Article ; Online: The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis.
International journal of molecular sciences
2020 Volume 21, Issue 14
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 ...
| 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. |
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| MeSH term(s) | Angiogenesis Inhibitors/pharmacology ; Animals ; Animals, Genetically Modified ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Endothelial Cells/drug effects ; Endothelial Cells/enzymology ; Endothelial Cells/metabolism ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/enzymology ; Endothelium, Vascular/metabolism ; Humans ; Lymphangiogenesis/genetics ; Lymphatic Metastasis/genetics ; Lymphatic Metastasis/pathology ; Lymphatic Vessels/drug effects ; Lymphatic Vessels/metabolism ; Male ; Methionyl Aminopeptidases/antagonists & inhibitors ; Methionyl Aminopeptidases/genetics ; Methionyl Aminopeptidases/metabolism ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/enzymology ; Neovascularization, Pathologic/metabolism ; O-(Chloroacetylcarbamoyl)fumagillol/pharmacology ; Xenograft Model Antitumor Assays ; Zebrafish |
| Chemical Substances | Angiogenesis Inhibitors ; METAP2 protein, human (EC 3.4.11.18) ; Methionyl Aminopeptidases (EC 3.4.11.18) ; O-(Chloroacetylcarbamoyl)fumagillol (X47GR46481) |
| Language | English |
| Publishing date | 2020-07-21 |
| Publishing country | Switzerland |
| Document type | Journal Article |
| ZDB-ID | 2019364-6 |
| ISSN | 1422-0067 ; 1422-0067 ; 1661-6596 |
| ISSN (online) | 1422-0067 |
| ISSN | 1422-0067 ; 1661-6596 |
| DOI | 10.3390/ijms21145148 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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