Clinicopathological and molecular analyses of primitive phenotypic transformation in cancer development

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06983
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Ushiku Tetsuo 東京大学, 大学院医学系研究科(医学部), 教授 (60376415)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 胃癌 / 胎児形質 / 腫瘍免疫回避機構 / 分子標的

Outline of Final Research Achievements

We aims to clarify clinicopathological and molecular characteristics of "gastric adenocarcinoma with primitive phenotype", the most aggressive subtype of gastric cancer, including AFP-producing, hepatoid, and fetal gut-like adenocarcinoma. We identified several cancer-related genes and genes associated with immune evasion specifically upregulated in this subtype from gene expression databases of gastric cancer. Further, expression profiles of these genes were tested using immunohistochemistry for a large cohort of stomach cancer. We demonstrated that some of these genes was specifically upregulated in this subtype and inhibition of these genes reduced growth of AFP-producing gastric cancer cell lines. Additionally, AFP-producing gastric cancers exhibited the highest level of PD-L1 expression, loss of HLA-class I expression, and HLA-G expression. Our observations would contribute to develop therapeutic strategy for this aggressive cancer.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

胃癌の悪性度は様々であり、特に悪性度の高い胃癌の治療戦略を確立することが胃癌撲滅のために重要な課題である。本研究は「胎児形質胃癌」という最も悪性の高い胃癌の一群に注目し、治療標的候補や免疫回避機構を明らかにすることで、この胃癌に最も効果的な治療方法を確立することを目指して実施された。多数の胃癌組織を対象とした遺伝子発現解析等から、この胃癌で特異的に高発現している遺伝子群を発見、これらの阻害薬により胃癌細胞株の増殖が抑制された。また胎児形質胃癌は他の胃癌に比べてより多様な腫瘍免疫回避機構を獲得していることが分かり、治療戦略上重要な知見と考えられる。