Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion.

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.

• Authors: Caiqi Ma, Chuanghua Luo, Haofan Yin, Yang Zhang, Wenjun Xiong, Ting Zhang, Tianxiao Gao, Xi Wang, Di Che, Zhenzhen Fang, Lei Li, Jinye Xie, Mao Huang, Liuqing Zhu, Ping Jiang, Weiwei Qi, Ti Zhou, Zhonghan Yang, Wei Wang, Jianxing Ma, Guoquan Gao, Xia Yang
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 21 Issue 4 Pg. 617-631 (07 2018) ISSN: 1436-3305 [Electronic] Japan
• PMID: 29243194 (Publication Type: Journal Article)

Chemical References

• LRP6 protein, human
• Low Density Lipoprotein Receptor-Related Protein-6
• Recombinant Proteins
• Serpins
• Vascular Endothelial Growth Factor C
• kallistatin

Topics

• Aged
• Animals
• Cell Line, Tumor
• Down-Regulation
• Female
• Humans
• Low Density Lipoprotein Receptor-Related Protein-6 (genetics)
• Lymphangiogenesis (physiology)
• Lymphatic Metastasis (pathology)
• Male
• Mice, Inbred BALB C
• Middle Aged
• Recombinant Proteins (genetics, pharmacology)
• Serpins (blood, genetics, metabolism, pharmacology)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Vascular Endothelial Growth Factor C (metabolism)