以活體多參數磁振造影技術結合離體分析建立功能性評估神經膠質瘤之病程發展

神經膠質瘤（gliomas）是腦部常見的惡性腫瘤，即使經過治療，神經膠質瘤的病人仍有很差的預後。為更了解神經膠質瘤的病程發展以及治療後腫瘤生長情形，本論文致力於提出一個嶄新的觀察策略，以活體多參數磁振造影技術結合離體分析，建立功能性評估神經膠質瘤之病程發展。本論文中分為三個部分，分別就分子層面、細胞及其腫瘤生長環境，以及幹細胞治療療效之觀察，來展示此功能性評估策略之重要性與必要性。　　第一個部分利用骨橋素（osteopontin, OPN）作為標準分子，以活體多參數核磁共振造影技術結合離體分子與細胞分析方法，來綜合評估神經膠質瘤之生長情形。骨橋素是促進癌症共同特徵（the hallmarks of cancer）的關鍵因子，在細胞增生、血管新生以及腫瘤細胞之代謝上扮演重要角色。利用此綜合評估策略，可了解骨橋素和其他促進腫瘤生長的關鍵因子在神經膠質瘤病程發展上的重要性。第二部分，我們利用此功能性評估策略來觀察腫瘤生長環境如何影響神經膠質瘤的惡性程度，並進一步展示巨噬細胞的極化與分化是影響腫瘤惡性程度的重要因素。在腫瘤生長環境中，不同亞型的巨噬細胞將會影響該腫瘤的惡性程度，此發現將會對未來腫瘤標靶治療有所助益。由於傳統治療方法，如手術、放射線治療與化學療法等，對於神經膠質瘤並沒有顯著的治療效果，近年來，各種新興的療法不斷被研究者們所提出，因此，如何有效評估新興療法之成效是相當重要的議題。於本論文的第三部分，我們以核磁共振造影結合免疫組織染色，來觀察神經幹細胞療法對於神經膠質瘤生長的影響與變化，並評估此治療方法對於神經膠質瘤之療效。　　本論文中所提出的功能性評估策略，在多個層面上都展示了其應用性與重要性，結合活體核磁共振造影技術與離體分析方法，能提供更多資訊進一步了解神經膠質瘤之病程發展，並有效的評估新興療法之成效，對於未來治療發展能有所貢獻。

關鍵字

核磁共振造影；骨橋素；巨噬細胞；腫瘤生成；神經幹細胞療法

並列摘要

Gliomas are aggressive brain tumors with poor prognosis and remain refractory to treatment. The purpose of this dissertation is providing a novel approach combining in vivo multi-parametric magnetic resonance imaging (MRI) and immunohistochemistry, with the assistance of in vitro cell culture assessments, to monitor the pathogenic development of gliomas. Three inter-related studies are included in this dissertation. The first part is to use osteopontin (OPN) as a model molecule to establish functional assessment of glioma pathogenesis using multi-parametric MRI combined with in vitro analyses, which can be further applied to assess the functional roles of other driver genes in promoting cancer hallmarks related to proliferation, angiogenesis and altered metabolism. In the second study, the multi-parametric MRI methods were performed to demonstrate the role of host microenvironment in dictating the aggressiveness of gliomas, through differential programming of tumor-associated macrophages. We show that the differential polarization of glioma-associated macrophages (GAMs) into M1 or M2 subtypes in different host microenvironments is associated with aggressive phenotypes of gliomas, suggesting that macrophage programming plays an important role in glioma development and that targeting GAMs may serve as a promising therapeutic approach. The third part is to combine T2-weighted MRI and immunohistochemical analyses to evaluate the effects of targeted migration of neural stem/progenitor cells (NSPCs) on tumor development in N-ethyl-N-nitrosourea (ENU)-induced rat brain tumor model.

並列關鍵字

MRI ； OPN ； macrophage ； tumorigenesis ； stem cell therapy

參考文獻

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以活體多參數磁振造影技術結合離體分析建立功能性評估神經膠質瘤之病程發展

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