纖維蛋白溶酶原活化系統(PAS)除了控制體內凝血功能外，最近幾年也被發現可藉由影響血管新生以及細胞移行，而參與調控腫瘤的生長、侵犯甚至轉移。此系統中，u-PA已經被證實會持續透過細胞表面的接受體(u-PAR)，增加活化能力的活性，並分解細胞外間質進而促進腫瘤細胞侵犯及轉移。動物實驗的證據也顯示，高表現量的u-PA及u-PAR與某些腫瘤較差的預後有密切的關係。
凝血酶調節素(TM) 是一種表現於血管內皮細胞表面的醣蛋白，也是生理上重要的抗凝血因子。除了內皮細胞外，近幾年，TM也被發現會表現在某些腫瘤細胞上，例如：肺癌、膀胱癌、黑色素細胞瘤。此外，許多體外的研究均指出，TM表現量的多寡與腫瘤細胞轉移能力之間具負向相關性。在其他的實驗室中，過去尚未發表的報告也顯示，在腫瘤細胞中，u-PA會分解細胞表面的TM，被切割出來呈游離形式的TM會增加血管新生的能力，進而促進腫瘤的生長。因此，希望藉由本研究釐清TM、PAS和癌症三者間的相互關係。
在初步的細胞實驗中，我們發現TM的表現量似乎在高惡性度的細胞株有增加的趨勢。然而，進一步的細胞侵襲性的研究卻發現相反的結果，TM的表現量越低，細胞越能穿透阻擋的介質。在臨床檢體的分析研究中，低TM表現的病人似乎有較長的無疾病存活期以及較高的復發率。然而，這兩樣皆無統計上的意義。因此，TM表現量的多寡，對於肺癌病人的預後，尚待釐清。

Plasminogen activator system (PAS) controls not only the intravascular fibrin deposition but also involves in tumor growth, invasion and metastasis, through the effect on angiogenesis and cell migration. One of the components of PAS, named urokinase-type plasminogen activator (u-PA), has been shown to be involved in cancer metastasis through accumulating plasminogen activation activity via its receptor, urokinase receptor (u-PAR) on the cell surface. The causal role of u-PA in cancer metastasis has been demonstrated in experimental model system with animal tumor metastasis and that high level of u-PA and u-PAR have also suggested poor prognosis in some tumor types.
Thrombomodulin (TM) is an endothelial-cell-membrane glycoprotein that forms a complex with thrombin, converting the latter from procoagulant to an anticoagulant enzyme. TM has been shown to exist not only on endothelial cells but also on several types of tumor cells, including lung cancers. Several studies also indicated that the expression level of TM in tumor cells had an inverse correlation in their clinical outcome. Un-published data from Professor Hua-Lin Wu’s lab had shown that the expression of TM in tumor cells was cleaved by u-PA (part of PAS), and the proteolytic TM fragments may further promote tumor growth by enhancing tumor angiogenesis. However, the clinical relevance in lung cancer is still unknown.
In initial cell culture study, I found high TM expression in more malignant cell lines, such as AS-2 and CL1-5. However, conflicting result in cell invasiveness assay showed TM knockdown CL1-5 cells have more potent invasion ability. In clinical lung cancer specimen analyses, low TM expression patient tended to have longer disease free survival days but higher recurrence rate. Due to some limitations, the results were not statistically significant. Therefore, the clinical correlation of TM expression and prognosis is still undetermined.

Chu, Y. W., P. C. Yang, S. C. Yang, Y. C. Shyu, M. J. Hendrix, R. Wu and C. W. Wu (1997). Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 17(3): 353-360.
Doll, S. R. (2000). Smoking and lung cancer. Am J Respir Crit Care Med 162(1): 4-6.
Duffy, M. J. (2004). The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 10(1): 39-49.
Esmon, C. T. (1987). The regulation of natural anticoagulant pathways. Science 235(4794): 1348-1352.
Furuta, J., A. Kaneda, Y. Umebayashi, F. Otsuka, T. Sugimura and T. Ushijima (2005). Silencing of the thrombomodulin gene in human malignant melanoma. Melanoma Res 15(1): 15-20.
Hanly, A. M., M. Redmond, D. C. Winter, S. Brophy, J. M. Deasy, D. J. Bouchier-Hayes and E. W. Kay (2006). Thrombomodulin expression in colorectal carcinoma is protective and correlates with survival. Br J Cancer 94(9): 1320-1325.
Harris, L., H. Fritsche, R. Mennel, L. Norton, P. Ravdin, S. Taube, et al. (2007). American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33): 5287-5312.
Herbst, R. S., J. V. Heymach and S. M. Lippman (2008). Lung cancer. N Engl J Med 359(13): 1367-1380.
Jemal, A., R. Siegel, E. Ward, T. Murray, J. Xu, C. Smigal and M. J. Thun (2006). Cancer statistics, 2006. CA Cancer J Clin 56(2): 106-130.
Kim, S. J., E. Shiba, H. Ishii, T. Inoue, T. Taguchi, Y. Tanji, Y. Kimoto, M. Izukura and S. Takai (1997). Thrombomodulin is a new biological and prognostic marker for breast cancer: an immunohistochemical study. Anticancer Res 17(3C): 2319-2323.
Kuper, H., H. O. Adami and P. Boffetta (2002). Tobacco use, cancer causation and public health impact. J Intern Med 251(6): 455-466.
Liu, P. L., J. R. Tsai, C. C. Chiu, J. J. Hwang, S. H. Chou, C. K. Wang, et al. (2010). Decreased expression of thrombomodulin is correlated with tumor cell invasiveness and poor prognosis in nonsmall cell lung cancer. Mol Carcinog 49(10): 874-881.
Machtay, M. and B. Jeremic (2003). Complex and controversial issues in locally advanced non-small cell lung carcinoma. Semin Surg Oncol 21(2): 128-137.
Ogawa, H., S. Yonezawa, I. Maruyama, Y. Matsushita, Y. Tezuka, H. Toyoyama, et al. (2000). Expression of thrombomodulin in squamous cell carcinoma of the lung: its relationship to lymph node metastasis and prognosis of the patients. Cancer Lett 149(1-2): 95-103.
Pyke, C., P. Kristensen, E. Ralfkiaer, J. Grondahl-Hansen, J. Eriksen, F. Blasi and K. Dano (1991). Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 138(5): 1059-1067.
Renyi-Vamos, F., J. Tovari, J. Fillinger, J. Timar, S. Paku, I. Kenessey, et al. (2005). Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res 11(20): 7344-7353.
Schneider, B. J. (2008). Non-small cell lung cancer staging: proposed revisions to the TNM system. Cancer Imaging 8: 181-185.
Suzuki, K., H. Kusumoto, Y. Deyashiki, J. Nishioka, I. Maruyama, M. Zushi, et al. (1987). Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J 6(7): 1891-1897.
Temel, J. S., J. A. Greer, A. Muzikansky, E. R. Gallagher, S. Admane, V. A. Jackson, et al. (2010). Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363(8): 733-742.
Weiler, H., V. Lindner, B. Kerlin, B. H. Isermann, S. B. Hendrickson, B. C. Cooley, et al. (2001). Characterization of a mouse model for thrombomodulin deficiency. Arterioscler Thromb Vasc Biol 21(9): 1531-1537.
Wilhelm, S., M. Schmitt, J. Parkinson, W. Kuhn, H. Graeff and O. G. Wilhelm (1998). Thrombomodulin, a receptor for the serine protease thrombin, is decreased in primary tumors and metastases but increased in ascitic fluids of patients with advanced ovarian cancer FIGO IIIc. Int J Oncol 13(4): 645-651.
Wu, C. T., Y. H. Chang, P. Lin, W. C. Chen and M. F. Chen (2014). Thrombomodulin expression regulates tumorigenesis in bladder cancer. BMC Cancer 14: 375.
Yang, P. C., K. T. Luh, R. Wu and C. W. Wu (1992). Characterization of the mucin differentiation in human lung adenocarcinoma cell lines. Am J Respir Cell Mol Biol 7(2): 161-171.
Yonezawa, S., I. Maruyama, K. Sakae, A. Igata, P. W. Majerus and E. Sato (1987). Thrombomodulin as a marker for vascular tumors. Comparative study with factor VIII and Ulex europaeus I lectin. Am J Clin Pathol 88(4): 405-411.