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: Peng Zhang, Dongxu He, Zhen Chen, Qiongxi Pan, Fangfang Du, Xian Zang, Yan Wang, Chunlei Tang, Hong Li, He Lu, Xiaoqiang Yao, Jian Jin, Xin Ma
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 118 Pg. 18-30 (Oct 15 2016) ISSN: 1873-2968 [Electronic] England
• PMID: 27520484 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Anthracyclines
• Antineoplastic Agents
• Biomarkers
• Bridged-Ring Compounds
• Neoplasm Proteins
• Receptors, Notch
• Taxoids
• taxane
• Doxorubicin
• Paclitaxel

Topics

• Animals
• Anthracyclines (adverse effects, therapeutic use)
• Antineoplastic Agents (adverse effects, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, toxicity)
• Biomarkers (metabolism)
• Breast Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Bridged-Ring Compounds (adverse effects, therapeutic use)
• Doxorubicin (adverse effects, therapeutic use)
• Endothelium, Vascular (drug effects, metabolism, pathology)
• Female
• Humans
• MCF-7 Cells
• Mice, Nude
• Microvessels (drug effects, metabolism, pathology)
• Neoplasm Proteins (agonists, antagonists & inhibitors, genetics, metabolism)
• Neovascularization, Pathologic (chemically induced, metabolism, pathology)
• Paclitaxel (adverse effects, therapeutic use)
• RNA Interference
• Receptors, Notch (agonists, antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Specific Pathogen-Free Organisms
• Taxoids (adverse effects, therapeutic use)
• Xenograft Model Antitumor Assays