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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

01-12-2021 | Metastasis | Research

Tumor cell-derived SPON2 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by activating PYK2 in CRC

Authors: Chengmei Huang, Ruizhang Ou, Xiaoning Chen, Yaxin Zhang, Jiexi Li, Yihao Liang, Xiaohui Zhu, Lei Liu, Mingzhou Li, Dagui Lin, Junfeng Qiu, Guanglong Liu, Lingjie Zhang, Yuanyuan Wu, Huiyi Tang, Yanmin Liu, Li Liang, Yanqing Ding, Wenting Liao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

Tumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment. Tumor cell-derived spondin 2 (SPON2) is an extracellular matrix glycoprotein that has complicated roles in recruitment of macrophages and neutrophils during inflammation. Overexpression of SPON2 has been shown to promote tumor cell migration in colorectal cancer (CRC). However, the mechanism by which SPON2 regulates the accumulation of TAMs in the tumor microenvironment (TME) of CRC is unknown.

Methods

Immunohistochemistry was used to examine SPON2 expression in clinical CRC tissues. In vitro migration assays, transendothelial migration assays (iTEM), and cell adhesion assays were used to investigate the effects of SPON2 on monocyte/macrophage migration. Subcutaneous tumor formation and orthotopic implantation assays were performed in C57 BL/6 mice to confirm the effects of SPON2 on TAM infiltration in tumors.

Results

SPON2 expression is positively correlated with M2-TAM infiltration in clinical CRC tumors and poor prognosis of CRC patients. In addition, SPON2 promotes cytoskeletal remodeling and transendothelial migration of monocytes by activating integrin β1/PYK2 axis. SPON2 may indirectly induce M2-polarization through upregulating cytokines including IL10, CCL2 and CSF1 expression in tumor cells. Blocking M2 polarization and Macrophage depletion inhibited the SPON2-induced tumors growth and invasion. Furthermore, blocking the SPON2/integrin β1/PYK2 axis impairs the transendothelial migration of monocytes and cancer-promoting functions of TAMs in vivo.

Conclusions

Our findings demonstrate that SPON2-driven M2-TAM infiltration plays an important role during CRC tumor growth and metastasis. SPON2 may be a valuable biomarker guiding the use of macrophage-targeting strategies and a potential therapeutic target in advanced CRC.
Appendix
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Metadata
Title
Tumor cell-derived SPON2 promotes M2-polarized tumor-associated macrophage infiltration and cancer progression by activating PYK2 in CRC
Authors
Chengmei Huang
Ruizhang Ou
Xiaoning Chen
Yaxin Zhang
Jiexi Li
Yihao Liang
Xiaohui Zhu
Lei Liu
Mingzhou Li
Dagui Lin
Junfeng Qiu
Guanglong Liu
Lingjie Zhang
Yuanyuan Wu
Huiyi Tang
Yanmin Liu
Li Liang
Yanqing Ding
Wenting Liao
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02108-0

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