The Role of Methionine Aminopeptidase 2 in Lymphangiogenesis

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.

EGR1 Enhances Lymphangiogenesis via SOX18-Mediated Activation of JAK2/STAT3 Pathway

“…A number of studies have been reported that factors involved in angiogenesis also have an effect on lymphangiogenesis. For instance, MetAp2 has been reported to have a dual role in the formation of blood and lymphatic vessels [ 5 ]. EGR1 has been demonstrated to have a critical role in blood vessel formation [ 16 – 18 ].…”

“…The progression of lymphangiogenesis involves a number of molecules and pathways. VEGF is suggested to be the most important regulator in lymphatic generation and is wildly used as a therapeutic target against diseases associated with lymphatic generation, such as cancer [ 5 , 6 ]. However, there are many other factors involved in lymphangiogenesis.…”

“…Similar to angiogenesis, lymphangiogenesis is the process by which new lymphatic vessels are formed [ 19 ]. Multiple angiogenesis-related regulators have also been reported to be involved in lymphangiogenesis [ 5 , 19 , 20 ]. Therefore, we hypothesized that EGR1 may also have a crucial function in the progression of lymphangiogenesis.…”

Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models

“…It is important to note that the studies performed focused on the impact of MetAP2 inhibition on the tumor and endothelial cell compartments but did not investigate modulation of the immune system. Immune modulatory effects of MetAP2 inhibition have been investigated anecdotally, but further, more systematic studies in immune-competent mouse tumor models are required to better characterize its function ( 32, 33 ). Further development of M8891 will be managed by the Oncoteq AG subsidiary of Cureteq AG ( 34 ), which licensed M8891 from Merck KGaA following the determination of the recommended phase II dose in a phase Ia trial ( 35 ) and the strategic portfolio decision by Merck KGaA.…”

Attacking Cancer Progression and Metastasis

“…The role of methionine aminopeptidase 2 (MetAp2), an intracellular enzyme known to modulate angiogenesis, in lymphangiogenesis has been described by Rawnaque Esa et al [9]. 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.…”