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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Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by hypoxic regions, yet they are not impeded by the oxidative stress in their microenvironment. PDA’s high resilience raises the need to find new effective therapeutic targets. This study investigated methionine aminopeptidase 2 (MetAp2) — a metallopeptidase known to play an important role in tumor progression — as a potential target for treating PDA by blocking its activity. Immunohistology of patient-derived PDA tissue sections revealed high expression of MetAp2 in metastatic regions compared with primary sites. Pancreatic cancer cells (cell lines and patient derived) exhibited high expression levels of MetAp2 and significant inhibition of proliferation upon exposure to a selective MetAp2 inhibitor. The growth of Orthoptic pancreatic PancOH7 tumors in mice was significantly suppressed when MetAp2 inhibitor was administered orally. Our finding revealed that the inhibition of MetAp2 in cells was associated with a significant reduction in glutathione (GSH) levels, a substance known for its role in alleviating oxidative stress, which suggests a possible rationale for the anti-cancer activity in highly hypoxic tumors such as PDA. Taken together, our results indicate that MetAp2 can be a studied as a target in PDA and possibly in other tumors with high expression levels of MetAp2 which are not necessarily highly angiogenic tumors.