A novel humanized Frizzled-7-targeting antibody enhances antitumor effects of Bevacizumab against triple-negative breast cancer via blocking Wnt/?-catenin signaling pathway

Abstract Background Anti-angiogenic therapy has been widely applied to the clinical treatment of malignant tumors. However, efficacy such treatments called into question, especially in triple-negative breast cancer (TNBC). Bevacizumab, first anti-angiogenic agent approved by FDA, actually increases invasive and metastatic properties TNBC cells, resulting from activation Wnt/?-catenin signaling response hypoxia. As a critical receptor signaling, Frizzled-7 (Fzd7) is aberrantly expressed TNBC, indicating Fzd7 potential target for developing drugs be combined with agents. Methods Hybridoma technique antibody humanization were utilized generate Fzd7-targeting (SHH002-hu1). Biolayer interferometry (BLI) assay near infrared (NIR) imaging conducted detect affinity targeting ability SHH002-hu1. Next, whether SHH002-hu1 could suppress invasion migration cells induced Bevacizumab validated, underlying molecular mechanisms elucidated luciferase reporter western blot assays. The nude-mice transplanted models established assess anti-TNBC activities when Bevacizumab. Then, effects on putative stem-like evaluated immunofluorescence (IF). Further, tumor-initiating self-renew capacity studied secondary nude mouse xenograft model sphere formation assay. In addition, adaptation hypoxia detection vasculogenic mimicry (VM) hypoxia-inducible factor-1? (HIF-1?) transcriptional activity. Results novel humanized (SHH002-hu1) exhibited extremely high Fzd7, specifically targeted + tumor tissues. repressed invasion, epithelial-mesenchymal cell transformation (EMT) through abating signaling. significantly enhanced inhibit growth via reducing subpopulation further attenuating Bevacizumab-enhanced cells. Moreover, effectively restrained disrupting Conclusion enhances shows preventing recurrence, suggesting good candidate synergistic together