title: Chemotherapy enhances tumor vascularization via Notch signaling-mediated formation of tumor-derived endothelium in breast cancer.
abstract: 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.
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors: Peng
authors: P
authors: Zhang
authors: National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi, China.
authors: Dongxu
authors: D
authors: He
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors: Zhen
authors: Z
authors: Chen
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors: Qiongxi
authors: Q
authors: Pan
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors: Fangfang
authors: F
authors: Du
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors: Xian
authors: X
authors: Zang
authors: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors: Yan
authors: Y
authors: Wang
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China.
authors: Chunlei
authors: C
authors: Tang
authors: DIFEMA, Merci (EA 3829), Faculté de Médecine et de Pharmacie, Université de Rouen, F-76183 Rouen, France.
authors: Hong
authors: H
authors: Li
authors: INSERM, UMR-S1165, Hôpital Saint Louis, IUH, Université Paris Diderot, F-75010 Paris, France.
authors: He
authors: H
authors: Lu
authors: School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
authors: Xiaoqiang
authors: X
authors: Yao
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China. Electronic address: jinjian31@126.com.
authors: Jian
authors: J
authors: Jin
authors: School of Pharmaceutical Sciences, Jiangnan University, Wuxi, China; School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. Electronic address: maxin@jiangnan.edu.cn.
authors: Xin
authors: X
authors: Ma
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000633:toxicity; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000009:adverse effects / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use; D034622:RNA Interference; D051880:Receptors, Notch / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D015415:Biomarkers; D001952:Bridged-Ring Compounds; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D043823:Taxoids; C080625:taxane; D004317:Doxorubicin; D017239:Paclitaxel
keywords: Breast cancer cells; Chemotherapy; Endothelial cells; Notch signaling