Inhibitory Activity of Bevacizumab to Differentiation of Retinoblastoma Cells

Abstract

Vascular endothelial growth factor (VEGF) is a major regulator in retinal and choroidal angiogenesis, which are common causes of blindness in all age groups. Recently anti-VEGF treatment using anti-VEGF antibody has revolutionarily improved the visual outcome in patients with vaso-proliferative retinopathies. Herein, we demonstrated that bevacizumab as an anti-VEGF antibody could inhibit differentiation of retinoblastoma cells without affection to cellular viability, which would be mediated via blockade of extracellular signal-regulated kinase (ERK) 1/2 activation. The retinoblastoma cells expressed VEGFR-2 as well as TrkA which is a neurotrophin receptor associated with differentiation of retinoblastoma cells. TrkA in retinoblastoma cells was activated with VEGF treatment. Interestingly even in the concentration of no cellular death, bevascizumab significantly attenuated the neurite formation of differentiated retinoblastoma cells, which was accompanied by inhibition of neurofilament and shank2 expression. Furthermore, bevacizumab inhibited differentiation of retinoblastoma cells by blockade of ERK 1/2 activation. Therefore, based on that the differentiated retinoblastoma cells are mostly photoreceptors, our results suggest that anti-VEGF therapies would affect to the maintenance or function of photoreceptors in mature retina.

Domain I-IV of β2-glycoprotein I inhibits advanced glycation end product-induced angiogenesis by down-regulating vascular endothelial growth factor 2 signaling

“…One important pathogenic mechanism in PDR is neovascularization, which is promoted by various factors, including hypoxia, local inflammation and angiogenic factors, including VEGF and FGF-2 (13,14). VEGF, particularly VEGF-A, is a key factor promoting angiogenesis by binding with its receptors, VEGFR-1 and VEGFR-2.…”

Antitumor Response to Combined Antiangiogenic and Cytotoxic Chemotherapy in Recurrent Metastatic Chromophobe Renal Cell Carcinoma: Response Signatures and Proteomic Correlates

“…Bevacizumab binds to VEGF, thereby preventing it from binding to, and activating its cognate receptors. VEGF stimulation has also been shown to promote ERK phosphorylation, and cell proliferation, while bevacizumab removed this effect by blockade of ERK1/2 activation 31,32 thus likely disrupting the activated MAPK/ERK pathway in this tumor. It has also been hypothesized that bevacizumab-induced “normalization” of vascular architecture produces a transient, and long term hemodynamic phenomenon which improves chemotherapy delivery to tumor tissue 27 .…”

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

“…Thus, all these data together suggest that ␤2 integrin antibody rescued the retinal vascular hyperpermeability induced by VEGF through the cytoskeleton rearrangement and also that ␤2 integrin can serve as an effective therapeutic target for VEGF-induced retinal vascular hyperpermeability. DISCUSSION VEGF is a trophic factor for neuronal and endothelial cells in the retina, as well as a driving factor for vascular hyperpermeability (10,11,36). Thus, therapeutic targets other than VEGF have been searched to circumvent potential toxicity of anti-VEGF agents.…”

“…However, VEGF not only promotes vascular permeability, but also plays an important role in the survival of normal endothelial and neuronal cells in the retina (10,11). Furthermore, VEGF affects various downstream intracellular molecular pathways that are associated with the maintenance of retinal endothelial cells (9,12).…”