J Cancer 2021; 12(15):4686-4697. doi:10.7150/jca.58698

Research Paper

Pentraxin-3 inhibits milky spots metastasis of gastric cancer by inhibiting M2 macrophage polarization

Xinye Cui1, Tao Qin2, Zhengdong Zhao3, Guang Yang3, Jaceline Gislaine Pires Sanches4, Qingqing Zhang4, Shujun Fan4, Liang Cao1✉, Xiang Hu1✉

1. Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian 116011, P.R. China.
2. Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, Shandong 266071, P. R. China.
3. Department of General Surgery, The Second Affiliated Hospital, Dalian Medical University, Dalian 116027, P.R. China.
4. Department of Pathology, Dalian Medical University, Dalian 116044, P. R. China.

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Citation:
Cui X, Qin T, Zhao Z, Yang G, Sanches JGP, Zhang Q, Fan S, Cao L, Hu X. Pentraxin-3 inhibits milky spots metastasis of gastric cancer by inhibiting M2 macrophage polarization. J Cancer 2021; 12(15):4686-4697. doi:10.7150/jca.58698. Available from https://www.jcancer.org/v12p4686.htm

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Abstract

Purpose: Recent studies have indicated that Pentraxin-3 (PTX3) is related to invasion, migration and metastasis of gastric cancer cells (GCCs). However, the function of PTX3 in stemness and tumor-associated macrophages (TAMs) polarization in GC has not yet been revealed. Here, we investigated the role of PTX3 in TAMs polarization and stemness in gastric cancer (GC), and further explored the effect of PTX3 on milky spot metastasis of gastric cancer.

Methods: PTX3 expression in human gastric cancer tissues was examined with immunohistochemistry (IHC). The influence on stemness of gastric cancer cells was examined by sphere formation assay and western blot. qRT-PCR, IHC and flow cytometry were used to evaluate M1/M2 macrophage signatures. The effects of PTX3 on TAM polarization and milky spots were investigated in vitro and in vivo. The possible mechanism of PTX3 on targeted cytokines and pathway were analyzed by qRT-PCR and western blot.

Results: We found that PTX3 was low expressed in gastric carcinoma tissues and associated with stemness and polarization of macrophages. The upregulation of PTX3 inhibited the stemness of GCCs. Furthermore, PTX3 suppressed the polarization of M2 macrophages in the milky spots in vivo and in vitro and inhibited the metastasis of GC into milky spots. PTX3 restrained the expression of interleukin-4 (IL-4) and IL-10 via the inhibition of phosphorylation of the c-Jun N-terminal protein kinase 1/2 (JNK1/2) in GCCs.

Conclusion: These results revealed a novel mechanism of PTX3 in GC, which may participate in the development and metastasis of GC by affecting stemness and macrophage polarization. PTX3 should be considered as a crucial biomarker and may be potentially used in targeted therapy in GC progression.

Keywords: PTX3, Gastric cancer, Milky spot, Macrophage polarization