Identification of key factors to drive metastasis of progressive colorectal cancers: A search focusing transient players at early stage of metastasis

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K10555
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Toho University
• Principal Investigator: ARITA Michitsune 東邦大学, 医学部, 助教 (80307719)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: TrkB / EMAST / 大腸癌 / 低酸素

Outline of Final Research Achievements

In this study, we aimed to identify factors driving metastasis of colorectal cancers (CRCs) showing elevated microsatellite alterations at selected tetra-nucleotide repeats (EMAST), which is known to be a type of microsatellite instability and to correlate with poor prognosis of CRCs. At first, we planed to concentrate cells acquired metastatic ability in an EMAST-inducible culture condition achieved by hypoxia and TP53 inactive mutation. However, as the concentration has been failed, we focused to find genes which are significantly up- or down-regulated in the EMAST-inducible condition. As a result, we found tropomyosin receptor kinase B (TrkB), which has been known to be a poor prognostic marker of neuroblastoma. We revealed that TrkB also promoted hypoxic cell growth of CRC cell lines. Hypoxia is well known to be an environment for acquisition of metastatic ability of tumor cells. Taken together, TrkB might be indicated to play a role for CRC metastasis in hypoxia.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

近年、一部の免疫チェックポイント阻害薬が高頻度のマイクロサテライト不安定性（MSI-High）を示すがんに奏功することが示された。一方、進行性大腸癌においてはMSI-High癌は比較的予後良好とされ、むしろ、MSI-Highではない癌が問題となる。EMASTはマイクロサテライト不安定性の一形式であり、MSI-Highとは排他的な関係にある。しかも、大腸癌の予後と負に相関する。本研究では、EMASTを誘導する低酸素下で細胞増殖を担う分子としてTrkBを見いだした。期間内に達成できなかった手法の改善やTrkBの大腸癌悪性化における役割の解明を進めることで、社会に一層貢献できるものと考える。