Histological analysis of global DNA methylation in GISTs to overcome their imatinib resistance: integration of diagnostic pathology with GIST model mice towards the development of epigenetic therapy

2016 Fiscal Year Final Research Report

• Project/Area Number: 25460485
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hyogo Medical University
• Principal Investigator: MATSUDA Ikuo 兵庫医科大学, 医学部, 講師 (50335452)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: GIST / イマチニブ / 耐性 / エピゲノム / 5-メチルシトシン / 5-ヒドロキシメチルシトシン / PD-L1 / 血管内皮

Outline of Final Research Achievements

A tyrosine kinase inhibitor imatinib is known to be effective for gastrointestinal stromal tumors (GISTs), a hallmark of which is a constitutive activation of KIT tyrosine kinase by c-kit gene mutation. In order to overcome imatinib resistance in GISTs, imatinib-resistant GISTs were compared with imatinib-naive GISTs as follows in the present investigation. 5-hydroxymethylcytosine was immunohistochemically shown to be globally decreased in imatinib-resistant GISTs as well as in high-risk imatinib-naive GISTs, compared with low-risk imatinib-naive GISTs. On the other hand, in contrast to imatinib-naive GISTs, endothelial induction of PD-L1 was observed in both in and outside of imatinib-resistant GISTs. Imatinib-resistance of GISTs seems to be rather associated with endothelial expression of PD-L1 than global epigenetic change such as decrease in 5hmc. This may be a rational for PD-L1 therapy in order to overcome imatinib resistance of GISTs.

Free Research Field

病理診断学、分子生物学・生化学、臨床腫瘍学