期刊
CANCER BIOLOGY & MEDICINE
卷 17, 期 2, 页码 418-432出版社
CHINA ANTI-CANCER ASSOC
DOI: 10.20892/j.issn.2095-3941.2019.0215
关键词
HUVEC; CD105; bevacizumab; anlotinib; TGF beta
资金
- Tianjin Municipality Science and Technology Commission Projects [13ZCZCSY20300, 12ZCDZSY15600]
- CSCO (Chinese Society of Clinical Oncology) Special Foundation for Tumor Anti-angiogenesis Therapy [Y-S2014011]
- Scientific Research Foundation for Doctoral Program of Tianjin Cancer Institute & Hospital, Tianjin Medical University [B1614]
- Science & Technology Development Fund of Tianjin Education Commission for Higher Education [2017KJ201]
Objective: Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor (VEGF) with clear clinical benefits. However, overall survival of some cancer types remains low owing to resistance to bevacizumab therapy. While resistance is commonly ascribed to tumor cell invasion induced by hypoxia-inducible factor (HIF), less attention has been paid to the potential involvement of endothelial cells (ECs) in vasculature activated by anti-angiogenic drugs. Methods: Human umbilical vein ECs (HUVECs), bEnd.3 cells, and mouse retinal microvascular ECs (MRMECs) were treated with bevacizumab under conditions of hypoxia and effects on biological behaviors, such as migration and tube formation, examined. Regulatory effects on TGF beta 1 and CD105 (endoglin) were established via determination of protein and mRNA levels. We further investigated whether the effects of bevacizumab could be reversed using the receptor tyrosine kinase inhibitor anlotinib. Results: Bevacizumab upregulated TGF beta 1 as well as CD105, a component of the TGF beta receptor complex and an angiogenesis promoter. Elevated CD105 induced activation of Smad1/5, the inflammatory pathway and endothelial-mesenchymal transition. The migration ability of HUVECs was enhanced by bevacizumab under hypoxia. Upregulation of CD105 was abrogated by anlotinib, which targets multiple receptor tyrosine kinases including VEGFR2/3, FGFR1-4, PDGFR alpha/beta, C-Kit, and RET. Conclusions: Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGF beta 1 pathway and upregulation of CD105 expression. Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.
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