Neutralizing dentin sialophosphoprotein facilitates tumor vascular normalization in colorectal cancer by blocking the crosstalk between tumor cells and endothelial cells.

Irregular, curved, and uneven shapes of tumor vessels contribute to a malignant microenvironment, promoting metastasis. In this study, using patient-derived xenograft models, we observed that tumors derived from metastatic colorectal cancer (CRC) tissues exhibited increased vascular density, hypoxia, and permeability, but reduced perfusion and pericyte coverage, compared with tumors derived from non-metastatic CRC tissues. We conducted a high-throughput microarray analysis to determine the molecular mechanisms underlying compromised vessel structures. Dentin sialophosphoprotein (DSPP) was identified as the most upregulated gene in metastatic CRC with abnormal vasculature. Clinically, high DSPP expression is strongly correlated with poor prognosis and advanced CRC stages. DSPP stimulates tumor vessel abnormalization and CRC metastasis in vivo, and acts as a novel ligand of alpha(v)beta (3) integrin (αvβ3), which is predominantly expressed in tumor vessels. DSPP could directly bind to the peptide segment (amino acids 368-411) of αvβ3 on the cytoplasmic membrane of endothelial cells, activating the mitogen-activated protein kinase signaling pathway. Subsequently, therapeutic targeting of DSPP with human DSPP antibody or TFA, a selective inhibitor of the αvβ3, was investigated to effectively induce tumor vessel normalization and suppress tumor metastasis in mice. Additionally, interleukin-17 F (IL-17F) was identified as an upstream regulator of DSPP expression, which promotes DSPP transcription via p65 binding to its promoter. Therefore, targeting the DSPP/αvβ3 axis to promote tumor vessel normalization and inhibit tumor metastasis represents a new strategy for the clinical implementation of combination targeted therapies in patients with advanced CRC.