Inflammatory Molecule, PSGL-1, Deficiency Activates Macrophages to Promote Colorectal Cancer Growth through NF{kappa}B Signaling

P-selectin glycoprotein ligand 1 (SELPLG/PSGL-1) is an inflammatory molecule that is functionally related to immune cell differentiation and leukocyte mobilization. However, the role of PSGL-1 in tumor development remains unknown. Therefore, this study investigates the mechanistic role of PSGL-1 in the development of intestinal tumors in colorectal cancer. ApcMin/+ mice are highly susceptible to spontaneous intestinal adenoma formation, and were crossbred with PSGL1-null mice to generate compound transgenic mice with a ApcMin/+;PSGL-1–/– genotype. The incidence and pathologic features of the intestinal tumors were compared between the ApcMin/+ mice and ApcMin/+;PSGL-1–/– mice. Importantly, PSGL-1–deficient mice showed increased susceptibility to develop intestinal tumors and accelerated tumor growth. Mechanistically, increased production of the mouse chemokine ligand 9 (CCL9/MIP-1) was found in the PSGL-1–deficient mice, and the macrophages are likely the major source of macrophage inflammatory protein-1 gamma (MIP-1). Studies in vitro demonstrated that macrophage-derived MIP-1 promoted colorectal cancer tumor cell growth through activating NFB signaling. Conversely, restoration of the PSGL-1 signaling via bone marrow transplantation reduced MIP-1 production and attenuated the ability of ApcMin/+;PSGL-1–/– mice to generate intestinal tumors. In human colorectal cancer clinical specimens, the presence of PSGL-1–positive cel...

Source: Molecular Cancer Research - April 2, 2017 Category: Cancer & Oncology Authors: Li, J., Zhou, Z., Zhang, X., Zheng, L., He, D., Ye, Y., Zhang, Q.-Q., Qi, C.-L., He, X.-D., Yu, C., Shao, C.-k., Qiao, L., Wang, L. Tags: Oncogenes and Tumor Suppressors Source Type: research