Mechanism how scirrhous-type gastric cancer is formed

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K06832
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Fukamachi Hiroshi 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (70134450)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: スキルス胃がん / がん幹細胞 / ｍTOR阻害剤 / 免疫チェックポイント阻害剤 / 初代培養 / PDX / 分子標的治療

Outline of Final Research Achievements

We established patient-derived xenograft (PDX) lines from diffuse-type gastric cancer (GC), and searched for drugs that suppressed their growth. We found that mechanistic target of rapamycin (mTOR) inhibitor strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells. Diffuse-type GCs could be classified into two clusters, and we found that genomically stable subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived cells were included. Further analysis showed that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells We estimated that about 9% and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively. We thus conclude that mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.

Free Research Field

分子腫瘍医学

Academic Significance and Societal Importance of the Research Achievements

本研究で我々は、mTOR阻害剤がスキルス胃がん幹細胞の増殖を特異的に抑制すること、スキルス胃がんの一部は分化型胃がんから派生し、多くの突然変異を持つことを明らかにした。これまで、スキルス胃がんは正常胃上皮細胞から形成され、突然変異は少ないと考えられてきた。突然変異が少ない腫瘍細胞は免疫チェックポイント阻害剤に反応しないので、スキルス胃がんの治療には免疫チェックポイント阻害剤は使われていない。我々の研究は、スキルス胃がんの一部は免疫チェックポイント阻害剤に反応性が高いことを示唆している。本研究で同定された薬剤が、スキルス胃がんの治療に著効を示すか否かは今後の検討課題である。