The role of methionine aminopeptidase 2 in lymphangiogenesis

Rawnaq Esa, Eliana Steinberg, Dvir Dror, Ouri Schwob, Mehrdad Khajavi, Myriam Maoz, Yael Kinarty, Adi Inbal, Aviad Zick, Ofra Benny*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

During the metastasis process, tumor cells invade the blood circulatory system directly from venous capillaries or indirectly via lymphatic vessels. Understanding the relative contribution of each pathway and identifying the molecular targets that affect both processes is critical for reducing cancer spread. Methionine aminopeptidase 2 (MetAp2) is an intracellular enzyme known to modulate angiogenesis. In this study, we investigated the additional role of MetAp2 in lymphangiogenesis. A histological staining of tumors from human breast-cancer donors was performed in order to detect the level and the localization of MetAp2 and lymphatic capillaries. The basal enzymatic level and activity in vascular and lymphatic endothelial cells were compared, followed by loss of function studies determining the role of MetAp2 in lymphangiogenesis in vitro and in vivo. The results from the histological analyses of the tumor tissues revealed a high MetAp2 expression, with detectable sites of co-localization with lymphatic capillaries. We showed slightly reduced levels of the MetAp2 enzyme and MetAp2 mRNA expression and activity in primary lymphatic cells when compared to the vascular endothelial cells. The genetic and biochemical manipulation of MetAp2 confirmed the dual activity of the enzyme in both vascular and lymphatic remodulation in cell function assays and in a zebrafish model. We found that cancer-related lymphangiogenesis is inhibited in murine models following MetAp2 inhibition treatment. Taken together, our study provides an indication that MetAp2 is a significant contributor to lymphangiogenesis and carries a dual role in both vascular and lymphatic capillary formation. Our data suggests that MetAp2 inhibitors can be effectively used as anti-metastatic broad-spectrum drugs.

Original languageAmerican English
Article number5148
JournalInternational Journal of Molecular Sciences
Volume21
Issue number14
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
Funding: This study was kindly supported by grants from the Marie Curie Career Integration Grants (CIG) (No. 0305116), Israel; Cancer Association (ICA) (No. 0394691), Israel Foundation of Science. (ISF) (No. 0394883),

Funding Information:
This study was kindly supported by grants from the Marie Curie Career Integration Grants (CIG) (No. 0305116), Israel; Cancer Association (ICA) (No. 0394691), Israel Foundation of Science. (ISF) (No. 0394883),.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Angiogenesis
  • Cancer
  • Lymphangiogenesis
  • MetAp2
  • Metastasis

Fingerprint

Dive into the research topics of 'The role of methionine aminopeptidase 2 in lymphangiogenesis'. Together they form a unique fingerprint.

Cite this