Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion
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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.
These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer.
KeywordsKallistatin Lymphangiogenesis LRP6 NF-ҡB VEGF-C Lymph node metastasis Gastric cancer
This study was supported by National Nature Science Foundation of China, Grant Numbers: 81572342, 81770808, 81600641, 81471033, 81370945, 81400639, 81570871, 81570764; National Key Sci-Tech Special Project of China, Grant Numbers: 2013ZX09102053, 2015GKS355. Program for Doctoral Station in University, Grant Number: 20130171110053; Key Project of Nature Science Foundation of Guangdong Province, China, Grant Numbers: 2015A030311043, 2016A030311035. Guandong Natural Science Fund, Grant Numbers: 2014A030313073, 2015A030313103, 2015A030313029. Guandong Science and Technology Project (2014A020212023, 2015B090903063, 2017A020215075); Key Sci-tech Research Project of Guangzhou Municipality, China, Grant Numbers: 2014J4100162, 201508020033, 2016A020214001, 201607010200, 201707010084; Changjiang Scholars and Innovative Research Team in University, number 985, project PCSIRT 0947; Fundamental Research Funds for the Central Universities of China (youth program 13ykpy06, 14ykpy05, 16ykpy24). 2017 Milstein Medical Asian American Partnership Foundation Research Project Award in Translational Medicine. The funding agencies had no role in study design, data collection, and analysis; decision to publish; or preparation of the manuscript.
X.Y. and G.G. designed the experiments and revised the manuscript; C.M., C.L., and H.Y. carried out the majority of the experiments and analyzed the data; C.M. organized the figures and wrote the manuscript; others participated in the experiments. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest, including relevant financial interests, activities, relationships, or affiliations.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or a substitute for it was obtained from all patients included in the study.