artemin promotes de novo angiogenesis in er negative mammary carcinoma through activation of twist1-vegf-a signallingartemin促进新创血管生成在er阴性乳腺癌twist1-vegf-a信号激活.pdf

ARTEMIN Promotes De Novo Angiogenesis in ER Negative Mammary Carcinoma through Activation of TWIST1-VEGF-A Signalling 1 2,3,4 2 1 1 2 Arindam Banerjee , Zheng-Sheng Wu , Peng-Xu Qian , Jian Kang , Dong-Xu Liu , Tao Zhu *, Peter E. Lobie5* 1 Liggins Institute, University of Auckland, Auckland, New Zealand, 2 Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China, 3 Department of Pathology, Anhui Medical University, Hefei, Anhui, People’s Republic of China, 4 Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China, 5 Cancer Science Institute of Singapore and Department of Pharmacology, National University of Singapore, Singapore, Singapore Abstract The neurotrophic factor ARTEMIN (ARTN) has been reported to possess a role in mammary carcinoma progression and metastasis. Herein, we report that ARTN modulates endothelial cell behaviour and promotes angiogenesis in ER-mammary carcinoma (ER-MC). Human microvascular endothelial cells (HMEC-1) do not express ARTN but respond to exogenously added, and paracrine ARTN secreted by ER-MC cells. ARTN promoted endothelial cell proliferation, migration, invasion and 3D matrigel tube formation. Angiogenic behaviour promoted by ARTN secreted by ER-MC cells was mediated by AKT with resultant increased TWIST1 and subsequently VEGF-A expression. In a patient cohort of ER-MC, ARTN positively correlated with VEGF-A expression as measured by Spearman’s rank correlation analysis. In xenograft experiments, ER-MC cells with forced expression of ARTN produced tumors with increased VEGF-A expressio