Dextran Sulfate Inhibits Angiogenesis and Invasion of Gastric Cancer by Interfering with M2-type Macrophages Polarization

Abstract

Purpose: To explore the effect of dextran sulfate (DS) on the angiogenesis, invasion, and migration of gastric cancer cells through 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 macrophage, immunocytochemistry, western blot, ELISA, and transwell migration assay were used to evaluate the effect of DS on the polarization of macrophage, 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 promoting 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.

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…Guo et al. validated the promoting effects on the angiogenesis of M2 TAMs in GC 60 . Moreover, the promoting effects of M2 TAMs on angiogenesis in GC were confirmed by Tang et al 83 .…”

“…52 Guo et al validated the promoting effects on the angiogenesis of M2 TAMs in GC. 60 Moreover, the promoting effects of M2 TAMs on angiogenesis in GC were confirmed by Tang et al 83 Notably, high microvessel density (CD105) was observed in the tissues with high infiltration of M2 TAMs using immunohistochemical (IHC) staining. 124…”

“…Furthermore, EVs containing ApoE derived from M2 TAMs activated the PI3K–Akt pathway to enhance the cell migration of GC cells 38 . Several studies have reported and validated the promoting effects of M2 TAMs on cell migration and invasion in GC 14,60,61,85,88,109,113–116 …”

“…57,58 The inhibition of nuclear factor-kappa B (NF-κB) induced the M1 polarisation of TAMs by promoting transcription of pro-inflammatory cytokines and reducing the secretion of IL-4 and IL-10, 33,39 while activation of NF-κB enhanced the polarisation of M2 TAMs. 42 Similarly, targeting STAT pathway decreased the M2 polarisation of TAMs of macrophages, 59,60 and activating the JAK2/STAT3 pathway facilitated the polarisation of M2 TAMs by increasing the secretion of IL-6 and IL-8. 51,61 As a key communication medium in the TME, 62 EVs exert a critical function in inducing the polarisation of TAMs.…”

“…16 Furthermore, Guo et al reported that dextran sulphate reduced the promoting effects of M2 TAMs on the angiogenesis, and migratory and invasive abilities of GC cells using co-culture assays. 60 Shi et al revealed that targeting DKK1 can effectively repolarise TAMs from M2 to M1 and augment the tumour-killing function of CD8 + T cells and the efficacy of PD-1 inhibitors by blocking PI3K/AKT signalling of macrophages in vitro and in vivo. 81 Moreover, combining an Au agent for chemotherapy and immunotherapy obtained satisfactory tumour-killing results by targeting TAMs in the TME in vitro and in vivo.…”