1: Wnt Signaling Shapes the Histologic Variation in Diffuse Gastric Cancer

Gastroenterology

November 2020, DOI: 10.1053/j.gastro.2020.10.047

Kazuhiro Togasaki, Shinya Sugimoto, Yuki Ohta, Kosaku Nanki, Mami Matano, Sirirat Takahashi, Masayuki Fujii, Takanori Kanai, Toshiro Sato

Diffuse gastric cancer, a particularly malignant type of stomach cancer, is often composed of two components: signet ring cell carcinoma and poorly differentiated adenocarcinoma. However, the mechanism by which it presents with this histological appearance, consisting of multiple cell types, was unknown. In this study, we cultured cells from patients with diffuse gastric cancer ex vivo using organoid culture technology. We demonstrated that the cells morphologically change from poorly differentiated adenocarcinoma to signet ring cell carcinoma depending on the presence or absence of Wnt and R-spondin in the culture medium, and that this is also reproduced in xenograft tissues depending on the distance from fibroblasts. Furthermore, using gene-editing technology, we successfully reproduced signet ring cell carcinoma by introducing the E-cadherin gene abnormality characteristic of diffuse gastric cancer into normal gastric cells and adjusting the culture medium. This is the first study to reveal how signet ring cell carcinoma is formed in response to genetic mutations and the tumor microenvironment. It is expected to be a new breakthrough for treatments aiming for a complete cure of gastric cancer by targeting specific cells.

(Toshiro Sato, Class of '76, The Sakaguchi Laboratory [Organoid Medicine]; Kazuhiro Togasaki, Class of '93)

Journal of Hepatology .

2021; 74 (3): 511-521. doi: 10.1016/j.jhep.2020.09.033.

Rei Morikawa, Nobuhiro Nakamoto, Takeru Amiya, Po-Sung Chu, Yuzo Koda, Toshiaki Teratani, Takahiro Suzuki, Yutaka Kurebayashi, Akihisa Ueno, Nobuhito Taniki, Kentaro Miyamoto, Akihiro Yamaguchi, Shunsuke Shiba, Tadashi Katayama, Kosuke Yoshida, Yoshiaki Takada, Rino Ishihara, Hirotoshi Ebinuma, Michiie Sakamoto, Takanori Kanai

Due to lifestyle changes, the number of patients with non-alcoholic steatohepatitis (NASH) is on the rise, with some cases progressing to liver cirrhosis or hepatocellular carcinoma. The detailed mechanisms of NASH pathogenesis have not been fully elucidated, and there are currently few effective therapeutic drugs. In recent years, the involvement of the immune system in its pathogenesis has been reported, and it is anticipated as a new therapeutic target. This study revealed for the first time that the chemokine receptor CCR9 and its ligand CCL25 are directly involved in liver fibrosis and NASH-associated hepatocarcinogenesis. Analysis of samples from 65 NASH patients and model mice revealed that CCR9 is highly expressed in liver macrophages and stellate cells, and that CCR9 deficiency suppresses liver fibrosis and carcinogenesis. Furthermore, it was demonstrated that the administration of a CCR9 antagonist suppresses the progression from fatty liver to NASH, suggesting a new potential therapeutic application (Figure). It is expected that the further development of this research will lead to the creation of new biomarkers and novel treatments for NASH.

(Nobuhiro Nakamoto, Class of '77, Division of Gastroenterology, Department of Internal Medicine)