Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma

Kim, Eugene; Serur, Anna; Huang, Jianzhong; Manley, Christina; McCrudden, Kimberly W.; Frischer, Jason S.; Soffer, Samuel Z.; Ring, Laurence E.; New, Tamara; Zabski, Stephanie M.; Rudge, John S.; Holash, Jocelyn; Yancopouloš, George D.; Kandel, Jessica J.; Yamashiro, Darrell J.

doi:10.1073/pnas.172398399

Cited by 291 publications

(195 citation statements)

References 14 publications

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“…The VEGF signaling pathway can be inhibited at various levels, that is, by blocking the activity of VEGF with monoclonal antibodies, 69 blocking the VEGFR with specific inhibitors 70 or interfering with the tyrosine kinases activated by the VEGF/VEGFR interaction. 71 Systemically administered antibodies to VEGF-A accumulate selectively in tumor vessels in much higher concentrations than in normal tissue.…”

Section: Vegf As a Potential Target For Antiangiogenic Treatmentmentioning

confidence: 99%

Vascular endothelial growth factor and its receptors in multiple myeloma

et al. 2003

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Multiple myeloma (MM) progresses from an avascular to a vascular phase (active MM) accompanied by a significant increase in microvessel density in the bone marrow. This article summarizes the literature concerning the specific role played by vascular endothelial growth factor (VEGF) in this process. Recent applications of antiangiogenic agents that interfere with VEGF signaling and block MM progression are also described.

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Section: Vegf As a Potential Target For Antiangiogenic Treatmentmentioning

confidence: 99%

Vascular endothelial growth factor and its receptors in multiple myeloma

et al. 2003

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“…In the tumour periphery, in contrast, a robust angiogenic response was observed. Vessel cooption has now been observed in different tumour types like human melanoma (Döme et al, 2002), neuroblastoma (Kim et al, 2002), and ovarian cancer (Zhang et al, 2003), it can persist during the entire period of tumour growth and it can even represent the only source for nutrients in angiogenesis-independent tumour growth (Sakariassen et al, 2006). From these experimental observations the anatomy of solid, vascularized tumour grown within in a vascularized tissue displays a characteristic compartmentalization into essentially three regions (Holash et al, 1999a, Döme et al, 2002: I) The highly vascularized tumour perimeter with a microvascular density (MVD) that is substantially higher than the MVD of the surrounding normal tissue.…”

Section: Introductionmentioning

confidence: 99%

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

Welter

Bartha

Rieger

2009

Journal of Theoretical Biology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d m a n u s c r i p t AbstractWe formulate a theoretical model to analyse the vascular remodelling process of an arterio-venous vessel network during solid tumour growth. The model incorporates a hierarchically organized initial vasculature comprising arteries, veins and capillaries, and involves sprouting angiogenesis, vessel cooption, dilation and regression as well as tumour cell proliferation and death. The emerging tumour vasculature is non-hierarchical, compartmentalized into well characterized zones and transports efficiently an injected drug-bolus. It displays a complex geometry with necrotic zones and "hot spots" of increased vascular density and blood flow of varying size. The corresponding cluster size distribution is algebraic, reminiscent of a self-organized critical state.The intra-tumour vascular-density fluctuations correlate with pressure drops in the initial vasculature suggesting a physical mechanism underlying hot-spot formation.

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“…First, clinical and animal data show that for metastatic tumors in brains, lungs or livers, induction of angiogenesis is not a prerequisite as for these tumors the preexistent vascular bed may allow tumor growth (Pezzella et al, 1997;Al-Mehdi et al, 2000;Neves et al, 2001;Vermeulen et al, 2001;Kim et al, 2002;Kusters et al, 2002;Passalidou et al, 2002;Auguste et al, 2005). Secondly, recent reports demonstrated the presence of intravascular endothelium-covered tumor cell clusters in the primary tumor as origin of metastasis (Sugino et al, 1993(Sugino et al, , 2002(Sugino et al, , 2004.…”

Section: Introductionmentioning

confidence: 99%

Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

et al. 2007

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How and why tumors metastasize is still a matter of debate. The assumption is that mutations render tumor cells with a metastatic phenotype, enabling entrance in and transport through lymph or blood vessels. Distant outgrowth is thought to occur only in a suitable microenvironment (the seed and soil hypothesis). However, the anatomical location of most metastases in cancer patients suggests entrapment of tumor cells in the first microcapillary bed that is encountered. We here investigated how vascular endothelial growth factor-A (VEGF-A) attributes to the metastatic process. We describe here that VEGF-A enhances spontaneous metastasis by inducing intravasation of heterogeneous tumor cell clusters, surrounded by vessel wall elements, via an invasionindependent mechanism. These tumor clusters generate metastatic tissue embolisms in pulmonary arteries. Treatment of tumor-bearing mice with the antiangiogenic compound ZD6474 prevented the development of this metastatic phenotype. This work shows that tumors with high constitutive VEGF-A expression metastasize via the formation of tumor emboli and provides an alternative rationale for anti-VEGF-A therapy, namely to inhibit metastasis formation.

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Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma

Abstract: These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.

Cited by 291 publications

References 14 publications

Vascular endothelial growth factor and its receptors in multiple myeloma

Vascular endothelial growth factor and its receptors in multiple myeloma

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

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