MICAL2 is expressed in cancer associated neo-angiogenic capillary endothelia and it is required for endothelial cell viability, motility and VEGF response
| Autor: | Elena Tenedini, Francesca Scebba, Marianna Vitiello, Gabriele Berti, Ivana Barravecchia, Laura Poliseno, Carla Vindigni, Angela Pucci, Sara Mariotti, Marco Cecchini, Debora Angeloni, Chiara Maria Mazzanti, Silvio Bicciato, Enrico Tagliafico, Chiara De Cesari |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A 0301 basic medicine Angiogenesis Gene Expression CCG-1423 MICAL2 Cardiac myxoma Glioblastoma Inflammation neo-angiogenesis 0302 clinical medicine Cell Movement Neoplasms Anilides Myocytes Cardiac RNA Small Interfering Neovascularization Pathologic Chemistry Microfilament Proteins Endothelial stem cell 030220 oncology & carcinogenesis Benzamides Molecular Medicine Immunohistochemistry RNA Interference medicine.symptom Oxidoreductases Cell Survival Neovascularization Physiologic Motility 03 medical and health sciences medicine Animals Humans Rats Wistar Molecular Biology Cell Proliferation Endothelial Cells Cancer medicine.disease Rats Gene expression profiling 030104 developmental biology Cancer cell Cancer research Blood Vessels |
| Popis: | The capacity of inducing angiogenesis is a recognized hallmark of cancer cells. The cancer microenvironment, characterized by hypoxia and inflammatory signals, promotes proliferation, migration and activation of quiescent endothelial cells (EC) from surrounding vascular network. Current anti-angiogenic drugs present side effects, temporary efficacy, and issues of primary resistance, thereby calling for the identification of new therapeutic targets. MICALs are a unique family of redox enzymes that destabilize F-actin in cytoskeletal dynamics. MICAL2 mediates Semaphorin3A-NRP2 response to VEGFR1 in rat ECs. MICAL2 also enters the p130Cas interactome in response to VEGF in HUVEC. Previously, we showed that MICAL2 is overexpressed in metastatic cancer. A small-molecule inhibitor of MICAL2 exists (CCG-1423). Here we report that 1) MICAL2 is expressed in neo-angiogenic ECs in human solid tumors (kidney and breast carcinoma, glioblastoma and cardiac myxoma, n = 67, were analyzed with immunohistochemistry) and in animal models of ischemia/inflammation neo-angiogenesis, but not in normal capillary bed; 2) MICAL2 protein pharmacological inhibition (CCG-1423) or gene KD reduce EC viability and functional performance; 3) MICAL2 KD disables ECs response to VEGF in vitro. Whole-genome gene expression profiling reveals MICAL2 involvement in angiogenesis and vascular development pathways. Based on these results, we propose that MICAL2 expression in ECs participates to inflammation-induced neo-angiogenesis and that MICAL2 inhibition should be tested in cancer- and noncancer-associated neo-angiogenesis, where chronic inflammation represents a relevant pathophysiological mechanism. |
| Databáze: | OpenAIRE |
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