2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/656765摘要：目前認為惡性腫瘤的細胞族群是由一群不同的細胞所組成，可藉由不同的細胞表面標記與在小鼠上的腫瘤形成能力來加以區分，其中有一小群細胞稱做癌症幹細胞 (cancer stem cells)，具有和一般幹細胞相似的特性，亦即可以自我更新並且可能分化為不同的細胞。以往認為癌症幹細胞 (CSC) 和癌症的初始發生與細胞增生有關，且在許多癌細胞都證實，癌症幹細胞也和抗藥性息息相關。由於黑色素細胞癌是目前人類最惡性的癌症之一，它極易轉移，又對現有大部分的化學治療藥物都有抗性，因此迄今仍無極有效的化學治療藥物。近幾年來的研究顯示，人類的黑色素細胞癌具有類似幹細胞的少數特定族群，這些細胞又被稱為惡性黑色素細胞癌初始細胞 (malignant-melanoma-initiating cell, MMIC) 或惡性黑色素細胞癌幹細胞 (malignant melanoma stem cell, MMSC)，已被證實和黑色素細胞癌的初始發生、降低免疫反應、化療抗藥性有關。然而，目前我們對於癌症幹細胞在黑色素細胞癌轉移過程中所扮演的角色卻不甚了解，特別是有關癌症幹細胞與微環境因子的交互作用對癌細胞轉移的影響。我們的初步研究顯示，在A2058、A375、MeWo等三株人類黑色素癌細胞中，A2058較能培養出腫瘤球細胞，而且這些由A2058細胞所篩選出的腫瘤球具有較高表現的CD133+，同時也有較高的趨化激素受體CXCR4表現量；此外，我們也發現病患新鮮腫瘤組織中，大約有3.5%的CD133+細胞。本研究的目的，便是想藉由目前已知的篩選癌症幹細胞方法，篩選出細胞株或病患腫瘤檢體中的黑色素細胞癌幹細胞，進行以下研究:1. 第一年：探討各種黑色素細胞癌幹細胞是否有較強的侵襲、移動與轉移能力。2. 第二年：探討調控黑色素細胞癌幹細胞轉移的機轉，特別是已知重要因素CXCR4在其中所扮演的角色。3. 第三年：探討微環境因子調控色素細胞癌幹細胞轉移的分子機制。期望藉由本研究，能使我們對於癌症幹細胞在黑色素細胞癌轉移過程中所扮演的角色與其分子調控機制，有更多的了解，並由此開發出針對黑色素細胞癌早期轉移加以抑制的嶄新治療策略。<br> Abstract: Cancers are frequently composed of heterogeneous cell populations with differential expression of cell surface markers and different ability to propagate tumors in mouse models. Only rare cell populations within a heterogeneous tumor are capable of tumor propagation. These tumorigenic cell subsets, known as cancer stem cells (CSC), are thought to be responsible for generating and maintaining tumor heterogeneity. Evidence has emerged that CSCs represent a subpopulation of cells within cancers that is characterized by increased resistance to chemotherapy.Melanoma is the most aggressive cancer in humans, with a propensity to metastasize, and is resistant to most of the current therapeutic regimens. Recent findings of melanoma subsets with embryonic-like differentiation plasticity and increased tumorigenic potential suggest the existence of malignant-melanoma-initiating cell (MMIC) or malignant melanoma stem cell (MMSC), which may contribute to the initiation, impaired immune response and therapeutic failure in melanoma. However, only very few studies investigated the roles of MMSCs in melanoma metastasis, especially the interactions between CSCs and micro-environmental factors. Our preliminary data showed that among A2058, A375, and MeWo cells, only A2058 cells have higher spheroid-forming potential. Furthermore, these A2058 spheroid cells have higher expression of CD133 surface marker and also higher expression of CXCR4, indicating these cells may have higher metastasis ability. In addition, we also successfully identified about 3.5% of CD133+ cells within freshly isolated melanoma cells from patients. In this study, we will isolate various types of MMSCs from melanoma cell lines or fresh melanoma specimens excised from patients. The specific aims of this project are:1. In the 1st year, we will examine whether MMSCs have higher potential in invasion, migration and metastasis or not.2. In the 2nd year, we will investigate the mechanisms involved in regulating invasion, migration and metastasis of MMSCs, especially the roles of CXCR4.3. In the 3rd year, we will study the molecular mechanisms involved in microenvironmental regulation of CXCR4 expression and metastasis of MMSCs.The results of this project will provide us a better understanding about the roles and molecular regulation of MMSCs in melanoma metastasis, and will also contribute insight into novel therapeutic strategy to inhibit MMSC metastasis and improve therapy for melanoma.癌症幹細胞趨化激素受體CXCR4黑色素細胞癌轉移Cancer stem cellsCXCR4MelanomaMetastasis