- 學位論文
骨橋蛋白、血管內皮生長因子、尿激酶型血纖維蛋白溶解酶原活化因子與酶原活化劑抑制劑第一型在惡性肋膜積水形成中扮演的角色
Role of Osteopontin, Vascular Endotheliol Growth Factor, Urokinase-type Plasminogen Activator and Plasminogen Activator Inhibitor in Malignant Pleural Effusions
摘要
肺癌與乳癌發展中末期常有惡性肋膜積水的發生，造成癌症病人的呼吸困難。惡性肋膜積水具有不同的特性及外觀，可以從血清狀自由流動甚或到血性多纖維沉澱。惡性肋膜積水的臨床處置經常需要治療性胸腔穿刺引流後，施行肋膜沾黏術以緩解病人症狀。但如此的處置成功機率不一，目前並無好的預測因子，亦無法延長病人的存活。因此發展有效的惡性肋膜積水治療方式有其必要性。已知肋膜腔內癌細胞可以分泌促生長的因子及增加蛋白水解以利於癌細胞的生長。而研究發現有些促生長的因子可以直接調節蛋白水解酶的表達及活性。血管內皮生長因子(vascular endothelial growth factor, VEGF)以及尿激酶型血纖維蛋白溶解酶原活化因子(urokinase-type plasminogen activator, uPA)被證實可以增加肋膜的通透性，造成惡性肋膜積水的累積，並且增加血管的通透性、促進癌細胞的增生及移行。而骨橋蛋白(osteopontin, OPN)被發現可以作用於肋膜細胞調控u-PA與VEGF的表達，進而影響惡性肋膜積水的生成。此外，肋膜腔內u-PA與其拮抗劑酶原活化劑抑制劑第一型（plasminogen activator inhibitor，PAI-1）的相對表現決定了肋膜腔內促凝血活性(procoagulant)及溶纖活性(fibrinolytic activities)的平衡。PAI-1的增加，雖可能造成惡性肋膜積水的膿液嚴重區隔(loculation)增加肋膜積水處理上的困難，但相反地，肋膜積水中內生性PAI-1的增加可預測病人後續施行肋膜沾黏治療 (pleurodesis)較高的成功率，或可阻絕癌細胞擴散帶來較高存活率，即良好預後因子。在此研究計畫，我們收集初診斷未經治療癌症病人之惡性肋膜積水檢體，測定惡性肋膜積水中OPN、VEGF、u-PA及PAI的含量。藉由分析追蹤惡性肋膜積水中OPN、VEGF、u-PA及PAI的含量，與病人癌症種類、癌症轉移性、年齡、性別分類，由結果得知，台灣肺癌與乳癌伴隨肋膜積水患者中，E2、VEGF與OPN與其癌症轉移性呈現正相關係數並同時有顯著差異性。
並列摘要
Malignant pleural effusions frequently cause respiratory compromise in cancer patients. The characteristics of malignant pleural fluid vary widely from free-flowing to fibrinous and from serosanguineous to bloody. Previous reports demonstrate that drainage followed by instillation of sclerosing agents is useful for controlling pleural effusion and improving the quality of life of patients. However, the efficacy of this treatment is variable and does not extend the survival of cancer patients. Clearly, a more effective therapy for malignant pleural effusion is needed. Rapid growing cancer cells frequently secrete growth-promoting polypeptides and also produce high amounts of proteolytic activity. Several works have indicated growth factors have an ability to modulate the expression of proteolytic enzymes. Vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (u-PA) are discovered to increase vascular permeability, cell proliferation, and migration of endothelial cells. The interaction of pleural cells through growth factors may be involved in the local production and secretion of u-PA. On the othe hand, the plasminogen activator - plasminogen activator inhibitor system plays an important role in tumor cell invasion and metastasis. The ratio of u-PA and its antagonist plasminogen activator inhibitor-1 (PAI-1) determine the balance of procoagulant and fibrinolytic activities within the pleural space. An increased intrapleural fibrinolysis would lead to failure of pleurodesis. On the other hand, the over-expression of procoagulant activities precipitates fibrin deposition which results in loculated malignant pleural effusions and trapped lungs. However, the fibrin-generation process may prohibit tumor invasion and metastasis. We hypothesized the expression of PAI-1 as a patient’s endogenous response to cancer cells invasion where the ratio of u-PA and PAI-1 could determine the characteristic and treatment outcome of malignant pleural effusions. The level of VEGF, u-PA, and PAI-1 within the pleural fluid will be quantified by using enzyme-linked immunosorbent assay. The relative concentration between u-PA and PAI-1 will be measured and incorporated with the clinical outcome to generate a predictor model of the success of pleurodesis and survival. The inhibition of tumor angiogenesis is a key therapeutic strategy that holds great promise for the advancement of metastatic lung cancer therapy. We may consider targeting the VEGF and/or u-PA to control malignant pleural effusion along with chemotherapy to further improve the survival rate and life quality in cancer patient according to the results.
參考文獻
延伸閱讀
- Liu, C. H. (2020). HLA-B27訊息傳導路徑 誘導非組織特異性鹼性磷酸酶 以啟動僵直性脊椎炎贅骨生成的機制探討 [doctoral dissertation, Kaohsiung Medical University]. Airiti Library. https://www.airitilibrary.com/Article/Detail?DocID=U0011-2101202009460400
- 朱喬伶（2004）。探討Pyrrolidine Dithiocarbamate影響人類臍帶靜脈內皮細胞株與初級細胞對基質金屬蛋白酵素活化的作用與機轉差異〔碩士論文，臺北醫學大學〕。華藝線上圖書館。https://www.airitilibrary.com/Article/Detail?DocID=U0007-1704200714562985
- 王長富（2007）。觀察基質金屬蛋白酶-9, 麩胱甘肽過氧化酶及纖溶酶原激活物抑制物-1等發炎調控因子於牙周病及心血管疾病中所扮演的角色〔碩士論文，高雄醫學大學〕。華藝線上圖書館。https://doi.org/10.6832/KMU.2007.00036
- Chen, J. L., Fan, J., Chen, M. X., Dong, Y., & Gu, J. Z. (2012). Effect of Non-Anticoagulant N-Desulfated Heparin on Basic Fibroblast Growth Factor Expression, Angiogenesis, and Metastasis of Gastric Carcinoma In Vitro and In Vivo. Gastroenterology Research and Practice, 2012(), 263-268. https://doi.org/10.1155/2012/752940
- Huang, C. Y., Yang, K. Y., Chiu, C. H., Tsai, C. M., & Lee, Y. C. (2011). Newly Developing Osteoblastic Lesions during Epidermal Growth Factor Receptor Tyrosine KinaseInhibitor Treatment Do Not Necessarily Indicate Disease Progression. 胸腔醫學, 26(6), 363-368. https://doi.org/10.29806/TM.201112.0009