The Functional Requirement of the Chemokine Cxcl12-Cxcr4 Signaling in Glioma: Investigation Using a Murine Gene-Deficient Tumor Model.

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Project title/計畫英文名

Project Number/計畫編號

NSC101-2314-B002-037-MY2

Translated Name/計畫中文名

利用小鼠基因缺損之神經膠細胞瘤模式研究化學驅動激素Cxcl12-Cxcr4 訊息對神經膠細胞瘤之生物功能

Project Principal Investigator/計畫主持人

YONG-KWANG TU

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

賴達明

Start date/計畫起

01-08-2012

Expected Completion/計畫迄

12-07-2013

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。為了能達到「完全剔除」之目地，我們分離Cxcl12 與Cxcr4 基因剔除小鼠之神經膠質細胞，並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。目前已得到數個Cxcl12 及Cxcr4 基因剔除之星狀細胞瘤之細胞株。本計畫延續此成果，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，採用多種離體與活體之腫瘤生物學之實驗法，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。
Abstract: Glial cell tumor, or its malignant form, glioblastoma, is a highly notorious andtreatment-resistent 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/Sdf-1 and its receptor Cxcr4 and Cxcr7 play an important role inregulating glial cell tumor growth and migration pattern. Cxcl12 was found in glioblastomamultiforme, in the neurons and vascular endothelial cells around the leading edge of the tumor.The Cxcr4-bearing tumors seem to migrate along the Cxcl12 gradient. However, this findingis 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 the previous project wegenerated a homemade glioma cell lines derived from primary astrocytes of thegenetic-engineered mouse strain. We have successfully generated the Cxcr4-proficint,Cxcr4-deficient and Cxcl12-conditional knockout where the Cxcl12 ablation is inducible. Inthis successive project, we will perform several in vitro experimental approaches to explorethe differences between the wildtype glioma cells and those which lack Cxcl12 signaling. Invivo intracranial tumor model will be established to serve as a tumor angiogenesis andinvasion system. We will put emphasis on the change of angiogenesis and tumor progressionin a Cxcl12-deficient background and investigate the contribution of bone marrow-derivedcells. Our results will unravel the functional significance of Cxcl12 in tumor angiogenesis andinvasion and build a research foundation for future stem cell-based therapeutic studies.

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The Functional Requirement of the Chemokine Cxcl12-Cxcr4 Signaling in Glioma: Investigation Using a Murine Gene-Deficient Tumor Model.

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