2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657789摘要：卵巢癌在婦女惡性腫瘤中是死亡率排名第一位的疾病。卵巢癌的發生率在最近十年逐年上升，卵巢癌在台灣地區婦女惡化腫瘤發生率排名為第九位的疾病。以上數據顯示卵巢癌實在是一個值得重視的疾病，但在國內僅有少數的卵巢癌研究。雖然積極的減積手術和化學治療藥品已被廣泛地使用，近二十法年來卵巢癌病人的總存活只有稍為地改變。治療卵巢癌的基本問題在於一旦它的散佈超過了卵巢，卵巢癌的控制及治療將相當的困難。超過百分之七十的卵巢癌病人在被診療時已是晚期。研究卵巢癌的形成、進展和其轉移的機制將有助於我們了解這個疾病和發展未來新的卵巢癌治療方針。在先期的研究結果中，我們已經成功分離出人類類卵巢癌幹細胞(human cancer stem cell-like cells)，並加以培養。這些類卵巢癌幹細胞具抑制化療藥物誘發細胞死亡的能力，並在小鼠中具有致腫瘤生長能力。接著我們再以微矩陣分析將類卵巢癌幹細胞與卵巢癌細胞進行基因表現差異，發現mesothelin在類卵巢癌幹細胞與母體細胞相比有6倍以上的表現。我們再進一步的將mesothelin轉殖後發現這些基因轉殖細胞會表現出較多量的側群細胞(side-population)。在臨床檢體中，我們也已經證實病患血清中mesothelin濃度與卵巢癌的形成、進展和其轉移具有高度的關聯性。在細胞實驗中我們也證明mesothelin的過度表現會降低化療藥物對癌細胞的毒殺效果。這些現象與類卵巢癌幹細胞的生物特性十分吻合。因此我們想進一步了解mesothelin的表現是否與類卵巢癌幹細胞的形成有關? 為了進一步探討mesothelin在類卵巢癌幹細胞的角色與功能機制，我們設計了這個三年的計畫來回答上述的問題。我們將探討包括：第一，mesothelin與類卵巢癌幹細胞的生成是否具關連性。第二，探討mesothelin影響類卵巢癌幹細胞的生物性特徵如抗藥性及促癌發生的可能作用機制。第三，利用動物的研究模式與臨床檢體確認在先前體外觀察到mesothelin影響類卵巢癌幹細胞的生物特性的現象，並且評估逆轉mesothelin卵巢癌幹細胞的生物性特的方法和機轉。本計畫在利用相關的分子生物指標及進一步釐清相關的基因影響癌症發生的作用機轉以及對mesothelin的生物功能特性作詳細的探討，並提供將來可能的標靶性治療模式與理論基礎。<br> Abstract: Ovarian cancer has the highest mortality rate of gynecologic malignancies. The incidence of ovarian cancer has increased over the past decade and it has become the ninth cause of malignancies of women in Taiwan. From the above-mentioned data, ovarian cancer indeed is a disease that should be respected; however, there were only few of research work focusing on it in Taiwan. Despite the widespread use of aggressive cytoreductive surgeries and the introduction of chemotherapy regimens, the overall survival has changed little over the last two decades. The basic problem in treating epithelial ovarian cancer is that once it has spread beyond the ovary, it is exceedingly difficult to control and ultimately to cure. More than 70% of ovarian cancer patients were advanced stage when diagnosed. To study the mechanisms of carcinogenesis, progression, and metastasis of ovarian cancer will help us understand this disease and develop new treatment strategies for ovarian cancer in the future.In preliminary results, we have successfully isolated and cultured human cancer stem-like cells. These human cancer stem-like cells could inhibit chemotherapeutic drugs inducing cell death while also inducing tumor growth in vivo. Besides, by microarray analysis, we have observed that mesothelin expression levels increased more than 6-fold in cancer stem-like cell compared with maternal cells. Furthermore, data from ectopic-expressed mesothelin demonstrated that these transfectants could express a higher portion of side-population cells. In clinical samples, we further confirmed the expression of mesothelin is highly correlated with ovarian cancer development, progression, and metastasis. We also demonstrated that over-expressed mesothelin could erase the chemotherapeutic agent induced cyto-killing effect. These phenomena are highly similar to the biological properties of cancer stem cells. So we would like to understand if there are any correlations between mesothelin expression and the formation of cancer stem cells. To investigate the role and function of mesothelin on ovarian cancer stem-like cells, we have proposed this three-year project to elucidate the following issues: First, we will investigate the correlation of mesothelin expression and ovarian cancer stem-like cell generations. Second, we will investigate the possible mechanisms of mesothelin in affecting ovarian cancer stem-like cells properties including drug-resistance and tumorigenesis. Third, we will utilize in vivo animal models and clinical samples to elucidate whether the in vitro phenomena between mesothelin and ovarian cancer stem-like cells can also be observed in vivo and to evaluate the methods and mechanisms to reverse the mesothelin-promoting cancer stem-like cell properties. The results will provide a molecular biomarker and further related genetic information to evaluate the possible mechanisms to classify ovarian cancer tumorigenesis. These results might also offer a novel target therapy strategy and theory in the future.Mesothelin卵巢癌旁側細胞Mesothelinovarian cancerside-population