SPON2 Promotes Tumor-associated Macrophages Migration And Colorectal Cancer Metastasis

Colorectal cancer(CRC)is the third most common cancer in the world,with 1.8 million incident cases and 896,000 deaths in 2017.In spite of the improvement of clinical treatment reduced the incidence and mortality of CRC,there were 10%～25%of CRC patients with metastatic disease at initial diagnosis and the prognosis was extremely poor in CRC metastatic patients.It has been well established that the tumor microenvironment(TME)plays an important role in CRC metastasis.TME is the environment around tumor cells and is composed of the surrounding blood vessels,immune cells,fibroblasts,signaling molecules and the extracellular matrix(ECM).The interaction between cancer cells and the tumor TME is one of the essential factors to facilitate invasiveness and metastasis of cancer cells.Tumor associated macrophages(TAMs)are prominent tumor infiltrating immune cells in TME that suppresses antitumor immunity and foster tumor progression.TAMs infiltration into the TME is also associated with a poor prognosis in cancer patients.However,the role of TAMs in CRC is controversial.Some papers report that TAMs are beneficial to prognosis of patients.Notably,most of these studies did not consider the heterogeneity of TAMs(e.g.,the distinct pro-or anti-inflammatory subpopulations(Ml-TAMs and M2-TAMs)and their distribution within tumors.TAMs generally exhibit the M2-like state.Many recent studies provide strong evidence that TAMs facilitate CRC growth and progression,especially in metastatic colorectal cancer,large number of M2-TAMs infiltration are associated with poor prognosis in patients.The infiltration and functions of TAMs are tightly regulated by tumor cells.However,the impact of CRC tumor cells in the accumulation and polarization of TAMs has not yet been well established.TAMs are classically thought to be derived from peripheral blood monocytes.Monocytes are recruited to tumors,by chemokines,cytokines and their complement cascade,where they extravasate from the peripheral circulation and differentiate into TAMs.In mice,inhibition of CCL2-CCR2 signaling blocks the recruitment of inflammatory monocyte and reduces tumor growth and metastasis in breast cancer,hepatocellular cancer,and prostate cancer.CCL2 levels were elevated in patients with primary and metastatic CRC.CCL2-CCR2 signaling also plays an important role in CRC metastasis.In contrast to CCL2 inhibition in a breast cancer model,blocking of CCL2 did not alter myeloid cell recruitment.However,the prognostic relevance of TAMs in CRC patients are contradictory.It is essential to comprehensively understand the regulation of TAM accumulation and activity in order to tackle such barrier and to improve the efficiency of current therapies.SPON2(spondin-2,Mindin,DIL-1)belongs to the F-spondin family of secreted ECM proteins.Mouse SPON2 is expressed abundantly in lymphoid organs and lungs.It is an host innate immune regulator and represents a unique pattern-recognition molecule in the ECM for microbial pathogens.In addition,SPON2 serves as an Integrin ligand and is critical for the recruitment of macrophages and neutrophils.Moreover,increased SPON2 expression has been observed in the serum or tissue samples of malignant tumors such as ovarian cancer,prostate cancer.In CRC,upregulated SPON2 predicted poor prognosis of patients.Overexpression of SPON2 induces cell motility in vitro and CRC metastasis in mice.However,the mechanism underlying SPON2-mediated metastasis in CRC remains unknown.In the current study,we explore the potential role of tumor derived SPON2 in the recruitment of TAMs and promotion of tumor metastasis in CRC.In this study,we determine overexpression of SPON2 promotes the infiltration of TAM and promotes the CRC invasion.SPON2 is also associated with poor prognosis.We confirm that SPON2,as an Integrin ligand,can activate PYK2 to increase cytoskeleton protein reassembling,and promote TAMs transendothelial migration.Moreover,inhibition of SPON2 can reduce the infiltration of TAM.This research suggests that SPON2 can be used as a potential therapeutic target for regulating the immune response.