Chemotherapy enhances tumor vascularization via Notch signaling-mediated formation of tumor-derived endothelium in breast cancer.
It is believed that tumor cells can give rise to endothelial cells and tumor endothelium has a neoplastic origin. Yet, the stimuli and underlying mechanism remain unclear. Here, we demonstrate that adriamycin or paclitaxel, first-line chemotherapy agent, induced breast cancer cells to generate morphological, phenotypical and functional features of endothelial cells in vitro. In xenografts models, challenges from adriamycin or paclitaxel induced cancer cells to generate the majority of microvessels. Importantly, in breast cancer specimens from patients with neoadjuvant anthracycline-based or taxane-based chemotherapy, tumor-derived endothelial microvessels, lined by EGFR-amplified or/and TP53+-CD31+ endothelial cells, was significantly higher in patients with progressive or stable disease (PD/SD) than in those with a partial or complete response (PR/CR). Further, exposure to the Notch signaling inhibitor and gene silencing studies showed that Notch signaling inhibition or silencing Nothc4/Dll3 decreased endothelial markers and function of tumor-derived endothelial cells under chemotherapy treatment, which may be through VEGFR3. Thus, our findings demonstrate that chemotherapy induces functional tumor-derived endothelial microvessels by mediating Notch signaling and VEGF signaling, and may provide new targets for anti-angiogenesis therapy in breast cancer.
['Zhang|Peng|P|', 'He|Dongxu|D|', 'Chen|Zhen|Z|', 'Pan|Qiongxi|Q|', 'Du|Fangfang|F|', 'Zang|Xian|X|', 'Wang|Yan|Y|', 'Tang|Chunlei|C|', 'Li|Hong|H|', 'Lu|He|H|', 'Yao|Xiaoqiang|X|', 'Jin|Jian|J|', 'Ma|Xin|X|']
D000818:Animals D018943:Anthracyclines D000970:Antineoplastic Agents D000971:Antineoplastic Combined Chemotherapy Protocols D015415:Biomarkers D001943:Breast Neoplasms D001952:Bridged-Ring Compounds D004317:Doxorubicin D004730:Endothelium, Vascular D005260:Female D006801:Humans D061986:MCF-7 Cells D008819:Mice, Nude D055806:Microvessels D009363:Neoplasm Proteins D009389:Neovascularization, Pathologic D017239:Paclitaxel D034622:RNA Interference D051880:Receptors, Notch D015398:Signal Transduction D013047:Specific Pathogen-Free Organisms D043823:Taxoids D023041:Xenograft Model Antitumor Assays
Chemotherapy Endothelial cells Breast cancer cells Notch signaling