黑色素細胞瘤在皮膚癌中是最惡性的並且對於現有的臨床治療幾乎都產生抗性。化療藥物順鉑已是黑色素細胞瘤的第一線化療藥物之一，然而，黑色素細胞瘤對順鉑產生抗藥性原因仍然不清楚。在我們的研究中，我們發現順鉑會引起B16-F10黑色素細胞瘤的細胞型狀改變，而這改變與抗藥性和腫瘤幹細胞有密切關聯。我們發現順鉑會導致巨大細胞形成，巨大細胞的特徵包含細胞表面積增加和細胞核增大，這樣的變化是有劑量效應的。藉由共軛焦顯微鏡的觀察我們發現巨大細胞會變薄並且活動力下降。更重要的是: 黑色素細胞瘤的惡性指標S100在腫瘤檢體中的巨大細胞也表現得更多。腫瘤檢體和細胞培養都顯示巨大細胞不但具有增生的能力並且也表現抗藥性蛋白及腫瘤幹細胞標記。此外，藉由粒線體染劑和粒線體膜電位偵測方法，發現巨大細胞的粒線體有增生的現象，粒線體的膜電位較高並製造更多能量。這樣的結果顯示巨大細胞對能量的需求多於一般細胞。總結而言，我們的研究指出黑色素細胞瘤會改變它的型態來應付化療藥物順鉑。巨大細胞也會表現腫瘤幹細胞標記，這或許可以應用在病理檢驗上。最後，以抑制能量方式著手對付這些惡性並且需求較多能量的巨大細胞或許可以為治療黑色素細胞瘤提供更有效的治療。

Melanoma, which is the most aggressive form of skin cancer, is notoriously resistant to current cancer therapies. Cisplatin is a first-line chemotherapy drug for melanoma. However, the chemoresistance mechanism of melanoma cells to cisplatin therapy remains unclear. In this study, we investigated the morphological changes that are mediated by cisplatin in B16-F10 melanoma cells and the relationship between these changes and chemoresistances/cancer stemness. We observed that cisplatin enhanced the formation of giant cells, which exhibit increased cell surface and nuclear areas. Through confocal laser-scanning microscopy, we found that the giant cells exhibited reduced cell thickness and motilities. More importantly, the formation of melanocytic malignancy maker S100-positive giant cells was also found in cisplatin-treated melanoma in vivo. Expression analyses revealed that the giant cells were positive for the proliferation marker Ki-67 and expressed the melanoma stem cell markers ABCB5 and CD133 in vitro and in vivo. Through mitochondria tracking and JC-1 staining, we showed that the cisplatin-induced giant cells exhibit elevated mitochondria genesis and activities and increased levels of ATP synthesis. These results indicate the high energy demand of these giant cells. In summary, this study presents a novel cellular event that melanoma cells enlarge their cell size in response to cisplatin. Furthermore, these giant cells exhibit molecular markers and functions of cancer stem cells, which may be useful for the histopathologic examination of cancer stem cells. Finally, the targeting at the metabolic demand of giant cells may facilitate a novel anti-neoplastic strategy against melanoma.

Chapter 1 Cisplatin Induces the Giant Cells Formation in Melanoma Cells in vitro and in vivo
1-1 Introduction 1
1-2 Materials and Methods 9
1-3 Results 18
1-4 Discussion 33
1-5 Figures and Legends 38

Chapter 2 The Mechanisms Involved in Regulation of Cancer Stemness of the Giant Cells
2-1 Introduction 90
2-2 Materials and Methods 94
2-3 Results 97
2-4 Discussion 100
2-5 Figures and Legends 103

Chapter 3 Down regulation of PGC-1α by Short Hairpin
RNA-mediated Silencing attenuates the Tumorigenesity of
B16 Melanoma Cells
3-1 Introduction 111
3-2 Materials and Methods 114
3-3 Results 117
3-4 Discussion 120
3-5 Figures and Legends 123

Chapter 4 References
References 131

Chapter 5 Publications
Publications 141

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