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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doaj-7c215b93dea24270825eb436c1dc7ef92020-11-25T02:37:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-01215148514810.3390/ijms21145148The Role of Methionine Aminopeptidase 2 in LymphangiogenesisRawnaq Esa0Eliana Steinberg1Dvir Dror2Ouri Schwob3Mehrdad Khajavi4Myriam Maoz5Yael Kinarty6Adi Inbal7Aviad Zick8Ofra Benny9The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelThe Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelThe Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelThe Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelBoston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USASharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem 91120, IsraelDepartment of Medical Neurobiology, Institute for Medical Research - Israel-Canada, The Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem 9112002, IsraelDepartment of Medical Neurobiology, Institute for Medical Research - Israel-Canada, The Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem 9112002, IsraelSharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem 91120, IsraelThe Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, IsraelDuring 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.https://www.mdpi.com/1422-0067/21/14/5148MetAp2, angiogenesis, lymphangiogenesis, metastasis, cancer |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rawnaq Esa Eliana Steinberg Dvir Dror Ouri Schwob Mehrdad Khajavi Myriam Maoz Yael Kinarty Adi Inbal Aviad Zick Ofra Benny |
spellingShingle |
Rawnaq Esa Eliana Steinberg Dvir Dror Ouri Schwob Mehrdad Khajavi Myriam Maoz Yael Kinarty Adi Inbal Aviad Zick Ofra Benny The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis International Journal of Molecular Sciences MetAp2, angiogenesis, lymphangiogenesis, metastasis, cancer |
author_facet |
Rawnaq Esa Eliana Steinberg Dvir Dror Ouri Schwob Mehrdad Khajavi Myriam Maoz Yael Kinarty Adi Inbal Aviad Zick Ofra Benny |
author_sort |
Rawnaq Esa |
title |
The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis |
title_short |
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_sort |
role of methionine aminopeptidase 2 in lymphangiogenesis |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-07-01 |
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. |
topic |
MetAp2, angiogenesis, lymphangiogenesis, metastasis, cancer |
url |
https://www.mdpi.com/1422-0067/21/14/5148 |
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