Abstract
Despite the implication of vascular endothelial growth factor-A (VEGF-A) in the pathophysiology of uveal melanoma (UM), the anti-VEGF-A antibody bevacizumab yielded conflicting results on UM growth. Here, we evaluated whether bevacizumab and ranibizumab, a humanized Fab-fragment against VEGF-A, can enter UM cells and induce a sustained physiological response. The primary and metastatic UM cell lines Mel-270 and OMM-2.5 were exposed to bevacizumab or ranibizumab for one day and were maintained further in untreated medium for a total of three days. Both antibodies significantly reduced the levels of extracellular VEGF-A and the angiogenic potential of the conditioned medium after one day. These inhibitory effects of bevacizumab diminished by day three. Ranibizumab suppressed the metabolic activity, proliferation, and intracellular VEGF-A levels in a cell-type and concentration-dependent manner, whereas bevacizumab exerted no effect. Both drugs were detected inside early endosomes within the UM cells, with the stronger and sustained colocalization of ranibizumab. Our results therefore demonstrated the more potent and persistent suppressive activity of ranibizumab on the UM cells, possibly due to its higher level of uptake and prolonged intracellular retention. Further research on the endosome dynamics in UM cells might provide valuable insight into the response of these heterogenous tumors to therapeutic antibodies.
Highlights
Uveal melanoma (UM) is the most common primary intraocular malignancy arising in adults.Current treatments of UM depend on several clinical factors and include radiotherapy, enucleation, transpupillary thermotherapy, as well as local resection [1]
Our results demonstrated that ranibizumab can suppress the proliferation, metabolic activity, Vascular endothelial growth factor A (VEGF-A) levels, and angiogenic potential of UM cells more effectively than bevacizumab, possibly due to the uptake efficiency and longer retention of the former antibody inside the cells
These antibodies should not be regarded as external agents with a limited elimination half-life in ocular fluids, but their prolonged action inside the UM cells should be taken into consideration, as well
Summary
Uveal melanoma (UM) is the most common primary intraocular malignancy arising in adults.Current treatments of UM depend on several clinical factors and include radiotherapy, enucleation, transpupillary thermotherapy, as well as local resection [1]. Despite tremendous progress in the diagnosis and local control of the primary tumor, up to 50% of UM patients may develop systemic metastases, leading to their currently inevitable death from this disease [2]. Since metastases of UM occur generally through the hematogenous route, dissemination of the primary tumor cells into peripheral blood is a prerequisite [3]. Angiogenesis is a hallmark of tumor growth and invasion in primary UM and its metastatic disease [4,5]. Vascular endothelial growth factor A (VEGF-A) plays the central role in promoting angiogenesis by binding its specific tyrosine kinase VEGF receptors VEGF-R1 and VEGF-R2, which are primarily expressed on the surface of vascular endothelial cells [6,7]. VEGF-A can stimulate the proliferation, survival, Cancers 2019, 11, 868; doi:10.3390/cancers11060868 www.mdpi.com/journal/cancers
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