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 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.

Newly synthesized methionine aminopeptidase 2 inhibitor hinders tumor growth.

Methionine aminopeptidase 2 (MetAp2) inhibition has been recognized as a promising approach for suppressing angiogenesis and cancer progression. Small molecule fumagillol derivatives with adamantane side groups were synthesized and evaluated for MetAp2 inhibition activity, and a lead molecule with superior abilities to inhibit the enzymatic activity of MetAp2 was identified. The compound, referred to as AD-3281, effectively suppressed proliferation of cancer and endothelial cells and impaired tube formation of endothelial cells in vitro. When administered systemically, AD-3281 was well tolerated and led to a significant suppression of human melanoma and mammary tumor xenografts grown in mice. The activity in vivo was associated with reduced angiogenesis and tumor proliferation as detected histologically. In order to develop a formulation that can solubilize AD-3281 with a minimal content of organic solvents, biodegradable nanoparticles comprised of poly-lactic-co-glycolic acid (PLGA) were fabricated and characterized. Compared with the free compound, AD-3281-loaded nanoparticles showed an advantageous cellular availability and uptake, leading to higher activity in cells and better transport in three-dimensional (3D) cultures. Taken together, we introduce a novel MetAp2 inhibitor with high anti-cancer activity and a stable nano-formulation with a high potential for future clinical translation.

Methionine aminopeptidase 2 as a potential target in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by severe hypoxic regions, yet these regions 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 the suitability of methionine aminopeptidase 2 (MetAp2), a metallopeptidase known to play an important role in tumor progression, as a new target for treating PDA. In our examination of patient-derived PDA tissues, we found that MetAp2 is highly expressed in metastatic regions compared with primary sites. At the cellular level, we found that the basal expression levels of MetAp2 in pancreatic cancer cells were higher than its levels in endothelial cells. Pancreatic cancer cells showed a significant suppression of proliferation in a dose-dependent manner upon exposure to TNP-470, a selective MetAp2 inhibitor. In addition, a significant reduction in glutathione (GSH) levels - known for its importance in alleviating oxidative stress - was detected in all treated cells, suggesting a possible anti-cancer activity mechanism that would be feasible for treating highly hypoxic PDA tumors. Furthermore, in an orthotopic pancreatic cancer murine model, systemic oral treatment with a MetAp2 inhibitor significantly reduced tumors' growth. Taken together, our findings indicate that MetAp2 enhances tumor sensitivity to hypoxia and may provide an effective target for treating hypoxic tumors with high expression levels of MetAp2.