Tumor-associated macrophages mediate gastrointestinal stromal tumor cell metastasis through CXCL2/CXCR2

Hongke Cai; Yi Chen; Xi Chen; Weiping Sun; Yang Li

doi:10.1016/j.cellimm.2022.104642

Tumor-associated macrophages mediate gastrointestinal stromal tumor cell metastasis through CXCL2/CXCR2

Cell Immunol. 2023 Feb:384:104642. doi: 10.1016/j.cellimm.2022.104642. Epub 2022 Nov 21.

Authors

Hongke Cai¹, Yi Chen¹, Xi Chen², Weiping Sun¹, Yang Li³

Affiliations

¹ Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
² Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
³ Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. Electronic address: liyang_68813@hospital.cqmu.edu.cn.

PMID: 36577281
DOI: 10.1016/j.cellimm.2022.104642

Abstract

Background: Tumor-associated macrophages (TAMs) are linked with the progression and poor prognosis of multifarious solid tumors, but the regulatory mechanisms involved in gastrointestinal stromal tumors (GIST) remain indistinct. This study intended to delve into the job of TAM-derived chemokines in promoting metastasis in GIST microenvironment.

Methods: Expression levels of M2-TAM markers and CXCL2 in primary and metastatic tissues of GIST were analyzed by bioinformatics methods, and we analyzed the correlation between CXCL2 and M2-TAM markers. Immunofluorescence was applied to assay CXCL2 and M2-TAM marker protein (CD68 and CD206) expression in tumor tissues. Serum CXCL2 concentration in metastatic and non-metastatic patients was assayed by ELISA. The differentiation of THP-1 cells was tested by flow cytometry. Cell function test was utilized to analyze the viability, invasion and migration of GIST cells. Western blot was used to examine the expression of epithelial-mesenchymal transition (EMT)-related proteins. The mouse liver metastasis model was established, and the effects of CXCL2 and EMT-related genes on metastasis were confirmed by hematoxylin-eosin staining and immunohistochemistry experiments.

Results: Bioinformatics analysis ascertained that M2-TAM marker proteins and chemokine CXCL2 were highly expressed in GIST metastatic tissues, and CXCL2 and TAM were co-located in tumor tissues. Results of in vitro cell function experiments displayed that CXCL2 secreted by M2-TAM promoted the invasion, migration and EMT of GIST tumor cells, and the anti-CXCL2 antibody could block the metastasis promoting effect of CXCL2. Additionally, the silencing of CXCR2 in GIST cells inhibited the metastasis promoting effect of CXCL2. Animal studies further confirmed that CXCL2 promoted liver metastasis of GIST in vivo.

Conclusion: This study preliminarily revealed the mechanism of M2-TAM promoting tumor metastasis by secreting CXCL2 in GIST tumor microenvironment, and proffered theoretical reference for the development of immunotherapy strategies targeting M2-TAM.

Keywords: CXCL2; Gastrointestinal stromal tumors; Tumor associated macrophages; Tumor metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Gastrointestinal Stromal Tumors* / metabolism
Gastrointestinal Stromal Tumors* / pathology
Humans
Liver Neoplasms* / pathology
Macrophages
Mice
Tumor Microenvironment
Tumor-Associated Macrophages

Substances

Cxcl2 protein, mouse
Cxcr2 protein, mouse
CXCL2 protein, human
CXCR2 protein, human