Role of cancer associated fibroblast and extracellular matrices in the microenvironment of oral carcinoma

Research Project

Project/Area Number	16K11449
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Morphological basic dentistry
Research Institution	Nagasaki University
Principal Investigator	FUJITA Shuichi 長崎大学, 医歯薬学総合研究科(歯学系), 准教授 (00181355)
Research Collaborator	IKEDA Tohru SHIBATA Yasuaki NARUSE Tomofumi
Project Period (FY)	2016-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000) Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	口腔扁平上皮癌 / リンパ節転移 / 微小環境 / 細胞外基質 / 基質改変 / 免疫組織化学 / 扁平上皮癌 / リモデリング / LOX / MMP14 / S100A8 / TIMP1 / 多形腺腫由来癌 / 腺様嚢胞癌 / 粘表皮癌 / 多形腺腫 / LOXL2 / 口腔癌 / 癌関連線維芽細胞
Outline of Final Research Achievements	We studied immunohistochemical expression of LOX, MT1-MMP, S100A8 and TIMP-1, as regulators of extracellular matrix remodeling, in primary tumor and lymph nodes of oral squamous cell carcinoma patients. These factors were expressed not only in primary tumor cells but in stromal cells, such as cancer associated fibroblast, macrophage, dendritic cell and other inflammatory cells. The positive rates in tumor cells and/or stromal cells of LOX, MT1-MMP and TIMP-1 were correlated with lymphatic metastasis. The expressions of these factors are thought to useful to predict lymphatic metastasis. Marginal sinus histiocytosis (MSH) was more frequently observed in the lymph nodes of metastatic cases than metastasis-free cases. The rates of MSH containing macrophages positive for LOX and MT1-MMP in metastasis cases were significantly higher than in metastasis-free cases. These findings suggested LOX and MT1-MMP participate to construct the suitable microenvironment for colonization of SCC cells.
Academic Significance and Societal Importance of the Research Achievements	本研究は口腔扁平上皮癌のリンパ節転移は原発部位での細胞外基質の改変と相関性があることを示している。従って、リンパ節転移のない段階での生検材料を用いて、LOX, MT1-MMP, TIMP-1の発現を検査することによって、将来、転移するリスクが予想できる。また、転移にはリンパ節の周辺洞での細胞外基質の改変が関連していることが示唆されたことから、周辺洞でのマクロファージのLOXやMT1-MMPの発現を抑制したり、LOXやMT1-MMP陽性のマクロファージの流入を減少させることでリンパ節転移を予防できることが考えられる。