1. Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis
- Author
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Shintaro Yagi, Satoshi Takada, Ryohei Takei, Itasu Ninomiya, Tetsuo Ohta, Hiroyuki Takamura, Hidehiro Tajima, Ai Harashima, Sachio Fushida, Noriyuki Inaki, Seiichi Munesue, Tomoharu Miyashita, and Yasuhiko Yamamoto
- Subjects
Cancer Research ,Esophageal Neoplasms ,Carcinogenesis ,Immunology ,Adenocarcinoma ,medicine.disease_cause ,Barrett Esophagus ,Immune system ,Tumor Microenvironment ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Neoplastic transformation ,Reflux esophagitis ,Tumor microenvironment ,business.industry ,Chronic Esophagitis ,Esophageal cancer ,medicine.disease ,Metformin ,Rats ,Oncology ,Cancer research ,business - Abstract
Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett’s esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.
- Published
- 2021