臺灣博碩士論文加值系統

當一乳癌患者被鑑定為缺乏ER (estrogen receptor) 、 PR (progesterone receptor)及HER2蛋白時，即稱為三陰性乳癌(triple-negative breast carcinomas)。三陰性乳癌具有相當高機會復發、復發時間較早、一旦復發後治療工作相當困難等特性。
在本研究中，我們將三陰性乳癌病人的檢體組織區分為tumor burden zones、distal normal zones及介於兩區域中間的interface zones，並且自這三區中分離出纖維母細胞，分別命名為cancer-associated fibroblasts (CAFs)、normal zone fibroblasts (NFs)及interface zone fibroblasts (INFs) ，我們發現INFs相較於NFs和CAFs具有較快的生長速度。我們接著透過體外共同培養模式，研究不同部位的纖維母細胞與三陰性乳癌細胞株的分子訊息交互作用，我們發現， INFs最能有效地誘發乳癌細胞株從上皮細胞形態轉變成間質細胞形態，並且，INFs也能誘導乳癌細胞株vimentin的表現量增加及促進癌細胞移行的能力。這個發現闡明了INFs相較於NFs及CAFs，具有特別的生化調控意義，這項研究說明了INFs是一個具有複雜分子交互作用的區域，因此這些分子誘發了細胞內多條訊號傳遞路徑表現的結果使得癌症更加地惡化。
然而，我們的研究發現大黃素(emodin)抑制INFs所誘發的上皮細胞轉變成間質細胞的過程，大黃素抑制INFs誘發乳癌上皮細胞株形態的改變，增加E-cadherin的表現量及降低vimentin的表現量。此外，在細胞傷口癒合分析上發現，大黃素可抑制由INFs誘發乳癌細胞株的移行能力。

“Triple negative breast cancer” (TNBC) is defined as breast cancer which lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 proteins. TNBC is associated with a higher risk of distant recurrence, earlier time to recurrence, and worse prognosis after recurrence.
Fibroblasts were extracted from tissue in tumor burden zones, distal normal zones and interface zones between tumor and normal tissue of TNBC, and the corresponding fibroblasts were designated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). We found that INFs grow faster and expressed higher levels of vimentin than NFs and CAFs .The crosstalk between three types of fibroblasts and breast cancer cells was evaluated using an in vitro direct co-culture model. Compared with CAFs and NFs, INFs grown with breast cancer cells were significantly effective in inducing an epithelial-mesenchymal transition (EMT) in cancer cells, as indicated by induction of vimentin. Additionally, INFs promoted breast cell migration to a larger extent compared with NFs and CAFs. Taken together, these findings indicated that INFs isolated from the TNBC interface zone exhibits more robust biological modulatory activity than NFs and CAFs isolated from normal and tumor zones of the same tumor tissue, suggesting that the interface zone of the tumor represents a dynamic region vital to tumor progression.
Moreover, our results found that emodin inhibited epithelial-mesenchymal transition induced by INFs. Emodin would reverse INFs-induced morphological changes, up-regulated the expression of E-cadherin and down-regulated the expression of vimentin. Moreover, wound-healing and in vitro invasion assay showed that emodin could inhibit INFs-induced migration and invasion of TNBC cells.

第一章 緒論………………………………………………………………1
第一節、惡性腫瘤…………………………………………………………1
1.2.1、細胞轉形及起始階段(Transformation and initiation)…………..5
1.2.2、腫瘤生長階段(Neoplastic growth)……………………………..6
1.2.3、血管增生階段(Angiogenesis)………………………………….8
1.2.4、癌細胞侵犯階段(Invasion)…………………………………….9
1.2.4.1、細胞的延展作用(Extension of directed protrusion)…………11
1.2.4.2、細胞的錨定作用(anchoring of protrusions to the substrate or the ECM)……………………………………...11
1.2.4.3、actomyosin filament的鏈結階段……………………………11
1.2.4.4、最終階段……………………………………………………..12
第二節、乳癌(Human breast cancer cell carcinoma)……………………14
第三節、臨床上乳癌類型(breast cancer subtype)及治療方式
(breast cancer treatment)之介紹…………………………………………19
第四節、腫瘤微環境(tumor microenvironment)………………………23
1.4.1、內皮細胞(Endothelial cells)……………………………….24
1.4.2、基質組織(Stromal tissue)………………………………….25
1.4.2.1、基質細胞(Stromal cells)………………………………25
1.4.2.2、肌上皮細胞(Myoepithelial cells)…………………….27
1.4.2.3、癌症相關巨噬細胞(Tumor associated macrophages)…27
1.4.2.4、嗜中性白血球(neutrophils)……………………………28
1.4.2.5、脂肪細胞(adipocyte)…………………………………..28
1.4.3、細胞外基質(Extracellular matrix)……………………………29
第五節、癌症相關纖維母細胞(Cancer-associated fibroblasts;CAFs)…31
1.5.5.1、SDF-1……………………………………………………33
1.5.5.2、VEGF-A(VEGF)………………………………………...34
1.5.5.3、HGF……………………………………………………...34
1.5.5.4、TGF-β…………………………………………………….34
1.5.5.5、MMPs……………………………………………………..35
1.5.5.6、SDC-1……………………………………………………..36
第六節、上皮細胞轉換成間質細胞(epithelial-mesenchymal transition)…38第七節、大黃素(emodin)…………………………………………………41
第八節、研究動機…………………………………………………………43
第九節、實驗設計…………………………………………………………45
第二章、材料與方法………………………………………………………46
2.1 實驗材料………………………………………………………………46
2.2 儀器設備………………………………………………………………48
實驗方法……………………………………………………………………50
2.3 細胞培養………………………………………………………………50
2.4 細胞的活化……………………………………………………………51
2.5 檢體細胞初代培養……………………………………………………52
2.6 細胞增生速率分析(cell proliferation assay)…………………………53
2.7 纖維母細胞指定時間點指定細胞培養液的收集(conditional medium collection)…………………………………………………………………54
2.8 細胞形態觀察(morphology observation)……………………………55
2.9 西方墨點法分析(Western blot)………………………………………55
2.9.1 蛋白質的萃取(protein extraction)…………………………………56
2.9.2蛋白質濃度測定(protein quantification) ……………………………56
2.9.3蛋白質之電泳分析(protein electrophoresis) …………………………57
2.9.4 轉漬與影像呈現(protein transferring and fujifilming) ……………58
2.10 免疫螢光染色分析(Immunofluorescence Assay)…………………59
2.11細胞刮痕癒合能力分析(Cell wound healing Assay)………………61
2.12 蘇木紫與伊紅染色法(H&E staining)……………………………62
2.13 大黃素抑制細胞轉形成間質細胞之形態實驗……………………62
2.14 大黃素抑制細胞轉形成間質細胞之西方轉漬法實驗……………63
第三章、結果………………………………………………………………65
3.1 探討自臨床檢體組織分離之纖維母細胞之特性研究………………68
3.2 探討來自不同區域的三陰性乳癌纖維母細胞是否能促進三陰性乳癌細胞株發生上皮細胞與間質細胞轉換……………………………………72
3.2.1 探討在共培養模式下，來自於不同區域的三陰性乳癌纖維母細胞是否能促進三陰性乳癌細胞株轉形成間質細胞並且vimentin表現量上升………75
3.2.2 探討在共培養的模式下，來自不同區域的三陰性乳癌纖維母細胞是否能促進三陰性乳癌細胞爬行能力…………………………………77
3.3.探討大黃素(emodin)是否能夠抑制由INFs及CAFs所誘發的三陰性乳癌轉形成間質細胞形態…………………………………………………82
第四章、討論(Discussion)………………………………………………83
第五章、結論(Conclusion)………………………………………………87
第六章、參考文獻(Reference)…………………………………………89

1.圖一、行政院衛生署-台灣地區民國99年及100年國人十大死亡原因統計圖
2.圖二、行政院衛生署-台灣地區民國99年及100年主要癌症死亡人數占率
3.圖六、行政院衛生署-台灣地區民國99年v.s民國100年主要癌症死亡人數占率
4.表一、行政院衛生署-台灣地區民國100年國人十大死亡原因標準化死亡率統計圖
5.表二、行政院衛生署-全國女性主要癌症死亡原因
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