Cross-talk between cancer cells and fibroblasts during cancer progression.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07118
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: Takino Takahisa 金沢大学, GS教育系, 教授 (40322119)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 細胞外マトリックス / 細胞外マトリックス分解酵素 / マトリックスメタロプロテアーゼ / がん浸潤 / がん転移 / 細胞運動 / がん微小環境 / 線維芽細胞

Outline of Final Research Achievements

In this study, we demonstrated that iron upregulates the expression of membrane type1-matrix metalloproteinase (MT1-MMP), which induces MMP-2 activation and invasion of cancer cells. Iron depletion downregulated MT1-MMP expression, resulting in the suppression of MMP-2 activation in cancer cells. On the other hand, iron loading upregulated MT1-MMP expression, which promoted MMP-2 activation. This promotion of MMP-2 activation was inhibited by knockdown of MT1-MMP with siRNA, and treatment with either MMP inhibitor or antioxidant (N-acetyl-L-cysteine), suggesting the involvement of MT1-MMP and reactive oxygen species in iron-mediated MMP-2 activation. Treatment of cancer cells with iron chelator deferasirox resulted in the suppression of cell invasion into collagen gel. Deferasirox is an oral iron chelator with a long half-life and well tolerated in clinical trials. Thus, it may be used as the new anti-metastatic drug and achieved significant effect in different cancers therapy.

Free Research Field

がん生物学

Academic Significance and Societal Importance of the Research Achievements

固形がん患者の多くは転移が原因で死亡する。鉄の細胞内流入増加と排出低下は、がんの発生率増加と臨床成績悪化に結びつく。鉄の排出ポンプの過剰発現は、MMP-2、MT1-MMPやIL-6の発現を低下させ子宮がんの腹膜播種を阻害する。これらの研究結果と一致して、本研究ではMT1-MMP発現、MT1-MMPを含む細胞外小胞の分泌と細胞運動の亢進、即ちがん細胞浸潤に細胞内鉄が必要であることを示した。一方、ヒト正常線維芽細胞における鉄は、MT1-MMPを介したMMP-2活性化に大きな影響を及ぼさなかった。鉄キレート剤は、がん細胞周囲の正常線維芽細胞に影響しない抗転移薬として期待される。