drugs (NSAIDs) are linked to reduced colon cancer risk, suggesting a role for their targets in tumorigenesis.
- Cyclooxygenase-2 (COX-2) and its product prostaglandin E2 (PGE2) are implicated in gastrointestinal tumor progression.
Purpose of the Study:
- To review mouse genetic studies elucidating the molecular mechanisms of inflammatory networks in gastrointestinal tumors.
- To discuss the role of specific pathways, including Toll-like receptor (TLR)/MyD88 and COX-2/PGE2, in tumor development.
- To explore the contribution of immune cells like macrophages, mast cells, and regulatory T cells to tumor promotion.
Main Methods:
- Utilized genetically engineered and chemically induced mouse tumor models mimicking sporadic and inflammation-associated tumorigenesis.
- Focused on analyzing molecular mechanisms through genetic studies in these mouse models.
- Reviewed existing literature on inflammatory pathways and immune cell involvement in gastrointestinal cancer.
Main Results:
- Demonstrated that bacterial infection can activate the TLR/MyD88 pathway, inducing COX-2 in stromal cells like macrophages.
- Highlighted the importance of the COX-2/PGE2 pathway in establishing a pro-tumorigenic inflammatory microenvironment.
- Showed that cytokines like TNF-α and IL-6 activate NF-κB and Stat3, promoting tumor development via inflammatory networks.
Conclusions:
- The inflammatory network, involving pathways like TLR/MyD88 and COX-2/PGE2, is crucial for gastrointestinal tumor development and maintenance.
- Immune cells, particularly macrophages, play a significant role in orchestrating this pro-tumorigenic inflammatory microenvironment.
- Understanding these molecular mechanisms in mouse models provides insights into therapeutic strategies for gastrointestinal cancers.
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