乳癌癌細胞轉移與抗藥性產生之探討

The Study for the Mechanism of Drug Resistance in Breast Cancer Metastasis

張嘉裕(Chia-Yu Chang)

指導教授 ： 林泰元

國立臺灣大學/醫學院/藥理學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.01071

摘要

根據衛生署統計資料，乳癌為國人女性第二好發癌症，而且是癌症死因的第四位，可見乳癌威脅女性健康愈趨嚴重。對大多數乳癌病人來說，乳癌轉移造成的威脅是最大的，多數乳癌病患是死於乳癌轉移，而化療常用於治療乳癌轉移的病患，而癌症細胞對抗癌藥產生抗藥性通常會造成化療上的失敗。在最近報告指出，癌幹細胞(cancer stem cell)與癌症轉移以及癌症細胞抗藥性產生有很大的關係。我們想了解癌幹細胞在癌症轉移中抗藥性產生的情形，推測癌幹細胞在轉移中，受到轉移部位環境的影響進而產生抗藥性。我們利用乳腺球細胞(mammosphere)的培養方法篩選出一群癌幹細胞，將這群癌幹細胞培養在不同細胞外基質(extracellular matrix)，探討不同細胞外基質對癌幹細胞抗藥性產生的影響。在我們的結果發現，癌細胞在乳腺球細胞的形成過程中，會發生上皮-間質轉化(epithelial-mesenchymal transition)，也看到integrin α6, β1, β4表現的改變。乳腺球細胞對不同的細胞外間質的貼附能力是不同的，乳腺球細胞傾向貼附於膠原蛋白(collagen)和纖維蛋白(fibronectin)，而不貼附於層粘蛋白(laminin)。而當乳腺球細胞貼附在膠原蛋白，這群乳腺球細胞會對常用於乳癌治療上的抗癌藥，像是epirubicin, doxorubicin, paclitaxel, etoposide，有抗藥性的產生。而必須更進一步去了解細胞外間質對癌細胞抗藥性產生的詳細機轉，以解決臨床上化療失敗的問題及可能提供新的癌症治療方向。

關鍵字

癌幹細胞 ； 上皮-間質轉化 ； 細胞外間質 ； 抗藥性

並列摘要

Breast cancer is the second most common type cancer in women in Taiwan, and the fourth most common cause of cancer death. Most breast cancer patients die from tumor metastasis rather than from their primary tumors. In clinical, chemotherapy is usually given to treat breast cancer metastasis. Chemotherapy often fails to cure metastatic breast cancer due to drug resistance. In previous studies, cancer stem cells were involved in tumor metastasis and drug resistance. We hypothesize that microenvironment of metastatic sites, such like extracellular matrix may induce drug resistance of breast cancer stem cells. We isolated breast cancer stem cells by forming of mammosphere, and found the existence of epithelial-mesenchymal transition during mammosphere formation. We also observed that the expression of integrin α6, β1, β4 change during mammosphere formation. Mammospheres show different adhesion ability with various extracellular matrixes. Breast cancer stem cells favor to adhere on collagen type I, III, IV and fibronectin. Furthermore, adhesion of mammospheres to different collagen types enhanced drug resistance of epirubicin, doxorubicin, paclitaxel, etoposide. To further investigate the detailed mechanism of extracellular matrix-induced drug resistance on breast cancer stem cells is essential to solve the problem of chemotherapy fail in clinical and provide a new therapy target in breast metastatic tumor treatment.

並列關鍵字

cancer stem cell ； epithelial-mesenchymal transition ； integrin ； extracellular matrix ； drug resistance

參考文獻

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