硫酸葡聚糖通过干扰 M2 型巨噬细胞极化抑制胃癌血管生成和侵袭。
Dextran Sulfate Inhibits Angiogenesis and Invasion of Gastric Cancer by Interfering with M2-type Macrophages Polarization.
机构信息
Department of Pathophysiology, Changzhi Medical Collage, 046000, Changzhi, Shanxi, P.R. China.
School of Nursing, Ningxia Medical University, 750004, Yinchuan, Ningxia, P.R. China.
出版信息
Curr Cancer Drug Targets. 2022;22(11):904-918. doi: 10.2174/1568009622666220705095403.
PURPOSE
To explore the effect of dextran sulfate (DS) on the angiogenesis, invasion, and migration of gastric cancer cells by interfering with the polarization of M2-type macrophages.
METHODS
The infiltration of M2-type macrophages and microvascular density in gastric cancer and paracancerous tissues were analyzed using immunohistochemistry and immunofluorescence. The effects of DS on M2-type macrophages and the angiogenesis in metastatic tumors were investigated in the nude mice intraperitoneal metastasis model using immunohistochemistry and western blot. The differentiation and polarization of macrophages, immunocytochemistry, western blot, ELISA, and transwell migration assay were used to evaluate the effect of DS on the polarization of macrophages, immunocytochemistry, western blot, ELISA, and transwell migration assay were used to evaluate the effect of DS on the polarization and recruitment capacity of macrophages. Immunocytofluorescence, tube formation assay, transwell invasion assay, wound healing assay, and western blot were used to investigate the effect of DS on the angiogenesis, invasion, and migration-promoting phenotype of M2- type macrophage in a co-culture system of macrophages and gastric cancer cells.
RESULTS
The infiltration of M2-type macrophages and the microvascular density were highly expressed and positively correlated in the human gastric cancer tissue. DS can significantly inhibit the intraperitoneal metastases of gastric cancer in nude mice, and reduce the infiltration of M2-type macrophages and the angiogenesis in intraperitoneal metastatic tumors. Moreover, DS can prevent the polarization of M0-type macrophages to M2 type, reduce the expression of M2-type macrophage markers (CD206, CD163, IL-10, and Arg-1), down-regulate the IL-6-STAT3 pathway, and inhibit the recruitment capability of M2-type macrophages. Finally, the co-culture experiment showed that DS significantly reduced the enhancing effects of M2-type macrophages on the angiogenesis, invasion, and migration of gastric cancer cells, as well as down-regulated the related expressions of proteins (VEGF, N-cadherin, MMP-2 and Vimentin) in gastric cancer cells.
CONCLUSION
DS can reduce the infiltration of M2-type macrophages and the microvascular density in intraperitoneal metastases of gastric cancer in nude mice, and inhibit the angiogenesis, invasion, and migration of gastric cancer cells by interfering with the polarization of M2-type macrophages through repression of the IL-6/STAT3 signaling pathway.
目的
通过干扰 M2 型巨噬细胞极化，探讨葡聚糖硫酸酯（DS）对胃癌细胞血管生成、侵袭和迁移的影响。
方法
采用免疫组化和免疫荧光法分析胃癌及癌旁组织中 M2 型巨噬细胞浸润和微血管密度。采用免疫组化和 Western blot 检测 DS 对裸鼠腹腔转移模型中 M2 型巨噬细胞和转移瘤血管生成的影响。采用免疫细胞化学、Western blot、ELISA 和 Transwell 迁移实验评价 DS 对巨噬细胞分化和极化、免疫细胞化学、Western blot、ELISA 和 Transwell 迁移实验评价 DS 对巨噬细胞极化和募集能力的影响。免疫细胞荧光、管形成实验、Transwell 侵袭实验、划痕愈合实验和 Western blot 用于研究 DS 在巨噬细胞和胃癌细胞共培养系统中对 M2 型巨噬细胞血管生成、侵袭和迁移促进表型的影响。
结果
人胃癌组织中 M2 型巨噬细胞浸润和微血管密度高表达且呈正相关。DS 可显著抑制裸鼠胃癌的腹腔转移，减少 M2 型巨噬细胞浸润和腹腔转移瘤血管生成。此外，DS 可阻止 M0 型巨噬细胞向 M2 型极化，降低 M2 型巨噬细胞标志物（CD206、CD163、IL-10 和 Arg-1）的表达，下调 IL-6-STAT3 通路，抑制 M2 型巨噬细胞的募集能力。最后，共培养实验表明，DS 可显著降低 M2 型巨噬细胞对胃癌细胞血管生成、侵袭和迁移的增强作用，并下调胃癌细胞相关蛋白（VEGF、N-钙黏蛋白、MMP-2 和波形蛋白）的表达。
结论
DS 可减少裸鼠胃癌腹腔转移中 M2 型巨噬细胞浸润和微血管密度，通过抑制 IL-6/STAT3 信号通路干扰 M2 型巨噬细胞极化，抑制胃癌细胞的血管生成、侵袭和迁移。
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