Tumor-derived endothelial-specific molecule 1 elicits productive angiogenesis and tumor metastasis to promote bevacizumab resistance

Abstract

Abstract The development of drug resistance in malignant tumors leads to disease progression and creates a bottleneck in their treatment. Bevacizumab is widely used clinically, and acts by inhibiting angiogenesis to “starve” tumors. Although it has negligeable side effects and significant short-term effects, continuous treatment can readily induce rebound proliferation of tumor blood vessels, leading to drug resistance, however, the underlying mechanism remains unclear with no effective strategies to overcome this resistance. Previously, we found that the Fc portion of bevacizumab cooperates with the Toll-like receptor-4 (TLR4) ligand to induce M2b polarization in macrophages and secrete tumor necrosis factor-α (TNFα), which in its turn promotes immunosuppression, tumor metastasis, and angiogenesis. However, the downstream mechanism underlying TNFα-mediated bevacizumab resistance requires further investigation. Our RNA-Seq analysis results revealed that the expression of endothelial cell specific molecule-1 (ESM1) is significantly increased in drug-resistant tumors and promotes metastasis and angiogenesis in vitro and in vivo. Furthermore, TNFα induces the upregulation of ESM1, while ESM1 further regulates matrix metalloprotease-9, vascular endothelial growth factor, and delta-like ligand-4 molecules, thus, promoting metastasis and angiogenesis. Accordingly, the curative effect of bevacizumab is significantly improved by neutralizing ESM1 with the high-affinity anti-ESM1 monoclonal antibody 1-2B7 in bevacizumab-resistant animal models. This study provides important insights regarding the molecular mechanism by which TNFα-induced ESM1 expression promotes angiogenesis, which has important theoretical value and clinical significance for elucidating the mechanism of bevacizumab drug resistance and identifying appropriate biosimilars.