乳癌細胞之乳腺球群細胞與側群細胞之關聯性與抗藥性之探討

無論在全世界或台灣，乳癌都是造成癌症死亡的主因，也是女性最常見的癌症。乳癌細胞有很多種分類，若依據細胞雌激素受體(ER)、孕激素受體(PR)和人表皮生長因子受體2(HER-2)表現的不同，乳癌細胞可分為管狀A型(Luminal A)、管狀B型(Luminal B)、HER2過度表現型(HER2)、基底A型(Basal A)、基底B型(Basal B)，而不同類型的乳癌細胞有不同的生物特性與治療反應，也因為乳癌細胞的複雜性增加了乳癌治療的困難度。而化療是治療乳癌最常用的方式之一，但抗藥性和癌症復發是仍待解決的重要議題。根據癌幹細胞(cancer stem cell)假說，癌幹細胞是癌細胞中一小群具有幹細胞特性、癌症形成能力，且對化療藥較具抗藥性的細胞，而這可能是治療乳癌的關鍵。乳腺球群細胞(mammosphere)和側群細胞(side population)都被認為是乳癌幹細胞的指標，而我們發現側群細胞與乳腺球群細胞只表現在管狀型細胞。為了瞭解側群細胞與乳腺球群細胞之間的關係，我們測試側群細胞形成乳腺球群細胞之能力並且分析乳腺球群細胞中側群細胞的比例。結果發現，側群細胞比非側群細胞具有更高的乳腺球群細胞形成能力，且乳腺球群細胞比單層細胞具有更高的側群細胞比例，顯示出側群細胞中富含可形成乳腺球群細胞的細胞。我們研究乳癌細胞株（MCF7）的側群細胞特性，發現它比非側群細胞(non-side population)表現較高的ABC轉運蛋白(ABCG2)和幹細胞基因Notch-1,具較高的細胞簇(colony)形成能力，且對化療藥有較高的抗藥性，顯示出側群細胞確實具有癌幹細胞特性。此外，側群細胞的抗藥性會受到細胞外基質(extracellular matrix)影響而增高。由這些結果我們知道，乳腺球群細胞和側群細胞適用於管狀型乳癌幹細胞之辨識，且這兩群細胞可能是互相重疊的，若能針對這兩群細胞研究治療方法，就能增加管狀型乳癌細胞之治療效果。

關鍵字

癌幹細胞；側群細胞；乳腺球群細胞；抗藥性；管狀型乳癌細胞

並列摘要

Breast cancer is a leading cause of cancer-related death and is the most prevalent cancer among women worldwide, including Taiwan. There are many classifications of breast cancer cells. Based on the expressions of ER, PR, and HER2, breast cancer cells can be classified into Luminal A, Luminal B, HER2, Basal A, and Basal B subtypes. Because breast cancer is heterogeneous and complex that different types of breast cancer cells have different biological characteristics and respond differently to therapy, the treatment in breast cancer is challenging. Chemotherapy is one of the common therapeutic strategies in breast cancer, but drug resistance and recurrence are important issues to solve. According to the cancer stem cell hypothesis, cancer stem cells are a small population with stem cell-like properties, tumor-initiating ability, and more resistant to chemotherapy, and these may be critical in the treatment in breast cancer. Mammosphere and side population (SP) have been identified as candidates for breast cancer stem cells. We found that SP and mammosphere were more prevalent in the Luminal type than the Basal type breast cancer cells. To investigate the relationship between SP and mammosphere, we performed SP analysis on mammospheres and mammosphere formation assay on SP cells, and the results showed that mammospheres had higher SP expression than the monolayer cells. Furthermore, the SP had higher mammosphere formation ability than the NSP, suggesting that mammosphere-forming cells were enriched in SP cells. We investigated the characterizations of MCF7 SP cells, and we found they had higher ABCG2 and Notch-1 expressions, higher colony formation ability, and more resistant to chemotherapy than the non-side population (NSP), indicating that SP had cancer stem cell properties. Besides, the drug resistance of the SP could be increased on extracellular matrixes (ECMs). In conclusion, mammosphere and SP could identify the cancer stem cell population in Luminal type breast cancer cells, and these two populations might be overlapping. Therapeutic strategies targeting on these two populations may have significant effect on Luminal type breast cancer treatment.

並列關鍵字

cancer stem cell ； side population ； mammosphere ； drug resistance ； Luminal type breast cancer cell

參考文獻

Al-Hajj, M., M. S. Wicha, et al. (2003). "Prospective identification of tumorigenic breast cancer cells." Proc Natl Acad Sci U S A 100(7): 3983-3988.

Alvi, A. J., H. Clayton, et al. (2003). "Functional and molecular characterisation of mammary side population cells." Breast Cancer Res 5(1): R1-8.

Andre, F. and L. Pusztai (2006). "Molecular classification of breast cancer: implications for selection of adjuvant chemotherapy." Nat Clin Pract Oncol 3(11): 621-632.

Bhattacharya, S., A. Das, et al. (2007). "Maintenance of retinal stem cells by Abcg2 is regulated by notch signaling." J Cell Sci 120(Pt 15): 2652-2662.

Bleau, A. M., D. Hambardzumyan, et al. (2009). "PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells." Cell Stem Cell 4(3): 226-235.

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乳癌細胞之乳腺球群細胞與側群細胞之關聯性與抗藥性之探討

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