血纖維蛋白溶酶原(plasminogen, Plg) 屬於血纖維蛋白溶解系統(plasminogen activator (PA)/plasmin system, PAS)中的一員，經由尿激酶型血纖維蛋白溶解酶原活化因子(urokinase-type plasminogen activator, uPA)活化成血纖維蛋白溶酶 (plasmin, Plm)。Plm是負責溶解血塊的主要蛋白分解酵素，並且也在纖維蛋白溶解作用(fibriolysis)、細胞外基質(Extracellular matrix, ECM)的降解、細胞爬行(cell migration)、組織重塑(tissue remodeling)、傷口癒合 (wound healing)及血管新生 (angiogenesis)中扮演重要角色。在過去的文獻報導中指出，PAS在腫瘤的生成中扮演著重要的角色，例如：uPA在腫瘤生長中，促進血管新生作用，藉以促進腫瘤的生長。此外，血管靜止蛋白(angiostatin)，會抑制血管的生成。將腫瘤細胞以皮下注射的方法植入Plg+/+、Plg-/-老鼠的皮下，發現在失去Plg的老鼠身上，其原位腫瘤的生長會比較小，這所影響到的可能與巨噬細胞在腫瘤組織的浸潤以及血管生長的型態有關；而在當時的研究中宣稱，Plg與腫瘤的侵入、轉移沒有顯著的關係。但是在其他研究中，一些PAS的成員扮演著抑制腫瘤生長的角色。Plm會使得 (Metalloproteinase, MMPs)的活化進而幫助腫瘤細胞的入侵與轉移，但相反的Plm所引起的纖維蛋白溶解作用 (fibrinolysis)也可能會使得轉移的細胞存活率下降。所以過去的研究證據顯示，PAS對於腫瘤生長與轉移中扮演著兩種不同且相反的角色。在我們的實驗中發現，以尾靜脈注射B16F10黑色素瘤細胞株的轉移模式中，發現Plg-/-的老鼠在肺部所形成的黑色素瘤數量較Plg+/+多且有明顯的差異。而Lewis lung carcinoma cells (LLC)以及B16F10黑色素瘤細胞，在Plg的處理下細胞型態有所改變，且在Boyden chamber以及穿越內皮細胞層的試驗下， LLC與B16F10的爬行會被Plg所抑制並且有濃度上的趨勢，且Plg在對細胞生長以及細胞週期的分析下並無顯著的影響。此外，在我們的實驗中發現Plg對於原位腫瘤的生長有促進的作用，跟先前文獻的結果相符合。並且，LLC與B16F10在經過Plg的處理後，短時間內可以看到細胞外信號調節激酶 (Extracellular signal-regulated kinases, ERK) 磷酸化表現量上升。藉此我們推測，Plg對於腫瘤在轉移上有抑制的作用但是對於在原位腫瘤的生長有幫助。

The conversion of plasminogen (Plg) to plasmin (Plm) is catalyzed by plasminogen activators. Plasmin is the major proteolytic enzyme accounting for degradation of extracellular matrix (ECM) and dissolution of blood clots. In addition, Plm-mediated proteolysis can facilitate cell migration and promote tissue remodeling events such as wound healing and angiogenesis. It has been demonstrated that the components of Plg activation system (PAS) enhance tumorigenesis; for example, urokinase Plg activator (uPA) modulates endothelial cell proliferation and increases tumor angiogenesis. On the other hand, some of PAS suppress tumorigenesis. Angiostatin is a fragment of Plg that inhibits tumor angiogenesis. Serine proteases, including Plm, play an important role in tumor growth and tumor metastasis through releasing matrix bound growth factors and activating matrix metalloproteinases (MMPs). However, Plm-mediated fibrinolysis might decrease metastatic cell survival. These evidences suggest that PAS are paradoxically contributed to tumorigenesis. In this study, we will investigate the effects of Plg on tumor metastasis using Plg-deficiency (Plg-/-) mice. Our data showed that the number of lung metastatic nodules of B16F10 melanoma cells in wild type mice (Plg+/+) were less than those in Plg-/- mice in the experimental model of metastasis. In order to understand the mechanism of Plg-mediated effects, we used Lewis lung carcinoma cells (LLC) and B16F10 melanoma cells model system to detect cell properties. The cell morphology of LLC and B16F10 melanoma cell changed in a dose-dependent manner after the treatment of Plg. After Plg treatment, the migration of LLC and B16F10 melanoma cells was suppressed using Boyden chamber assay and transendothelial cell migration assay. On the other hand, we found that subcutaneous infection of tumor cells into Plg-/- mice resulted in reduced rate of tumor growth.Plg treatment could induce extracellular signal-regulated kinases (ERK) phosphorylation in B16F10 and LLC in a short period. These results indicate that Plg may suppress tumor metastasis through reduced cell migration but support primary tumor growth.

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