The Role of Vascular Endothelial Growth Factor-C (VEGF-C) in Human Lymphangiogenesis and Metastasis of Lung Adenocarcinoma

• Main Authors: Jen-Liang Su, 蘇振良
• Other Authors: 郭明良
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/11492506244183713297

博士 === 國立臺灣大學 === 毒理學研究所 === 92 === Mortality in cancer patients principally result from metastatic spread of cancer cells to distant organs. Tumor metastasis involves a series of complicated steps that includes the detachment of tumor cells from the primary tumor mass, microinvasion of tumor cells into stromal tissue, enter into the body’s circulatory system — known as intravasation and might extravasate from the circulation into the surrounding tissue. Clinical and pathological observations suggest that for many carcinomas, transport of tumor cells via lymphatics is the most common pathway of initial dissemination, with patterns of spread via afferent lymphatics following routes of natural drainage. Lymphangiogenesis is an important step in tumor cells metastatic spread through the lymphatic system, and potent to be the next cancer target for therapeutic intervention. Clinical findings have long suggested that by providing a pathway for tumor cell dissemination, tumor-associated lymphatics are a key component of metastatic spread. Recent publications have demonstrated that vascular endothelial growth factor (VEGF)-C, ligand for the VEGF receptor-3, is the lymphangiogenic factors that induce the formation of lymphatic vessels within and around tumors. In addition, these studies demonstrated that VEGF-C-overexpressing tumors increase intratumoral lymphangiogenesis, enhancing metastatic spread via the lymphatics. However, the regulation of these lymphangiogenic factors and the lymphangiogenesis process are not clear until now. Flt-4 has been proposed as a specific marker for lymphatic endothelial cells. Recent studies indicated that Flt-4 also expressed in a variety of human malignancies, including lung adenocarcinoma, colorectal adenocarcinoma, head and neck carcinoma, neuroblastoma, and Kaposi''s sarcoma. However, the biological significance of VEGF-C/ Flt-4 axis in cancer cells is completely unknown. In this dissertation, we attempted to elucidate the role of VEGF-C and Flt-4 in human lung adenocarcinoma, regarding the mechanisms by which expression of VEGF-C in tumors and defined the non-lymphangiogenic function of VEGF-C. The association between chronic inflammation and the development of cancer has been recognized. Cyclooxygenase-2 (COX-2), the inducible form of the COX enzymes, catalyzes synthesis of large amounts of prostaglandins with diversified biological activities, and its dysregulation plays a vital role in inflammation, tissue damage, and tumorigenesis. A great amount of evidence suggests the close association of up-regulation of COX-2 with tumor invasion and metastasis in human colorectal, breast, and lung tumors. In human lung tumors, COX-2 is predominantly expressed in adenocarcinomas, especially in patients with lymph node metastasis. It is tempting to speculate that certain un-identified downstream gene(s) of COX-2 may have a role in tumor metastasis. In the chapter 1, our work suggests a cause-effect link between COX-2 overexpression and tumor lymphangiogenesis through VEGF-C activity in lung adenocarcinoma. The up-regulation of VEGF-C by COX-2 through EP1/Src/HER-2/Neu signaling pathway was demonstrated in this study. Our findings also provide new therapeutic modalities for lymphangiogenesis as lymph node metastasis inhibitor by targeting COX-2. Expression of Flt-4 has been also reported that significantly correlated with the different stages and poorer survival in cervical and colorectal cancer, suggesting a role of VEGF-C/Flt-4 signaling in tumor progression. The migration and invasion ability of cancer cells play a critical role in tumor metastasis. In the chapter 2, we clearly provide a novel function of VEGF-C/Flt-4 axis in cell invasion and metastasis in lung adenocarcinoma. The promotion of cell mobility in response to VEGF-C was required the involvement of adhesion molecule contactin-1. The up-regulation of contactin-1 by VEGF-C through Src and p38 MAPK signaling pathway was demonstrated. VEGF-C/Flt-4 and/or its downstream effector contactin-1 may become a possible therapeutic target for patients with lung adenocarcinoma. In summary, our studies provide evidences for regarding the mechanisms by which expression of VEGF-C in tumors and the non-lymphangiogenic role of VEGF-C in lung adenocarcinoma metastasis. With progress in molecular biology of VEGF-C and Flt-4, its value as atherapeutic target is highly promising.