Abstract
BackgroundTumor-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.MethodsImmunohistochemistry 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.ResultsSPON2 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.ConclusionsOur 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.
Highlights
Tumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment
spondin 2 (SPON2) is positively correlated with M2‐TAM infiltration and poor prognosis in colorectal cancer (CRC) patients To analyze the correlation between SPON2 expression and immune cell populations, gene expression signature analyses (GSEA) were performed using TCGA-COAD and READ data (Supplementary Figure S1a)
Pearson correlation analysis showed that high SPON2 expression was significantly correlated with enrichment of suppressive immune cells, including M2-TAMs, regulatory T cells and MDSCs (Supplementary Figure S1b), especially in patients with stage IV CRC (Supplementary Figure S 1c)
Summary
Tumor-associated macrophages (TAMs) are key regulators of the complex interplay between cancer and the immune microenvironment. Overexpression of SPON2 has been shown to promote tumor cell migration in colorectal cancer (CRC). The mechanism by which SPON2 regulates the accumulation of TAMs in the tumor microenvironment (TME) of CRC is unknown. The tumor microenvironment (TME) has been shown to play an essential role in CRC progression and metastasis [3]. Understanding the components of the TME and their interplay with tumor cells is helpful for developing new strategies against metastatic CRC. Most of the macrophages located at the invasive front of advanced CRC tumors display the M2-TAM phenotype [12]. How tumor cells affect TAM accumulation and their protumoral phenotype in invasive CRC has not yet been well established
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