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

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.

Prognostic value and predictive biomarkers of phenotypes of tumour‐associated macrophages in colorectal cancer

“…In most solid tumours, high‐density macrophages infiltration has been related to evidently poor prognosis 11,26,27 . However, studies assessing the remarkableness of prognosis in different subtypes of TAMs infiltration in CRC remain controversial 28‐30 …”

“…11,26,27 However, studies assessing the remarkableness of prognosis in different subtypes of TAMs infiltration in CRC remain controversial. [28][29][30] We used IHC and IF to research the TAMs densities of tumour tissues and to confirm the correlation among TAMs, clinicopathological parameters and prognosis. Of the 64 cases, only 10 cases (15.6%) had a high level of protein expression level had a negative correlation with CD163 protein expression in CRC.…”

PARG suppresses tumorigenesis and downregulates genes controlling angiogenesis, inflammatory response, and immune cell recruitment

“…SPON2 is a host innate immunity regulator and an important molecule for efficient microbial response [ 100 ]. Positive correlation for SPON2 expression and cancer development, metastasis and invasiveness were shown for different types of tumors, such as ovarian, prostate, colorectal and renal [ 101 – 104 ]. In hepatocellular carcinoma, SPON2 is also upregulated compare to non-transformed tissue, but interestingly, patients with high SPON2 expression have a better overall survival rate.…”

Functional and Therapeutic Significance of Tumor-Associated Macrophages in Colorectal Cancer

“…TANs have functional similarities to TAMs. Both cells above exert a dual effect on CRC development with several isoforms, but the interactions between TAMs and TANs in CRC need to be further investigated (45,46). MDSCs possess immunosuppressive properties (47).…”