Ronghan Zhang1,2, Xiaogang Chen1,2, Shengwen Chen1,2, Jiajia Tang1,2, Feng Chen1,2, Yong Lin1,2, Peter Sol Reinach1,2, Xiyun Yan3,4,5, LiLi Tu1,2, Hongxia Duan6, Jia Qu7,8, Qiang Hou9,10. 1. School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325037, Zhejiang, China. 2. State Key Laboratory of Optometry, Ophthalmology and Visual Science, Wenzhou Medical University, Wenzhou, 325037, Zhejiang, China. 3. Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. 4. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. 5. Joint Laboratory of Nanozymes in Zhengzhou University, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. 6. Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. cherryshoen@ibp.ac.cn. 7. School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325037, Zhejiang, China. qujia@eye.ac.cn. 8. State Key Laboratory of Optometry, Ophthalmology and Visual Science, Wenzhou Medical University, Wenzhou, 325037, Zhejiang, China. qujia@eye.ac.cn. 9. School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, 270 Xueyuan Road, Wenzhou, 325037, Zhejiang, China. houqiang@wmu.edu.cn. 10. State Key Laboratory of Optometry, Ophthalmology and Visual Science, Wenzhou Medical University, Wenzhou, 325037, Zhejiang, China. houqiang@wmu.edu.cn.
Abstract
PURPOSE: Anti-angiogenesis drug therapy is ineffective in treating uveal melanoma since it only targets angiogenesis leaving vasculogenic mimicry aside. There is no effective clinical strategy targeting vasculogenic mimicry, yet. We show here that CD146 is a novel target to inhibit uveal melanoma progression since it regulates both uveal melanoma angiogenesis and vasculogenic mimicry activity. METHODS: CD146 inhibition was achieved with its specific siRNAs or antibody AA98. Tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation, migration, invasion of uveal melanoma cells were evaluated after CD146 inhibition. The underlying mechanisms were investigated by Western blot and immunofluorescence. Finally, uveal melanoma cells were injected subretinally into the eyes of nude mice and AA98 was administrated. Tumor size was revealed by H&E staining, and angiogenesis and vasculogenic mimicry were evaluated with CD31-PAS staining. RESULTS: CD146 inhibition induced declines in tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation of uveal melanoma cells. CD146 mediated VEGFR/AKT/p38/NF-κB and FAK/VE-cadherin signal cascades were partially responsible for these biological effects. CD146 blockade by siRNA or AA98 also resulted in inhibition of migration and invasion as well as EMT process of uveal melanoma cells. The physiological relevance of such declines was confirmed by showing that AA98 treatment markedly suppressed the tumor growth, angiogenesis and vasculogenic mimicry induced by implantation of uveal melanoma cells into the eyes of nude mice. CONCLUSIONS: CD146 is a novel mediator of both angiogenesis and vasculogenic mimicry in uveal melanoma. Its antibody AA98 has the potency to be developed as a new antibody drug for treating uveal melanoma. Our results warrant further assessment of CD146 as a potential target to improve therapeutic management of uveal melanoma in a clinical setting.
PURPOSE: Anti-angiogenesis drug therapy is ineffective in treating uveal melanoma since it only targets angiogenesis leaving vasculogenic mimicry aside. There is no effective clinical strategy targeting vasculogenic mimicry, yet. We show here that CD146 is a novel target to inhibit uveal melanoma progression since it regulates both uveal melanoma angiogenesis and vasculogenic mimicry activity. METHODS: CD146 inhibition was achieved with its specific siRNAs or antibody AA98. Tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation, migration, invasion of uveal melanoma cells were evaluated after CD146 inhibition. The underlying mechanisms were investigated by Western blot and immunofluorescence. Finally, uveal melanoma cells were injected subretinally into the eyes of nude mice and AA98 was administrated. Tumor size was revealed by H&E staining, and angiogenesis and vasculogenic mimicry were evaluated with CD31-PAS staining. RESULTS: CD146 inhibition induced declines in tube formation and migration of primary human retinal microvascular endothelial cells and tube-like structure formation of uveal melanoma cells. CD146 mediated VEGFR/AKT/p38/NF-κB and FAK/VE-cadherin signal cascades were partially responsible for these biological effects. CD146 blockade by siRNA or AA98 also resulted in inhibition of migration and invasion as well as EMT process of uveal melanoma cells. The physiological relevance of such declines was confirmed by showing that AA98 treatment markedly suppressed the tumor growth, angiogenesis and vasculogenic mimicry induced by implantation of uveal melanoma cells into the eyes of nude mice. CONCLUSIONS: CD146 is a novel mediator of both angiogenesis and vasculogenic mimicry in uveal melanoma. Its antibody AA98 has the potency to be developed as a new antibody drug for treating uveal melanoma. Our results warrant further assessment of CD146 as a potential target to improve therapeutic management of uveal melanoma in a clinical setting.
Authors: Justin C Moser; Jose S Pulido; Roxana S Dronca; Robert R McWilliams; Svetomir N Markovic; Aaron S Mansfield Journal: Melanoma Res Date: 2015-02 Impact factor: 3.599
Authors: Ahmad A Tarhini; Paul Frankel; Kim A Margolin; Scott Christensen; Christopher Ruel; Janice Shipe-Spotloe; David R Gandara; Alice Chen; John M Kirkwood Journal: Clin Cancer Res Date: 2011-08-31 Impact factor: 12.531
Authors: Irene Christa Notting; Guy Sam Omer Antoon Missotten; Bianca Sijmons; Zita Francisca Helena Maria Boonman; Jan Ernest Everard Keunen; Gabriel van der Pluijm Journal: Curr Eye Res Date: 2006-09 Impact factor: 2.424
Authors: A J Maniotis; R Folberg; A Hess; E A Seftor; L M Gardner; J Pe'er; J M Trent; P S Meltzer; M J Hendrix Journal: Am J Pathol Date: 1999-09 Impact factor: 4.307
Authors: Christine D M Roelofsen; Annemijn P A Wierenga; Sjoerd van Duinen; Robert M Verdijk; Jaco Bleeker; Marina Marinkovic; Gregorius P M Luyten; Martine J Jager Journal: Ocul Oncol Pathol Date: 2020-12-15