The VEGF Pathway in Cancer and Disease: Responses, Resistance, and the Path Forward

Kieran, Mark W.; Kalluri, Raghu; Cho, Yoon Jae

doi:10.1101/cshperspect.a006593

Cited by 174 publications

(118 citation statements)

References 191 publications

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“…[102][103] The current view on the anti-VEGF therapy, using an anti-VEGF antibody or VEGFR inhibitors, is not as optimistic as it was several years ago. 104 Despite rather disappointing results of recent clinical studies, drug targeting of the angiogenic process stimulated and accelerated the development of alternative antiangiogenic approaches. [103][104] Moreover, pathological angiogenesis shares many pathways, most notably VEGF/VEGFR2, with physiological processes, thus hindering both the success and safety of anti-VEGF therapy.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

“…104 Despite rather disappointing results of recent clinical studies, drug targeting of the angiogenic process stimulated and accelerated the development of alternative antiangiogenic approaches. [103][104] Moreover, pathological angiogenesis shares many pathways, most notably VEGF/VEGFR2, with physiological processes, thus hindering both the success and safety of anti-VEGF therapy. 105 Despite the great importance of VEGF during oxidative stress-induced angiogenesis, there are a variety of VEGFindependent signaling pathways implicated in pathological angiogenesis, such as the ROS/ATM/p38a and CEP/TLR2/MyD88 pathway, which may reduce the efficacy of anti-VEGF therapy.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

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Oxidative stress in angiogenesis and vascular disease

Kim

Byzova

2014

Blood

549

388

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Despite the damaging effect on tissues at a high concentration, it has been gradually established that oxidative stress plays a positive role during angiogenesis. In adults, physiological or pathological angiogenesis is initiated by tissue demands for oxygen and nutrients, resulting in a hypoxia/reoxygenation cycle, which, in turn promotes the formation of reactive oxygen species (ROS). The ROS can be generated either endogenously, through mitochondrial electron transport chain reactions and nicotinamide adenine dinucleotide phosphate oxidase, or exogenously, resulting from exposure to environmental agents, such as ultraviolet or ionizing radiation. In many conditions, ROS promotes angiogenesis, either directly or via the generation of active oxidation products, including peroxidized lipids. The latter lipid metabolites are generated in excess during atherosclerosis, thereby linking atherogenic processes and pathological angiogenesis. Although the main mechanism of oxidative stress-induced angiogenesis involves hypoxia-inducible factor/vascular endothelial growth factor (VEGF) signaling, recent studies have identified several pathways that are VEGF-independent. This review aims to provide a summary of the past and present views on the role of oxidative stress as a mediator and modulator of angiogenesis, and to highlight newly identified mechanisms.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

Section: Therapeutic Implicationsmentioning

confidence: 99%

Oxidative stress in angiogenesis and vascular disease

Kim

Byzova

2014

Blood

549

388

View full text Add to dashboard Cite

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“…Among them, VEGF has been used as the prime antiangiogenic target in the clinic for the last decade (4). Unfortunately, in contrast to the promising results from preclinical studies, the use of these antiangiogenic agents as monotherapy has yielded only modest therapeutic benefit in some tumor types, whereas it has failed in others (5)(6)(7). Moreover, after an initial response, resistance to this therapy is often observed.…”

Section: Introductionmentioning

confidence: 99%

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

Hawinkels

Vinuesa

Paauwe

et al. 2016

Clinical Cancer Research

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Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap.Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis.Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. An immunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone.Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.

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“…2 The vascular endothelial growth factor (VEGF) family and its receptor system, by endogenously producing vascular cytokines, contribute to angiogenesis, vasodilatation, and increased microvascular permeability. 3,4 In recent years, the development and commercialization of anti-VEGF drugs have revolutionized the therapy of patients with intraocular neovascularization. 5 Nevertheless, the precise mechanism underlying the regulation of VEGF protein expression in intraocular angiogenesis of diabetic retinopathy remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

Sun

et al. 2013

Eye

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Purpose Mü ller cells have important roles in the pathogenesis of diabetic retinopathy by promoting cell proliferation and inducing the production of vascular endothelial growth factor (VEGF) under hyperglycemic conditions. The objective of this study was to determine the potential mechanism of Mü ller cell proliferation and VEGF production due to high-glucose conditions. Methods Primary cultured rat Mü ller cells were incubated with medium containing variable concentrations of glucose and/or embelin, a specific inhibitor of X-linked inhibitor of apoptosis protein (XIAP), for 72 h. The proliferation of Mü ller cells was assessed by the MTT assay. The expression and/or phosphorylation of 146 proteins were assessed using protein pathway array. Results High concentrations of glucoseinduced Mü ller cell proliferation and altered expression and/or phosphorylation of 47 proteins that have been identified to have key roles in several important signaling pathways (XIAP, VEGF, HIF1a, NFkB, etc) and are involved in the regulation of cell survival, proliferation, or apoptosis. However, Mü ller cell alterations induced by highglucose conditions were counteracted by the XIAP inhibitor embelin, and 26 proteins/ phosphorylations (out of 47) were restored to their normal levels. Nine proteins, including NFkB p65, p-p38, tumor necrosis factor-a, urokinase-type plasminogen activator, CREB, IL-1b, HCAM, estrogen receptor-a, and p-Stat3, were involved in regulatory networks between XIAP and VEGF. Conclusions The current study suggests that XIAP may be a potential regulator that can mediate a series of pathological changes induced by high-glucose conditions in Mü ller cells. Therefore, embelin could be a potential agent for the prevention and treatment of diabetic retinopathy.

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The VEGF Pathway in Cancer and Disease: Responses, Resistance, and the Path Forward

Cited by 174 publications

References 191 publications

Oxidative stress in angiogenesis and vascular disease

Oxidative stress in angiogenesis and vascular disease

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

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