神經膠質瘤 (Glioma) 是最常見也是最惡性的原發性中樞神經系 統腫瘤,其強大的侵襲性使其在臨床上 90%-95% 的患者在發現罹患 此疾病後平均存活率僅兩年[1],而該腫瘤強大的侵襲力與腫瘤血管 新生能力、腫瘤相關巨噬細胞及腫瘤缺氧區分佈有密切關係。研究指 出腫瘤所分泌的血管新生相關基因 sdf-1 會影響腫瘤生長速率並改 變腫瘤的侵襲能力[2, 3]。本研究以小鼠星狀細胞 (ALTS1C1) 作為研 究的模型,過表達 sdf-1 基因來探討其對腫瘤微環境的影響。首先, 利用 liposome 轉殖 DNA 的方式建立 ALTS1C1-SDF-1 細胞株。觀 察 SDF-1 對細胞分裂與增生能力的影響,再以組織免疫染色法探討 腫瘤微血管密度、巨噬細胞及缺氧區域的病理狀態,最後藉由流式細 胞儀分析腫瘤相關巨噬細胞 (TAMs) 與微膠細胞 (Microglia) 在腫 瘤生長各時期的比例分佈。實驗結果發現新建立的 ALTS1C1-SDF-1 腦腫瘤模式小鼠最短生存天數僅 21 天,相較於 ALTS1C1 腫瘤小數 平均存活天數(29天)大幅的縮短,且 ALTS1C1-SDF-1 腫瘤具備許多 臨床上高度侵襲性的腦腫瘤特性,包括表現量較高的腫瘤血管密度、 分佈密集的腫瘤相關巨噬細胞和較低的缺氧區;從不同時期的腫瘤相 關巨噬細胞比例分佈結果再次証實 Sdf-1 的分泌會增加腫瘤內巨噬 細胞的分佈數量。本論文研究提供了一個俱有高度侵襲能力的臨床腦 腫瘤小鼠模式,可以用來研發設計腦腫瘤治療的新策略。

Gliomas are the most common primary neoplasms of the central nervous system (CNS) in adults. The powerful tumor invasiveness is
closely related to tumor angiogenesis, tumor-associated macrophages and hypoxia. Studies indicate that stroma-derived factor -1 (SDF-1), one of tumors-secreted angiogenesis-related factors, affects tumor growth rate and tumor invasion capability. In this study, we used mouse astrocytoma cells, ALTS1C1, as a research model to over-express sdf-1 gene in order to establish an invasive tumor model and study the tumor microenvironments of an invasive astrocytoma. Firstly, the ALTS1C1-SDF-1 cell line was established by using transgenic DNA liposome method. Secondly, the relationship between SDF-1 and tumor cell migration, proliferation, tumor microvessel density, or tumor -associated macrophages was studied by immunohistochemical (IHC) apprach. Finally, the relative change of microglia and macrophage during tumor progression was examined by flow cytometery. This study has successfully established an invasive brain tumor model and provided evidences to demonstrate that SDF-1 acts as a chemoattractant or survival factor for TAM tropism toward hypoxic tumor region. This brain tumor model serves an important tumor model for the design of new treatment protocol against the invasive glioma.

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