Acta Pharmaceutica Sinica. B | The DSPP/αvß3 Signaling Axis Inhibits Colorectal Cancer Metastasis by Regulating Tumor Vascular Normalization

This study reveals the pro-metastatic role of IL17F in the colorectal cancer microenvironment and its transcriptional regulation of DSPP, providing a novel intervention node for experimental designs related to tumor vascular abnormality, suggesting that targeting DSPP may enhance the efficacy of anti-angiogenic therapies.

 

Literature Overview

The article titled "Neutralizing dentin sialophosphoprotein facilitates tumor vascular normalization in colorectal cancer by blocking the crosstalk between tumor cells and endothelial cells," published in Acta Pharmaceutica Sinica. B, systematically investigates how crosstalk between tumor cells and endothelial cells drives vascular abnormality and metastasis in colorectal cancer (CRC). Using patient-derived xenograft (PDX) models, high-throughput screening, and functional validation, the study uncovers a novel mechanism by which dentin sialophosphoprotein (DSPP) acts as a key mediator of tumor vascular dysregulation. The authors further elucidate the DSPP-integrin αvß3 (ITGAV/ITGB3) signaling axis that activates the MAPK pathway and identify IL17F as an upstream regulator that promotes DSPP expression via NF-κB, providing a theoretical basis for targeting cell-cell interactions in the tumor microenvironment.

Background Knowledge

Colorectal cancer is the third most common cancer worldwide, and metastatic cases have extremely poor prognoses, necessitating a deeper understanding of metastasis mechanisms to develop effective interventions. Abnormal tumor vasculature—characterized by high density, excessive permeability, poor perfusion, and low pericyte coverage—is a key feature of the tumor microenvironment that promotes metastasis. Although current anti-angiogenic therapies (e.g., anti-VEGF) can induce tumor vascular normalization (TVN), their efficacy is limited and resistance often develops. Therefore, identifying new regulators of vascular abnormality remains a critical challenge. While roles of SIBLING family proteins (e.g., OPN, BSP) in cancer have been studied, the function of DSPP in colorectal cancer remains unclear. This study focuses on key questions: Is DSPP abnormally expressed in mCRC? Does it promote vascular abnormality by affecting endothelial cell function? Can it serve as a novel target for TVN? These scientific inquiries form the logical foundation of the research.

 

 

Research Methods and Experiments

The authors used PDX models combined with clinical tissue samples to compare vascular characteristics between metastatic and non-metastatic CRC, finding that mCRC exhibited higher vascular density, hypoxia, and permeability, but lower perfusion and α-SMA+ pericyte coverage. High-throughput microarray analysis identified DSPP as significantly upregulated in mCRC. Subsequent knockdown of DSPP in HCT116 and SW620 cells using shRNA and sgRNA significantly inhibited tube formation in HUVECs and angiogenesis in the CAM model, while reducing tumor growth and metastasis in vivo. Conversely, DSPP overexpression exacerbated vascular abnormalities and metastasis. To validate the direct mechanism, GST pull-down and surface plasmon resonance (SPR) assays confirmed that DSPP directly binds ITGAV/ITGB3, with interaction domains further verified by Co-IP and molecular docking simulations. Treatment with the MAPK inhibitor AZD6244 or the αvß3 inhibitor Cyclo(-RGDfK) reversed DSPP-induced vascular abnormalities, indicating dependence on the FAK/MAPK pathway.

Key Conclusions and Perspectives

• DSPP expression is significantly upregulated in mCRC patient tissues and PDX models and correlates with poor prognosis, suggesting its potential as a biomarker for CRC progression and guiding future experimental designs for prognostic evaluation
• DSPP, secreted by CRC cells, directly binds ITGAV/ITGB3 on endothelial cells, activating the MAPK signaling pathway and driving tumor vascular abnormality, providing direct evidence for tumor-endothelial crosstalk and highlighting this ligand-receptor axis as a priority for validation in follow-up mechanistic studies
• IL17F upregulates DSPP transcription by binding to the DSPP promoter via NF-κB (p65), thereby promoting vascular abnormality and metastasis, revealing a novel pathway by which inflammatory cytokines regulate the tumor microenvironment and suggesting IL17F as an upstream target for modulating DSPP expression
• Anti-DSPP antibodies or αvß3 inhibitors effectively induce tumor vascular normalization, improving perfusion, reducing hypoxia, and suppressing metastasis, indicating clinical translational potential for targeting the DSPP/αvß3 axis and supporting further testing in combination therapies

Research Significance and Prospects

This study not only identifies DSPP as a novel αvß3 ligand promoting metastasis in colorectal cancer but also delineates a complete IL17F→DSPP→αvß3→MAPK signaling cascade, offering new therapeutic targets for strategies aimed at normalizing tumor vasculature. In drug development, anti-DSPP monoclonal antibodies or small-molecule inhibitors could complement existing anti-angiogenic therapies, particularly in patient subpopulations with high IL17F expression. For clinical monitoring, serum DSPP levels may serve as a liquid biopsy biomarker to predict metastatic risk or treatment response. In disease modeling, generating DSPP-knockout PDX or GEMM models will help elucidate its dynamic role in tumor evolution and advance the development of precision intervention strategies.

 

 

Conclusion

This study systematically elucidates the central role of DSPP in colorectal cancer metastasis, molecularly linking inflammatory signaling (IL17F), tumor-secreted factors, and endothelial dysfunction. By identifying the DSPP/αvß3 axis as a key driver of tumor vascular abnormality, the research offers new insights into breaking the vicious cycle within the tumor microenvironment. Targeting this pathway not only suppresses metastasis but also improves drug delivery through vascular normalization, thereby enhancing the efficacy of chemotherapy and immunotherapy in combination regimens. In the future, incorporating DSPP into molecular classification systems for colorectal cancer may enable more precise risk stratification and personalized treatment. From bench to bedside, this discovery lays a crucial foundation for optimizing comprehensive management strategies for advanced colorectal cancer patients, offering new intervention avenues for refractory mCRC.

 

Chaoqun Liu, Rui Zhou, Weiwei Liu, Wandie Lin, and Liang Zhao. Neutralizing dentin sialophosphoprotein facilitates tumor vascular normalization in colorectal cancer by blocking the crosstalk between tumor cells and endothelial cells. Acta Pharmaceutica Sinica. B.