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.
Highlights
Cancer metastasis is associated with a high mortality rate and is the primary cause of cancer morbidity
In patient-derived breast cancer tissues, we found that Methionine aminopeptidase 2 (MetAp2) is expressed and co-localized with lymphatic vessels
We found that the basal expressions of MetAp2 and its activities in human lymphatic endothelial cells (LECs) versus vascular endothelial cells (VECs) were comparable, with slightly higher levels in VECs
Summary
Cancer metastasis is associated with a high mortality rate and is the primary cause of cancer morbidity. VEGF, which is overexpressed in most cancers and functions as a crucial regulator in angiogenesis and lymphangiogenesis [3,7,8,9], has become an important target for inhibiting tumor metastasis. There are two forms of MetAp in eukaryotes: MetAp1 and MetAp2, the latter having received more interest This is because the induction of Metap was shown to mediate cell proliferation and lead to G1 arrest when inhibited [13,14,15,16,17], since it affects protein synthesis via the post-translation removal of methionine [18,19,20,21]. Given MetAp2’s major role in protein synthesis in activated vascular endothelial cells, we hypothesize that MetAp2 affects lymphangiogenesis by mediating the lymphatic endothelium formation via shared mechanisms. Our data suggest that MetAp2 is a mediator of both angiogenesis and lymphangiogenesis and that its inhibition may slow cancer progression and metastasis
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