臺灣博碩士論文加值系統

中文摘要
子宮頸癌是國人婦女惡性腫瘤發生率排名第一位的疾病。子宮頸癌的治療在第一期及第二期初以手術治療為主，雖然其治療已有不錯的成果，仍有百分之二十的婦女因此病而復發進而死亡。關於子宮頸癌的預後及轉移研究為數雖多，但主要在探討子宮頸腫瘤細胞本身的生物特徵。本研究嘗試由腫瘤血管新生及其生長因子之角度切入，以能量都卜勒超音波經體內的觀察，提供腫瘤血管新生可以作為疾病嚴重度和轉移的預測指標。進一步闡述能量都卜勒超音波在組織學與細胞生物學上的基礎，也發現血管內皮細胞生長因子可以作為子宮頸癌病人術後復發的重要指標。最後更研究血管內皮細胞生長因子，除了促進血管內皮細胞分裂之外，也有抗細胞凋亡之功能。這些發現為子宮頸癌的分子生物學研究及其臨床治療，提供了一個重要的方向。
首先我們在104及35位接受手術的子宮頸癌病人，發現彩色都卜勒超音波測得的血流訊號和腫瘤血管新生具有關聯。雖然彩色都卜勒超音波測得的腫瘤內動脈血管阻力係數無法作為量化子宮頸癌血管新生的指標，但有無可測得的腫瘤內動脈血管阻力係數可作為子宮旁組織侵犯和骨盆腔淋巴結轉移的排除篩檢工具。以能量都卜勒超音波測得的腫瘤內血管係數則可作為量化子宮頸癌腫瘤血管新生的指標。
接著我們發現在90位接受手術的子宮頸癌病人，其疾病的嚴重度和轉移的能力可以利用血管係數、顯微血管密度和細胞質中內皮細胞生長因子濃度反應出來。此外經能量都卜勒超音波測得的血管係數具有其在組織學上及細胞生物學上的基礎，因為以Sperman相關分析顯示血管係數、顯微許管密度和細胞質中內皮細胞生長因子濃度分別呈現正相關性。當腫瘤內血管係數 >12時必須高度懷疑子宮頸癌病人有淋巴結轉移的可能性，放射線治療可能比手術治療對這些病人要來得適當。
為了瞭解血管內皮細胞生長因子在子宮頸癌所扮演的角色，我們收集了135例具有完整臨床追蹤資料且經手術切除其子宮頸癌的病人。其中位數追蹤時間為27.0個月。子宮頸癌腫瘤組織比正常子宮頸組織有明顯地較高的細胞質中血管內皮細胞生長因子濃度(154.0 versus 0.0 pg /mg protein, P<0.001)。當以多變項危險模式分析時，只有過量表達血管內皮細胞生長因子(危險比例9.92, P=0.001)仍然是統計上獨立的危險因子。病人有過量表達細胞質中血管內皮細胞生長因子蛋白質濃度者有顯著地較差的無病存活期間(log-rank-test, P=0.004)。子宮頸癌腫瘤內細胞質中血管內皮細胞生長因子的濃度高低不但可以反應出子宮頸癌的嚴重性，也是子宮頸癌病人預後的危險因子。
血管內皮細胞生長因子除了促進內皮細胞細胞分裂之外，是否還有其他的功能呢? 利用臍靜脈血管內皮細胞的實驗模式，我們發現缺乏生長因子和血清時，大部分的臍靜脈血管內皮細胞會造成細胞凋亡。絕大多數的凋亡細胞是從培養皿中分離而懸浮於培養液中。我們發現血管內皮細胞生長因子可以抑制臍靜脈血管內皮細胞失去生長因子的細胞凋亡的比例。當臍靜脈血管內皮細胞在沒有任何內皮細胞生長因子和血清的M199溶液中時，其Mcl-1蛋白質表達明顯地下降。當接受血管內皮細胞生長因子的刺激後，其Mcl-1的蛋白質表達量在第1個小時就立刻升高。血管內皮細胞生長因子可能經由調節Mcl-1的表達對臍靜脈血管內皮細胞造成抑制細胞凋亡的效果。血管內皮細胞生長因子不但具有促進內皮細胞分裂的能力更有延緩細胞凋亡的功能。
論文總結:
第一、能量都卜勒超音波測得的腫瘤內血管係數不但可作為量化子宮頸癌腫瘤血管新生的指標也有其臨床上的應用價值。此外血管係數亦具有組織學上及細胞生物學上的基礎。
第二、血管內皮細胞生長因子在臨床上可以作為子宮頸癌病人預後的危險因子，在功能上它更有延緩細胞凋亡的功能。
第三、從臨床的觀察到病理組織至臍靜脈血管內皮細胞的實驗模式，證明了腫瘤血管新生和血管內皮細胞生長因子在子宮頸癌扮演了相當重要的角色。

ABSTRACT
Cervical cancer is the most frequent neoplasm of women in Taiwan. The primary treatment of cervical cancer with stages I and IIa is surgery. Although the result of treatment for these patients is good, about 20% of these cervical cancer patients are expected to die of the disease due to recurrence. There were many studies on the prognosis and metastasis of cervical cancer, but most of them focused on the biologic characteristics of cervical cancer cells. This study tried to evaluate the prognosis and metastasis of cervical cancer with tumor angiogenesis and its related growth factors. Tumor angiogenesis assessed by power Doppler ultrasound with “in vivo” observation could be a predictive parameter of disease severity and metastatic potential. Furthermore, we elucidated the histologic and cellular biologic bases of power Doppler ultrasound. Besides, vascular endothelial growth factor could be an important parameter for the recurrence of cervical cancer patients after surgery. Finally, we evaluated vascular endothelial growth factor not only promotes mitosis of endothelial cell but also has the function of anti-apoptosis. These findings provide an important guide for studying the molecular biology and clinical treatment of cervical cancer.
First we found that the blood flow signal assessed by color and power Doppler ultrasound had correlated with tumor angiogenesis in 104 and 35 cervical cancer patients undergoing surgery. Although the intratumoral arterial resistance index could not be the parameter to quantitate angiogenesis of cervical cancer, the detectable or undetectable intratumoral arterial resistance index could be a negative screening tool for parametrial invasion and pelvic lymph node metastasis. Vascularity index assessed by power Doppler ultrasound and quantitative imaging system could be a new parameter to quantitate tumor angiogenesis of cervical cancer.
Second, we found that the disease severity and metastatic ability could be reflected by vascularity index, microvessel density and cytosol vascular endothelial growth factor in 90 cervical cancer patients undergoing surgery. The vascularity index assessed by power Doppler ultrasound had its histologic and cellular biologic bases because the vascularity index, microvessel density and cytosol vascular endothelial growth factor revealed positive correlation by Sperman correlation analyses, respectively. Cervical cancer patients whose intratumoral vascularity index is higher than 12, lymph node metastasis should be highly suspected. Radiation rather than surgery seems to be a suitable therapy for these patients.
For understanding the role of vascular endothelial growth factor on cervical cancer, we collected 135 cervical cancer patients with surgery and complete clinical follow-up. The median time of follow-up was 27.0 months. The concentrations of cytosol vascular endothelial growth factor in cervical cancer tissues showed significantly higher than those in normal cervical tissues (154.0 versus 0.0 pg/mg protein, P <0.001)。Only over-expressed vascular endothelial growth factor is the independent risk factor (hazard ratio 9.92, P=0.001) by multivariate hazard model analysis. Patients with over-expressed vascular endothelial growth factor had significantly poorer disease-free interval (log-rank-test, P=0.004)。Cytosol vascular endothelial growth factor in cervical cancer tissues not only could reflect the severity of cervical cancer but also be a risk factor for prognosis of early-staged cervical cancer patients.
Is there any other function for vascular endothelial growth factor except promoting the mitosis of endothelial cell ? The human umbilical vein endothelial cell (HUVEC) was used as a model system to study the survival effect of vascular endothelial growth factor. We demonstrated that most of the HUVECs underwent apoptosis when serum and endothelial growth factor were deprived from the culture medium. Most apoptotic HUVECs became detached from the culture dishes. We found that vascular endothelial growth factor could inhibit the apoptotic percentage of HUVECs upon growth factor withdrawl. The Mcl-1 protein levels in HUVECs significantly decreased in the medium without serum and endothelial growth factor. When stimulated by vascular endothelial growth factor, the protein level of Mcl-1 in HUVECs was immediately elevated within one hour treatment. Vascular endothelial growth factor might regulate the expression of Mcl-1 to inhibit apoptosis of HUVECs. Vascular endothelial growth factor not only promote the mitotic ability of endothelial cell, but also have the ability of delaying apoptosis.
Conclusions:
1. Intratumoral vascularity index assessed by power Doppler ultrasound could be the parameter for quantitating angiogenesis of cervical cancer and has its histologic and cellular biologic bases. Vascularity index also has its value for clinical application.
2. Vascular endothelial growth factor clinically could be a risk factor of cervical cancer patients and it has the function of delaying cell apoptosis.
3. Tumor angiogenesis and vascular endothelial growth factor play important roles in cervical cancer from clinical observation to histopathology and experimental model of HUVECs.

封面
誌謝
目錄
表目錄
圖目錄
中文摘要
英文摘要
第一章緒言
一.本論文之研究背景
二.本論文研究之動機及目的
第二章彩色及能量都卜勒超音波(color and power Doppler ultrasound)在子宮頸癌的應用和腫瘤血重新生的關係
一.前言
二.材料與方法
三.結果
四.討論
五.結論
六.中文摘要
七.英文摘要
第三章 腫瘤內血管係數(vascularity index)與血管內皮細胞 生長因子(vascular endothelial growth factor)及子宮頸癌疾病致病力之關係
一.前言
二.材料與方法
三.結果
四.討論
五.結論
六.中文摘要
七.英文摘要
第四章 子宮頸癌之血管內皮細胞生長因子與子宮頸疾病侵襲力及其預後之關係
一.前言
二.材料與方法
三.結果
四.討論
五.結論
六.中文摘要
七.英文摘要
第五章 血管內皮細胞生長因子與細胞凋亡(apoptosis)的關係
一.前言
二.材料與方法
三.結果
四.討論
五.結論
六.中文摘要
七.英文摘要
第六章 論文總結
第七章
第八章 參考文獻
發表之相關論文

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