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Antiangiogenic Therapy Of Cerebral Melanoma Metastases Results In Sustained Tumor Progression Via Vessel Co-Option

W. Leenders, B. Kuesters, K. Verrijp, C. Maass, P. Wesseling, A. Heerschap, D. Ruiter, A. Ryan, R. D. de Waal
Published 2004 · Medicine

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Purpose: In the brain, tumors may grow without inducing angiogenesis, via co-option of the dense pre-existent capillary bed. The purpose of this study was to investigate how this phenomenon influences the outcome of antiangiogenic therapy. Experimental Design: Mice carrying brain metastases of the human, highly angiogenic melanoma cell line Mel57-VEGF-A were either or not treated with different dosages of ZD6474, a vascular endothelial growth factor (VEGF) receptor 2 tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor. Effect of treatment was evaluated using contrast-enhanced magnetic resonance imaging (CE- MRI) and (immuno)morphologic analysis. Results: Placebo-treated Mel57-VEGF-A brain metastases evoked an angiogenic response and were highlighted in CE-MRI. After treatment with ZD6474 (100 mg/kg), CE-MRI failed to detect tumors in either prevention or therapeutic treatment regimens. However, (immuno)histologic analysis revealed the presence of numerous, small, nonangiogenic lesions. Treatment with 25 mg/kg ZD6474 also resulted in efficient blockade of vessel formation, but it did not fully inhibit vascular leakage, thereby still allowing visualization in CE-MRI scans. Conclusions: Our data show that, although angiogenesis can be effectively blocked by ZD6474, in vessel-dense organs this may result in sustained tumor progression via co-option, rather than in tumor dormancy. Importantly, blocking VEGF-A may result in undetectability of tumors in CE-MRI scans, leading to erroneous conclusions about therapeutic efficacy during magnetic resonance imaging follow-up. The maintenance of VEGF-A-induced vessel leakage in the absence of neovascularization at lower ZD6474 doses may be exploited to improve delivery of chemotherapeutic agents in combined treatment regimens of antiangiogenic and chemotherapeutic compounds.
This paper references
10.1023/A:1026525121027
Angiostatin and Angiostatin-related Proteins
G. Soff (2004)
SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.
T. Fong (1999)
10.1172/JCI17929
Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.
G. Bergers (2003)
pathobiological and clinical aspects
(1997)
Vascular endothelial growth factor-A(165) induces progression of melanoma brain metastases without induction of sprouting angiogenesis.
B. Kuesters (2002)
10.1177/172460080101600102
Circulating Angiogenesis Regulators in Cancer Patients
K. Kuroi (2001)
10.1161/01.CIR.0000055324.34758.32
Small GTP-Binding Protein Rac Is an Essential Mediator of Vascular Endothelial Growth Factor-Induced Endothelial Fenestrations and Vascular Permeability
A. Eriksson (2003)
10.1002/1097-0215(200102)9999:9999<::AID-IJC1173>3.0.CO;2-L
The pattern of metastasis of human melanoma to the central nervous system is not influenced by integrin αvβ3 expression
B. Kuesters (2001)
10.1038/SJ.NEO.7900102
Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption.
J. Rubenstein (2000)
10.1073/pnas.0730882100
Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by αvβ3 and α5β1 integrins
Akulapalli Sudhakar (2003)
10.1038/sj.onc.1201245
Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4
M. Wang (1997)
10.1095/BIOLREPROD59.3.643
Vascular endothelial growth factor stimulates proliferation but not migration or invasiveness in human extravillous trophoblast.
A. Athanassiades (1998)
10.1016/S1535-6108(03)00133-8
Physiological levels of tumstatin, a fragment of collagen IV α3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via αVβ3 integrin
Y. Hamano (2003)
ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase.
A. Hirata (2002)
Anti-vascular endothelial growth factor receptor 2 antibody reduces tumorigenicity and metastasis in orthotopic prostate cancer xenografts via induction of endothelial cell apoptosis and reduction of endothelial cell matrix metalloproteinase type 9 production.
P. Sweeney (2002)
10.1023/A:1005746320099
Angiogenesis in brain tumors; pathobiological and clinical aspects
P. Wesseling (2004)
10.1073/pnas.172398399
Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma
E. Kim (2002)
10.1038/labinvest.3780440
Design of a Variant of Vascular Endothelial Growth Factor-A (VEGF-A) Antagonizing KDR/Flk-1 and Flt-1
W. Leenders (2002)
10.1002/path.966
Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia
P. Vermeulen (2001)
10.1002/path.1124
Vascularization of cutaneous melanoma involves vessel co‐option and has clinical significance
B. Döme (2002)
10.1007/978-1-4419-8871-3
Angiogenesis in Brain Tumors
M. Kirsch (2004)
Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model.
J. Drevs (2000)
10.1002/ijc.10727
Targeting of RGD‐modified proteins to tumor vasculature: A pharmacokinetic and cellular distribution study
A. J. Schraa (2002)
The pattern of metastasis of human melanoma to the central nervous system is not influenced by integrin alpha(v)beta(3) expression.
B. Kuesters (2001)
ZD 1839 ( Iressa ) Induces Antiangiogenic Effects through Inhibition of Epidermal Growth Factor Receptor Tyrosine Kinase 1
A. Hirata (2002)
10.1002/ijc.11102
Vascular endothelial growth factor‐A determines detectability of experimental melanoma brain metastasis in GD‐DTPA‐enhanced MRI.
W. Leenders (2003)
American Association for Cancer clincancerres.aacrjournals.org Downloaded from
(2004)
Determination of clonality of metastasis by cell-specific color-coded fluorescent-protein imaging.
N. Yamamoto (2003)
10.1002/(SICI)1097-0045(19980401)35:1<1::AID-PROS1>3.0.CO;2-O
Neutralizing anti‐vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo
P. Borgström (1998)
Prolonged treatment with angiostatin reduces metastatic burden during radiation therapy.
D. Gorski (2003)
10.1080/10623320212006
Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis.
W. Leenders (2002)
Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase
M Wang (1997)
Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma.
B. Kuesters (2003)
Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin.
Y. Hamano (2003)
10.1073/pnas.172398299
VEGF-Trap: A VEGF blocker with potent antitumor effects
J. Holash (2002)
10.2174/1389450033346830
Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis.
C. Kumar (2003)
carcinoma micro tumors in vivo
P Sweeney (1998)
ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration.
S. Wedge (2002)
10.1073/PNAS.98.3.1024
Interaction of endostatin with integrins implicated in angiogenesis.
M. Rehn (2001)
10.1073/PNAS.95.8.4625
An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGF-stimulated receptor autophosphorylation and proliferation of human endothelial cells.
G. Siemeister (1998)
Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2.
P. Kunkel (2001)
10.1096/fasebj.13.1.9
Vascular endothelial growth factor (VEGF) and its receptors
G. Neufeld (1999)
10.1074/jbc.M202771200
Endostatin Blocks Vascular Endothelial Growth Factor-mediated Signaling via Direct Interaction with KDR/Flk-1*
Y. Kim (2002)
10.1126/SCIENCE.1065298
Tumstatin, an Endothelial Cell-Specific Inhibitor of Protein Synthesis
Y. Maeshima (2002)
Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins.
Akulapalli Sudhakar (2003)



This paper is referenced by
10.1007/s10585-012-9542-9
Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases
Thomas Spanberger (2012)
10.1038/nm.4197
Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
Sophia Frentzas (2016)
10.1056/NEJMra0707704
EGFR antagonists in cancer treatment.
F. Ciardiello (2008)
Gene Therapy with Interferon Alpha and the Angiogenic Inhibitor, Vasostatin, in Neuroendocrine Tumors of the Digestive System
Minghui Liu (2007)
10.30699/IJP.13.1.45
Expression of Prostate-Specific Membrane Antigen (PSMA) in Brain Glioma and its Correlation with Tumor Grade
H. Saffar (2018)
10.1158/1078-0432.CCR-06-2659
The Biology of Metastasis to a Sanctuary Site
D. Palmieri (2007)
10.1186/s40880-016-0083-5
Mechanisms of vascularization in murine models of primary and metastatic tumor growth
Edina Bugyik (2016)
10.1158/1078-0432.CCR-11-0120
The Addition of Bevacizumab to Standard Radiation Therapy and Temozolomide Followed by Bevacizumab, Temozolomide, and Irinotecan for Newly Diagnosed Glioblastoma
J. Vredenburgh (2011)
10.1038/sj.bjc.6605219
Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer
E-M Boneberg (2009)
10.1016/j.ajpath.2014.10.017
Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel.
K. Akiyama (2015)
10.1038/srep23834
Imaging of Angiotropism/Vascular Co-Option in a Murine Model of Brain Melanoma: Implications for Melanoma Progression along Extravascular Pathways
L. A. Bentolila (2016)
10.1007/s10585-009-9238-y
Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model
Juan JuanYin (2009)
Antitumor activity of ZD 6474 in a metastatic orthotopic brain tumor model
Doosik Kong ()
Plexin D 1 Expression Is Induced on Tumor Vasculature and Tumor Cells : A Novel Target for Diagnosis and Therapy ?
I. Roodink (2005)
10.1186/1471-2407-9-444
Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme
J. J. Verhoeff (2008)
10.29011/ascr-107/100007
Pulmonary Lymphangitis Carcinomatosis of Clear Cell Renal Cell Carcinoma After Angiogenesis Inhibition
G. Kats-Ugurlu (2020)
Brain metastases: pathobiology and emerging targeted therapies Matthias PreusserDavid CapperAysegul Ilhan-MutluAnna Sophie Berghoff • Peter BirnerRupert BartschChristine MarosiChristoph Zielinski • Minesh P. MehtaFrank WinklerWolfgang WickAndreas von Deimling
M. Preusser (2012)
Neutrophil activation induces peripheral immunosuppression in glioblastoma and stroke
T. Sippel (2013)
10.3171/JNS.2005.103.4.0702
Gliomatosis cerebri: quantitative proof of vessel recruitment by cooptation instead of angiogenesis.
H. Bernsen (2005)
10.1158/1078-0432.CCR-07-1335
P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan
N. D. de Vries (2007)
10.1016/j.ejca.2009.08.004
Tumour control by whole brain irradiation of anti-VEGF-treated mice bearing intracerebral glioma.
J. Verhoeff (2009)
10.1093/carcin/bgr076
Distinct contributions of angiogenesis and vascular co-option during the initiation of primary microtumors and micrometastases.
C. Zhao (2011)
10.1371/journal.pone.0058262
Effects of Dual Targeting of Tumor Cells and Stroma in Human Glioblastoma Xenografts with a Tyrosine Kinase Inhibitor against c-MET and VEGFR2
Anna C Navis (2013)
10.1007/s10456-014-9420-y
Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions
N. Vasudev (2014)
10.1038/s41572-018-0055-y
Brain metastases
Achal Singh Achrol (2004)
10.1007/s10585-011-9428-2
Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and dynamic contrast enhanced MRI
M. Budde (2011)
10.1080/2162402X.2016.1172153
Embracing rejection: Immunologic trends in brain metastasis
S. Harrison Farber (2016)
10.1016/j.ccell.2017.02.009
The Microenvironmental Landscape of Brain Tumors.
Daniela F. Quail (2017)
Hemangioblastomas. Studies on the molecular genetic background.
J. Gijtenbeek (2006)
10.1038/nm.2072
Real-time imaging reveals the single steps of brain metastasis formation
Y. Kienast (2010)
10.5772/intechopen.89667
Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy
Sophia Frentzas (2020)
10.1016/j.semcancer.2020.09.001
Tumor Microenvironment Conditions that Favor Vessel Co-option in Colorectal Cancer Liver Metastases: A Theoretical Model.
M. Rada (2020)
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