Investigation on the endothelial-mesenchymal transition in lymphangioleiomyomatosis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09589
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Juntendo University
• Principal Investigator: Seyama Kuniaki 順天堂大学, 医学部, 先任准教授 (10226681)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: リンパ脈管筋腫症 / リンパ管内皮細胞 / 内皮間葉転換 / 内皮細胞増殖因子 / TSC遺伝子 / リンパ管新生 / フローサイトメトリー

Outline of Final Research Achievements

Since two types of LAM cells, cells with TSC2 mutations and those with wild-type TSC2, are known to exist in LAM lesions, we hypothesized that LAM cells with wild-type TSC2 might be derived from LAM-associated lymphatic endothelial cells (LAM-LEC) through endothelial-mesenchymal transition (EndoMT). To elucidate the pathobiology of LAM with special reference to the cell-cell interaction between LAM cells and LAM-LEC, we isolated LAM-LEC using flow cytometry-based method from explanted LAM lungs and resected LAM lung tissues by surgery. We investigated whether EndoMT can be induced in LAM-LEC by adding VEGF-D, TGF-beta;, GPNMB, or fibronectin in vitro culture system, but no EndoMT occurred. On the other hand, LAM-LEC showed distinct characteristics as compared normal lung LEC, suggesting phenotypic changes through interaction with LAM cells; LAM-LEC showed increased proliferation and migration with increased VEGFR-3 as compared with those of normal lung LEC.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

LAM病巣は、病理組織学的にはLAM細胞とリンパ管内皮細胞（LEC）の増殖により特徴付けられるが、LAM病巣中のLECには疾患に応じた機能的変化（フェノタイプの変化）を認めた。従って癌細胞と癌関連線維芽細胞との関係に類似した病態があり、両細胞の機能連関が病態形成や疾患進行に意義を持つことが示唆される。両者の機能連関のメカニズムを解明することは新規治療戦略の開発につながる可能性がある。