Genetic alterations in epithelial cells and construction of tumor microenvironment are important for tumor promotion and malignant progression. Our aim is to elucidate the role of inflammatory microenvironment in tumorigenesis through the following projects
Macrophage niche is important for tumor promotion. We found that TNF expressed by macrophages promotes Wnt signaling in gastric tumor epithelial cells, which contributes to tumorigenicity of cancer cells (Oguma K, et al, EMBO J, 2008).
Gan mice develop inflammation-associated gastric tumors by activation of Wnt and PGE2 pathways. Notably, gastric tumorigenesis was significantly suppressed in germfree Gan mice, suggesting the role of innate immune response in gastric tumorigenesis (Oshima H, et al, Gastroenterology, 2011).
Expression profile of microRNAs in Gan mouse tumors was examined. We found that tumor suppressor microRNA, miR-7, is downregulated by inflammation-dependent mechanism, which contributes to gastric tumorigenesis (Kong D, et al, Oncogene, 2012).
Disruption of Tnf gene in Gan mice caused significant suppression of gastric tumorigenesis. One of TNF-dependent factor, Noxo1, is also induced in normal stem cells, and plays a role in tumorigenicity of gastric cancer cells (Oshima H, et al, Oncogene, 2013).
Gastric tumorigenesis was significantly suppressed in Tnf-/- Gan mice. Bone marrow transplantation to Tnf-/- Gan mice from GFP transgenic mice resulted in gastric tumor development, indicating the role of bone marrow-derived macrophages in tumor promotion.
Bone marrow transplantation to Gan mice from GFP transgenic mice revealed significant infiltration of bone marrow-derived cells to tumor tissues, and most of them are F4/80-positive macrophages but not E-cadherin-positive epithelial cells.