2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/650751摘要：腦之星狀細胞瘤是一種生長快速且血管密度高的一種腦內腫瘤，由於其特性，病患之治療癒後率通常不佳。目前學界的研究顯示，化學激活素 Cxcl12 與腦癌細胞之浸潤有關，在腦癌周圍的神經血管細胞甚至腫瘤細胞本身常常增加 Cxcl12，而表現其受體Cxcr4 的腫瘤細胞則散佈在表現 Cxcl12 的細胞周圍，將兩種細胞共同培養會使腦癌細胞侵犯力增加，然而， Cxcl12 對於腫瘤侵犯度之必要性，學界目前也無直接証據。本實驗室利用 Cxcl12 條件型基因剔除小鼠，試圖進一步探討此課題。初步結果發現，Cxcl12 基因剔除鼠之腫瘤，其血管新生現象有減少的趨勢。週邊血中的血管前軀細胞也相對比正常的小鼠還要少；然而腫瘤生長並沒有明顯的差異，有可能是因為腫瘤本身分泌 Cxcl12。此計畫為了能達到「完全剔除」之目地，將由Cxcl12 與Cxcr4 基因剔除小鼠之神經膠質細胞利用培養與植入致癌基因使細胞癌化，以產出均質性、可在C57/BL6小鼠生長的腦癌，並利用腦腫瘤生長做為研究腫瘤血管新生與腫瘤浸潤的平台，觀察腫瘤生長與血管新生在Cxcl12 基因剔除小鼠上的變化，並且探討在Cxcl12 缺損狀態下，骨髓細胞移行的變化與最終對腫瘤血管新生的影響。本計畫將有助學界更進一步了解化學激活素在腫瘤移行浸潤血管新生的角色，並提供未來幹細胞臨床治療之研究基礎。<br> Abstract: Glial cell tumor, or its malignant form, glioblastoma, is a highly notorious andtreatment-resistant entity of adult brain tumor. The growth and metastasis of glial cell tumordepend on their interaction with the surrounding environment. It has been reported that thechemokine Cxcl12 and its receptor Cxcr4 and Cxcr7 play an important role in regulating glialcell tumor growth and migration pattern. Cxcl12 was found in glioblastoma multiforme, in theneurons and vascular endothelial cells around the leading edge of the tumor. TheCxcr4-bearing tumors seem to migrate along the Cxcl12 gradient. However, this finding isstill not been extensively studied and there is also lack of direct evidence whether Cxcl12 isrequired for this invasion process. We plan to investigate the requirement of Cxcl12 signalingaxis in glioma growth utilizing the gene targeting strategy. In our preliminary results, gliomacell line GL261, when implanted into Cxcl12-deficient mice brain, has less CD31+endothelium and recruits less CD11b-myeloid cells. The result reveals that Cxcl12-deficiencyin tumor environment might affect the tumor angiogenesis. To further delineate the impact ofloss of Cxcl12 or Cxcr4 in glioma cells, we will produce orthologous glioma tumor cellsdirectly from Cxcl12 conditional knockout and Cxcr4 knockout mice by oncogenictransformation of the primary astrocytes. Moreover, an intracranial tumor model will beestablished to serve as a tumor angiogenesis and invasion system. We will put emphasis onthe change of angiogenesis and tumor progression in a Cxcl12-deficient background andinvestigate the contribution of bone marrow-derived cells. Our results will unravel thefunctional significance of Cxcl12 in tumor angiogenesis and invasion and build a researchfoundation for future stem cell-based therapeutic studies.