Caiqi Ma1,2, Chuanghua Luo1,2, Haofan Yin2, Yang Zhang2, Wenjun Xiong3, Ting Zhang4, Tianxiao Gao5, Xi Wang2, Di Che1, Zhenzhen Fang2, Lei Li6, Jinye Xie2, Mao Huang2, Liuqing Zhu2, Ping Jiang2, Weiwei Qi2, Ti Zhou2, Zhonghan Yang2, Wei Wang2, Jianxing Ma7, Guoquan Gao8,9,10,11, Xia Yang12,13,14,15. 1. Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. 2. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. 3. Department of Gastrointestinal Surgery, Traditional Chinese Medicine Hospital of Guangdong Province, Guangzhou, China. 4. Department of Clinical Laboratory, Guangzhou First People's Hospital, Guangzhou, China. 5. Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510080, China. 6. Reproductive Medicine Center, the Third Hospital Affiliated to Guangzhou Medical University, Guangzhou, China. 7. Department of Physiology, University of Oklahoma, Health Sciences Center, Oklahoma City, OK, 73104, USA. 8. Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. gaogq@mail.sysu.edu.cn. 9. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. gaogq@mail.sysu.edu.cn. 10. China Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, 510080, China. gaogq@mail.sysu.edu.cn. 11. Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. gaogq@mail.sysu.edu.cn. 12. Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. yangxia@mail.sysu.edu.cn. 13. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. yangxia@mail.sysu.edu.cn. 14. Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-sen University, Guangzhou, 510080, China. yangxia@mail.sysu.edu.cn. 15. Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. yangxia@mail.sysu.edu.cn.
Abstract
BACKGROUND: Tumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor. METHODS AND RESULTS: Our recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancer patients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/IҡB/NF-ҡB signaling pathway in gastric cancer cells. CONCLUSIONS: These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.
BACKGROUND: Tumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor. METHODS AND RESULTS: Our recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancerpatients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/IҡB/NF-ҡB signaling pathway in gastric cancer cells. CONCLUSIONS: These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.