MICAL2 is expressed in cancer associated neo-angiogenic capillary endothelia and it is required for endothelial cell viability, motility and VEGF response

Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2111-2124. doi: 10.1016/j.bbadis.2019.04.008. Epub 2019 Apr 18.


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.

Keywords: CCG-1423; Cardiac myxoma; Glioblastoma; Inflammation; MICAL2; neo-angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Benzamides / pharmacology
  • Blood Vessels / metabolism
  • Blood Vessels / pathology
  • Cell Movement* / drug effects
  • Cell Proliferation
  • Cell Survival / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Gene Expression
  • Humans
  • Male
  • Microfilament Proteins / antagonists & inhibitors
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Neoplasms / blood supply
  • Neoplasms / pathology
  • Neovascularization, Pathologic
  • Neovascularization, Physiologic
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Wistar
  • Vascular Endothelial Growth Factor A / metabolism*


  • Anilides
  • Benzamides
  • CCG 1423
  • Microfilament Proteins
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • MICAL2 protein, human
  • Oxidoreductases