Tim-4 promotes the growth of colorectal cancer by activating angiogenesis and recruiting tumor-associated macrophages via the PI3K/AKT/mTOR signaling pathway

T-cell immunoglobulin domain and mucin domain-4 (Tim-4) is overexpressed in several tumors and is correlated with enhanced tumor development and metastasis. In this study, we investigated the physiological alterations and molecular events related to Tim-4 overexpression in a mouse model of colorectal cancer (CRC). In the current study, we observed that Tim-4 is upregulated in CRC tissues compared with neighboring normal tissues. In addition, statistical analysis revealed that elevated Tim-4 expression was strongly linked to distant metastasis, TNM stage and reduced overall survival duration in CRC patients. An orthotopic model was employed to explore the function of Tim-4 in CRC development through the implantation of Tim-4-overexpressing CT26 murine colon adenocarcinoma cells. It was observed that Tim-4 overexpression considerably enhanced CRC tumorigenesis in vivo and promoted angiogenesis through the upregulation of vascular endothelial growth factor (VEGF). In CT26 cells, Tim-4 overexpression increased the aldehyde dehydrogenase-1 (ALDH1) level, indicating an increase in cancer stem cell (CSC)-like properties. Furthermore, we determined that Tim-4 activates PI3K/AKT/mTOR signaling in CRC cells. Tim-4-overexpressing cancer cells recruited tumor-associated macrophages (TAMs), thereby accelerating cancer development. Therefore, our results strongly indicate that Tim-4 overexpression promotes proliferation and tumor stroma remodeling in CRC. PI3K/AKT/mTOR activation might be crucial in Tim-4-linked tumor development. This finding might offer a new strategy for therapeutic intervention.