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The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis

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 cance...

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Autores principales: Esa, Rawnaq, Steinberg, Eliana, Dror, Dvir, Schwob, Ouri, Khajavi, Mehrdad, Maoz, Miriam, Kinarty, Yael, Inbal, Adi, Zick, Aviad, Benny, Ofra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403956/
https://www.ncbi.nlm.nih.gov/pubmed/32708166
http://dx.doi.org/10.3390/ijms21145148
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author Esa, Rawnaq
Steinberg, Eliana
Dror, Dvir
Schwob, Ouri
Khajavi, Mehrdad
Maoz, Miriam
Kinarty, Yael
Inbal, Adi
Zick, Aviad
Benny, Ofra
author_facet Esa, Rawnaq
Steinberg, Eliana
Dror, Dvir
Schwob, Ouri
Khajavi, Mehrdad
Maoz, Miriam
Kinarty, Yael
Inbal, Adi
Zick, Aviad
Benny, Ofra
author_sort Esa, Rawnaq
collection PubMed
description 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.
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spelling pubmed-74039562020-08-11 The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis Esa, Rawnaq Steinberg, Eliana Dror, Dvir Schwob, Ouri Khajavi, Mehrdad Maoz, Miriam Kinarty, Yael Inbal, Adi Zick, Aviad Benny, Ofra Int J Mol Sci Article 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. MDPI 2020-07-21 /pmc/articles/PMC7403956/ /pubmed/32708166 http://dx.doi.org/10.3390/ijms21145148 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Esa, Rawnaq
Steinberg, Eliana
Dror, Dvir
Schwob, Ouri
Khajavi, Mehrdad
Maoz, Miriam
Kinarty, Yael
Inbal, Adi
Zick, Aviad
Benny, Ofra
The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis
title The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis
title_full The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis
title_fullStr The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis
title_full_unstemmed The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis
title_short The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis
title_sort role of methionine aminopeptidase 2 in lymphangiogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403956/
https://www.ncbi.nlm.nih.gov/pubmed/32708166
http://dx.doi.org/10.3390/ijms21145148
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