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Angiogenesis Laboratory

Angiogenesis research

For more information about the Angiogenesis Laboratory please go to www.angiogenesis.nl

The growth of tumors and their metastases depends on the formation of new blood vessels, a process that is called neo-vascularization or angiogenesis. Tumor cells which become deprived of oxygen and nutrients will produce growth factors that promote endothelial cells to proliferate and move towards the hypoxic tumor cell areas. Among tumor-induced pro-angiogenic factors, vascular endothelial growth factor (VEGF) has been recognized as one of the most important factors. Consequently, VEGF and its receptors (primarily VEGFR2) are primary targets for anticancer therapy. Evidence that inhibition of the VEGF-VEGFR pathway is of clinical benefit for cancer patients has resulted in approval of the monoclonal antibody bevacizumab (Avastin®), which is directed against VEGF, in combination with chemotherapy in colorectal cancer. Similarly, the VEGFR inhibitor sunitinib (Sutent®) provides clear clinical benefit for a subgroup of renal cell cancer patients.

Translational research

Our research aims at improving the understanding of tumor-induced angiogenesis and to develop novel anti-cancer strategies based on angiogenesis inhibition. Clinical trials with second and third generation VEGFR and VEGF inhibitors are performed. These clinical trials are accompanied by side-studies in order to learn more about the effects of anti-angiogenesis agents and their target, the tumor endothelium. These side-studies include investigation of circulating endothelial progenitor cells, immunological parameters, endothelium-specific marker proteins and complete protein profiles (proteomics); also the effects of anti-angiogenic therapy on the normal physiology of vessels (regulation of the blood pressure) and the use of new imaging techniques to monitor anti-tumor effects are studied.
The department has been on the forefront of fundamental, applied and clinical research. Examples are the identification of several tumor endothelial targets suitable for diagnostic imaging and also for therapeutic intervention (Thijssen et al, 2008). In addition, a trial of continuous endostatin administration and studies into the activity and toxicity of the first generation VEGFR inhibitors has been studied in relation to blood clotting disturbances and platelet biology. More recently, we have studied the antitumor response of sunitinib in renal cell cancer (van der Veldt et al., 2008), as well as mechanisms of sunitinib induced-hypertension (van der Veldt et al., 2009) and the potential value of blood-based markers of sunitinib activity (van Cruijsen et al., 2008; Vroling et al., 2009). Also a major interest of the department will be the elucidation of the complicated mechanisms of action and determinants of sensitivity or resistance as well as toxicity of current and future combinations of anti-angiogenic agents such as sunitinib or sorafenib (Gotink et al., 2009; Broxterman et al., 2009).


Some recent research highlights


Grant support from the Center for Translational Molecular Medicine (CTMM) and Top Institute Pharma (TIPharma) for research into novel ways to target angiogenesis as treatment for cancer. We have used a designer approach to develop angiostatic cytokine-like peptides that elicit anti-tumor activity through angiogenesis inhibition. The most active peptide was anginex, which is currently developed for clinical testing.

A molecular biological approach identified galectin-1 as the endothelial receptor for anginex. It is shown that targeting galectin-1 is applicable for diagnosis strategies as well as treatment of cancer. We also performed genomic screen by transcriptome subtraction techniques, for the discovery of other target molecules on tumor endothelial cells. These studies identified 17 endothelial genes to be overexpressed in tumor angiogenesis but not in physiological angiogenesis. The recently started projects will focus on the use of these targets for application in therapeutic as well as diagnostic strategies against cancer.

Find publications by : Arjan Griffioen , Henk VerheulJudy van BeijnumVictor Thijssen    in Pubmed .

Recent publications

2015

Griffioen AW. Angiostatic vaccines, an underestimated approach of cancer therapy. Oncotarget 2015; [2014 Nov 17, Epub ahead of print].

Kleibeuker EA, Schulkens IA, Castricum KC, Griffioen AW, Thijssen VL. Examination of the role of galectins during in vivo angiogenesis using the chick chorioallantoic membrane assay. Methods Mol Biol 2015; 1207: 305-315.

Schulkens IA, Kleibeuker EA, Castricum KC, Griffioen AW, Thijssen VL. Examination of the role of galectins and galectin inhibitors in endothelial cell biology. Methods Mol Biol 2015; 1207: 285-291.

Femel J, Huijbers EJ, Saupe F, Cedervall J, Zhang L, Roswall P, Larsson E, Olofsson H, Pietras K, Dimberg A, Hellman L, Olsson  AK. Thera-peutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. Oncotarget 2015; pii: 2628.

Läppchen T, Dings RP, Rossin R, Simon JF, Visser TJ, Bakker M, Walhe P, van Mourik T, Donato K, van Beijnum JR, Griffioen AW, Lub J, Robillard MS, Mayo KH, Grüll H. Novel analogs of antitumor agent calixarene 0118: Synthesis, cytotoxicity, click labeling with 2-[18F]fluoroethylazide, and in vivo evaluation. Eur J Med Chem 2015; 89: 279-295.

2014

van der Mijn JC, Sol N, Mellema W, Jiménez CR, Piersma SR, Dekker H, Schutte LM, Smit EF, Broxterman HJ, Skog J, Tannous BA, WürdingerT, Verheul HM. Analysis of AKT and ERK1/2 protein kinases in extracellular vesicles isolated from blood of patients with cancer. J Extracell Vesicles 2014; 3: 25657. doi: 10.3402/jev.v3.25657. eCollection 2014.

Ding X, Liu W, Weiss A, Li Y, Wong I, Griffioen AW, van den Bergh H, Xu H, Nowak-Sliwinska P, Ho CM. Discovery of a low order drug-cell response surface for applications in personalized medicine. Phys Biol 2014; 11(6): 065003. doi: 10.1088/1478-3975/11/6/065003.

Griffioen AW, Weiss A, Berndsen RH, Abdul UK, Te Winkel MT, Nowak-Sliwinska P. The emerging quest for the optimal angiostatic combination therapy. Biochem Soc Trans  2014; 42: 1608-1615. doi: 10.1042/BST20140193.

Griffioen AW, Thijssen VL. Galectins in tumor angiogenesis. Ann Transl Med 2014; 2(9): 90. doi: 10.3978/j.issn.2305-5839.2014.09.01.

Haan JC, Labots M, Rausch C, Koopman M, Tol J, Mekenkamp LJ, van de Wiel MA, Israeli D, van Essen HF, van Grieken NC, Voorham QJ, Bosch LJ, Qu X, Kabbarah O, Verheul HM, Nagtegaal ID, Punt CJ, Ylstra B, Meijer GA. Genomic landscape of metastatic colorectal cancer. Nat Commun 2014; 5: 5457. doi: 10.1038/ncomms 6457.

van der Mijn JC, Mier JW, Broxterman HJ, Verheul HM. Predictive bio- markers in renal cell cancer: insights in drug resistance mechanisms. Drug Resist Updates 2014; 17: 77-88.

Babae N, Bourajjaj M, Liu Y, Van Beijnum JR, Cerisoli F, Scaria PV, Verheul HM, Van Berkel MP, Pieters EH, Van Haastert RJ, Yousefi A, Mastrobattista E, Storm G, Berezikov E, Cuppen E, Woodle M, Schaap- veld RQ, Prevost GP, Griffioen AW, Van Noort PI, Schiffelers RM. Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma. Oncotarget 2014; 5: 6687-6700.

Schulkens IA, Heusschen R, van den Boogaart V, van Suylen R-J, Dingemans A-MC, Griffioen AW, Thijssen VL. Galectin expression profiling identifies galectin-1 and galectin-9Delta5 as prognostic factors in stage I/II non-small cell lung cancer. PLoS One 2014; 9 : e107988. doi: 10.1371/journal.pone.0107988. eCollection 2014.

Schulkens IA, Castricum KCM, Weijers EM, Koolwijk P, Griffioen AW, Thijssen VL. Metallothionein expression profiling in human endothelial cells and their role in angiogenesis in vitro. Vascular Pharmacol 2014; 51: 231-238.

Yousefi A, Bourajjaj M, Babae N, Noort PI, Schaapveld RQ, Van Beijnum JR, Griffioen AW, Storm G, Schiffelers RM, Mastrobattista E. Anginex lipoplexes for delivery of anti-angiogenic siRNA. Int J Pharm 2014; 472: 175-184.

Thijssen VL, Griffioen AW. Galectin-1 and galectin-9 in angiogenesis; A sweet couple. Glycobiology 2014; 24 :915-920. 

Bajou K, Herkenne S,  Thijssen VL, D'Amico S, Nguyen N, Bouché N, Tabruyn S, Srahna M, Carabin JY, Nivelles O, Paques C, Cornelissen I, Lion M, Noel A, Gils A, Vinckier S, Declerck PJ, Griffioen AW, Dewerchin M, Martial JA, Carmeliet P, Struman I. PAI-1 mediates the anti-angiogenic and pro-fibrinolytic effects of 16k-prolactin. Nature Med 2014; 20: 741-747.

van de Wiel MA, Neerincx M, Buffart TE, Sie D, Verheul HM. Shrink- Bayes: a versatile R-package for analysis of count-based sequencing data in complex study designs. BMC Bioinformatics 2014; 15: 116.

Koldenhof JJ, Witteveen PO, de Vos R, Walraven M, Tillier CN, Verheul HM, Teunissen SC. Symptoms from treatment with sunitinib or sorafenib: a multicenter explorative cohort study to explore the influence of patient-reported outcomes on therapy decisions. Support Care Cancer 2014; 22: 2371-2380.

Clavel CM, Paunescu E, Nowak-Sliwinska P, Griffioen AW, Scopelliti R, Dyson PJ. Discovery of a highly tumor-selective organometallic Ruthenium(II)-Arene complex. J Med Chem 2014; 57: 3546-3558.

Labots M, Buffart TE, Haan JC, van Grieken NC, Tijssen M, van de Velde CJ, Grabsch HI, Ylstra B, Carvalho B, Fijneman RJ, Verheul HM, Meijer GA. High-level copy number gains of established and potential drug target genes in gastric cancer as a lead for treatment development and selection. Cell Oncol  2014; 37: 41-52.

Weiss A, Van Beijnum JR, Bonvin D, Jichlinski P, Van den Bergh H, Dyson PJ, Griffioen AW, Nowak-Sliwinska P. Low-dose angiostatic tyrosine kinase inhibitors improve photodynamic therapy for cancer: lack of vascular normalization. J. Cell Mol Med 2014; 18: 480-491.

Sabrkhany S, Kuijpers MJE, Verheul HMW, Oude Egbrink MGA, Griffioen AW. Optimal human blood sampling for platelet research. Curr Angiogenesis 2014; 2: 157-161.

Heusschen R, Schulkens IA, van Beijnum J, Griffioen AW, Thijssen VL. Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis.  Biochim Biophys Acta 2014; 1842: 284-292.

Barrientos G, Freitag N, Tirado-González I, Unverdorben L, Jeschke U, Thijssen VL, Blois SM. Involvement of galectin-1 in reproduction: past, present and future. Hum Reprod Update 2014; 20: 175-193.

2013

Goos JA, Coupe VM, Diosdado B, Delis-Van Diemen PM, Karga C, Beliën JA, Carvalho B, van den Tol MP, Verheul HM, Geldof AA, Meijer GA, Hoekstra OS, Fijneman RJ. Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis. Br J Cancer 2013; 109: 2445-2452.

Nowak-Sliwinska P, Weiss A, Sickenberg M, Griffioen AW, Van den Bergh H. The role of photodynamic therapy in non-malignant and malignant eye disorders. J Anal Bioanal Tech 2013.doi: 10.4172/2155-9872.S1-007, 2013.

van Wijk XM, Thijssen VL, Lawrence R, van den Broek SA, Dona M, Naidu N, Oosterhof A, van de Westerlo EM, Kusters LJ, Khaled Y, Jokela TA, Nowak-Sliwinska P, Kremer H, Stringer SE, Griffioen AW, van Wijk E, van Delft FL, van Kuppevelt TH. Interfering with UDP-GlcNAc metabolism and heparan sulfate expression using a sugar analog reduces angiogenesis. ACS Chem Biol 2013; 8: 2331-2338.

Thijssen VL, Rabinovich GA, Griffioen AW. Vascular galectins: Regulators of tumor progression and targets for cancer therapy. Cytokine Growth Factor Rev 2013; 24: 547-548.

Kortenhorst MS, Wissing MD, Rodríguez R, Kachhap SK, Jans JJ, Van der Groep P, Verheul HM, Gupta A, Aiyetan PO, van der Wall E, Carducci MA, Van Diest PJ, Marchionni L. Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors. Epigenetics 2013; 8: 907-920.

Freitag N, Tirado-González I, Barrientos G, Herse F, Thijssen VL, Weedon-Fekjær SM, Schulz H, Wallukat G, Klapp BF, Nevers T, Sharma S, Staff AC, Dechend R, Blois SM. Interfering with gal-1-mediated angiogenesis contributes to the pathogenesis of preeclampsia. Proc Natl Acad Sci USA 2013; 110: 11451-11456.

Tugues S, Honjo S, König C, Padhan N, Kroon J, Gualandi L, Li X, Barkefors I, Thijssen VL, Griffioen AW, Claesson-Welsh L. Tetraspanin CD63 promotes VEGF receptor-2 / ß1 integrin complex formation, thereby regulating activation and downstream signaling in endothelial cells in vitro and in vivo. J Biol Chem 2013; 288: 19060-19071.

Heusschen R, Griffioen AW, Thijssen VL. Galectin-9 in tumor biology: A jack of multiple trades. Biochim Biophys Acta 2013; 1836: 177-185.

Bakker JL, Meijers-Heijboer H, Verheul H. Novel strategies towards the use of anti-angiogenic agents in breast cancer. Eur J Pharmacol 2013 Mar 29. pii: S0014-2999(13)00250-1. doi: 10.1016/ j.ejphar. 2013. 03.035. [Epub ahead of print].

Nazarov A, Baquié M,  Nowak-Sliwinska P,  Zava O, Van Beijnum JR,  Groessl M, Chisholm DM, Ahmadi A,  McIndoe SJ, Griffioen AW, Van den Bergh H, Dyson PJ. Synthesis and characterization of a new class of anti-angiogenic agent based on ruthenium clusters. Scientific Reports 2013; 3: 1485. doi: 10.1038/srep01485.

Lindenberg JJ, Lougheed SM, Van de Ven R, Zomer A, Santegoets SJ, Griffioen AW, Hooijberg E, Van den Eertwegh AJ, Thijssen VL, Scheper RJ, Oosterhoff D, De Gruijl TD. Functional characterization reveals STAT3 dependence of a dendritic cell-derived CD14+BDCA3/ CD141+ population arising upon IL-10-exposed maturation. Oncoimmunology 2013; 2(4): e23837.

Schulkens IA, Griffioen AW, Thijssen VL. Angiostatic cancer therapy by targeting galectins in the tumor vasculature. In: ACS SymposiumSeries: Galectins and Disease Implications for Targeted Therapeutics. Editors: A. Klysov, 2012, ACS Publications.

Schulkens IA, Kleibeuker EA, Castricum KC, Griffioen AW, Thijssen VL. Examination of the role of galectins and galectin inhibitors in endothelial cell biology, Methods Mol. Biol 2013; in press.

Kleibeuker EA, Schulkens IA, Castricum KC, Griffioen AW, Thijssen VL. Examination of the role of galectins during in vivo angiogenesis using the chick chorioallantoic membrane assay. Methods Mol. Biol. 2013; in press.

Westgeest HM, van Erp NP, Honeywell RJ, Hoekstra R, Peters GJ, Verheul HMW. Successful treatment of renal cell carcinoma with sorafenib after effective but hepatotoxic sunitinib exposure. J Clin Oncol 2013; 31: e83-e86. 

Heusschen R, Freitag N, Tirado-González I, Barrientos G, Moschansky P, Muñoz-Fernández R, Leno-Durán E, Klapp BF, Thijssen VL, Blois SM. Profiling Lgals9 splice variant expression at the fetal-maternal interface: implications in normal and pathological pregnancy. Biol Reprod 2013; 88: 22. doi: 10.1095/biolreprod.112. 105460.

Barrientos G, Tirado-González I, Freitag N, Kobelt P, Moschansky P, Klapp BF, Thijssen VL, Blois SM. CXCR4+ Dendritic cells promote angiogenesis during embryo implantation in mice. Angiogenesis 2013; 16: 417-427.

Van Beijnum JR, Nowak-Sliwinska P, Van den Boezem E, Hautvast P, Buurman WA, Griffioen AW. Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. Oncogene 2013; 32: 363-374.

2012

Margadant C, van den Bout I, van Boxtel AL, Thijssen VL, Sonnenberg A. Epigenetic regulation of galectin-3 expression by ß1 integrins promotes cell adhesion and migration. J Biol Chem  2012; 287: 44684-44693.

Michels M, van der Ven AJ, Djamiatun K, Fijnheer R, de Groot PG, Griffioen AW, Sebastian S, Faradz SM, de Mast Q. Imbalance of angiopoietin-1 and angiopoetin-2 in severe dengue and relationship with thrombocytopenia, endothelial activation, and vascular stability. Am J Trop Med Hyg 2012; 87: 943-946.

Tirado González I, Barrientos G, Freitag N, OttoT, Thijssen VL, Moschansky P, von Kwiatkowsk P, Klapp BF, Winterhager E., Bauersachs S, Blois SM. Uterine NK cells are critical in shaping DC immunogenic functions compatible with pregnancy progression. PlosOne 2012; 7: e46755. doi: 10.1371/journal.pone.0046755.

Van de Vijver P, Scheer L, Van Beijnum JR, Griffioen AW, Hackeng TM. Application of an omonasteine ligation strategy for the total chemical synthesis of the BRD7 bromodomain. Chem Comm 2012; 48: 9403-9405.

Jarzyna PA, Deddens LH, Kann BH, Ramachandran S, Calcagno C, Chen W, Gianella A, Dijkhuizen RM, Griffioen AW, Fayad ZA, Mulder WJM. Tumor angiogenesis phenotyping by nanoparticle-facilitated magnetic resonance and near-infrared fluorescence molecular imaging. Neoplasia 2012; 14: 964?973.

Eechoute K, van der Veldt AA, Oosting S, Kappers MH, Wessels JA, Gelderblom H, Guchelaar HJ, Reyners AK, van Herpen CM, Haanen JB, Mathijssen RH, Boven E. Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension. Clin Pharmacol Ther 2012; 92: 503-510.

Hadj JO,  Den Braven R, Tillier C, Schrijver HM, Verheul HMW, Van der Vliet HJ.  Reversible posterior leukoencephalopathy syndrome during sunitinib therapy for metastatic renal cell carcinoma. Oncology Lett 2012; 3: 1293-1296.

Griffioen AW, Mans L, de Graaf A, Nowak-Sliwinska P, de Hoog C, de Jong T, Vyth F, van Beijnum JR, Bex A, Jonasch E. Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res 2012; 18: 3961-3971.

Buffart TE, Carvalho B, van Grieken NC, van Wieringen WN, Tijssen M, Kranenbarg EM, Verheul HM, Grabsch HI, Ylstra B, van de Velde CJ, Meijer GA. Losses of chromosome 5q and 14q are associated with favorable clinical outcome of patients with gastric cancer. The Oncologist 2012; 17:  653-662.

Kleibeuker EA, Griffioen AW, Verheul HM, Slotman BJ, Thijssen VL. Combining angiogenesis inhibition and radiotherapy: A double-edged sword.  Drug Resist Updates 2012; 15: 173-182.

Heideman DA, Lurkin I, Doeleman M, Smit EF, Verheul HM, Meijer GA, Snijders PJ, Thunnissen E, Zwarthoff EC. KRAS and BRAF Mutation analysis in routine molecular diagnostics: comparison of three testing methods on formalin-fixed, paraffin-embedded tumor-derived DNA. J Mol Diagn 2012; 14: 247-255.

Weiss A,  van den Bergh H,  Griffioen AW, Nowak-Sliwinska P. Angiogenesis inhibition for the improvement of photodynamic therapy: The revival of a promising idea. Biochim Biophys Acta (Rev on Cancer) 2012; 1826: 53-70.

Adar Y, Stark M, Bram EE, Nowak-Sliwinska P, Van den Bergh H, Szewczk G, Sarna T, Skaladanowski A, Griffioen AW, Assaraf YG. Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug resistant cancers. Cell Death Dis 2012; 3: e293; doi:10.1038/ cddis.2012.30.

Bex A, Etto T, Vyth-Dreese F, Blank C, Griffioen AW. Immunological hetero-geneity of the RCC microenvironment: do targeted therapies influence immune response? Curr Oncol Rep 2012; 14: 230-239.

Paulis YWJ, Dinnes D, Soetekouw PM, Nelson PJ, Burdach S, Loewe RP, Tjan-Heijnen VCG, Von Luettichau I, Griffioen A.W. Imatinib reduces the vasculogenic potential of plastic tumor cells. Current Angiogenesis 2012; 1: 64-71.

Siemerink MJ, Klaassen I, Vogels IMC, Griffioen AW, Van Noorden CJF, Schlingemann RO. CD34 marks angiogenic tip cells in human vascular endothelial cell cultures. Angiogenesis 2012; 15: 151-163.

Reuwer AQ, Nowak-Sliwinska P, Mans L, Van der Loos CM, Von der Thüsen JH, Twickler MTB, Spek A, Goffin V, Griffioen AW, Borensztajn KS. Functional consequences of prolactin signaling in endothelial cells: a potential link with angiogenesis in pathophysiology? J Cell Mol Med 2012;  16: 2035-2048.

Van der Veldt AAM, Vroling L, de Haas RR, Koolwijk P, van den Eertwegh AJM, Haanen JBAG, van Hinsbergh VWM, Broxterman HJ, Boven E. Sunitinib-induced changes in circulating endothelial cell-related proteins in patients with metastatic renal cell cancer. Int J Cancer 2012; 131: E484-E493.

Nowak-Sliwinska P, Weiss A, Beijnum JR, Wong TJ, Ballini JP, Lovisa B, Bergh HV, Griffioen AW. Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion. J Cell Mol Med 2012; 16: 1553-1562.

Kluza E, Jacobs I, Hectors SJ, Mayo KH, Griffioen AW, Strijkers GJ, Nicolay K. Dual-targeting of a(v)ß(3) and galectin-1 improves the specificity of paramagnetic / fluorescent liposomes to tumor endothelium in vivo. J Control Release 2012; 158: 207-214.

Van der Veldt AAM, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, Verheul HM, Serne WEH, Lammertsma AA, Smit EF. Rapid decrease in deliver of chemotherapy to tumors after anti-VEGF therapy: omplications for scheduling of anti-angiogenic drugs. Cancer Cell 2012; 21: 82-91.

2011

Gotink KJ, Broxterman HJ, Labots M,  de Haas RR, Dekker H, Honeywell RJ,  Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW,  Assaraf YG, Pili R, Peters GJ, Verheul HMW. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res 2011; 17:7337-7346.

De Caterina R, Griffioen AW, Porreca F. Fraud in biomedical research - The role of journal Editors. Life Sci 2011; 89:755-756.

Nilsson RJ, Balaj L, Hulleman E, van Rijn S, Pegtel DM, Walraven M, Widmark A, Gerritsen WR, Verheul HM, Vandertop WP, Noske DP, Skog J, Wurdinger T. Blood platelets contain tumor-derived RNA biomarkers. Blood 2011; 118: 3680-3683. 

Laeremans H, Hackeng TM, van Zandvoort MA, Thijssen VL, Janssen BJ, Ottenheijm HC, Smits JF, Blankesteijn WM. Blocking of Frizzled signaling with a homologous peptide fragment of Wnt3a/Wnt5a reduces infarct expansion and prevents the development of heart failure after myocardial infarction. Circulation 2011; 124: 1626-1635.

Gianella A, Jarzyna PA, Mani V, Ramachandran S, Calcagno C, Tang J, Kann B, Dijk WJ, Thijssen VL, Griffioen AW, Storm G, Fayad ZA, Mulder WJ. A multifunctional nanoemulsion platform for imaging guided therapy evaluated in experimental cancer. ACS Nano 2011; 5:4422-4433.

Nowak-Sliwinska P, van Beijnum JR, Casini A, Nazarov A, Wagnieres G, Van den Bergh H, Dyson PJ, Griffioen AW. Organometallic ruthenium(II)-arene compounds with anti-angiogenic activity. J Med Chem 2011; 54:3895-3902.

Stancic M, van Horssen J, Thijssen VL, Gabius HJ, Bsibsi M, van der Valk P, Hoekstra D, Baron W. Increased expression of distinct galectins in multiple sclerosis lesions. Neuropathol Appl Neurobiol 2011; 37:654-671.

Bijnsdorp IV, Capriotti F, Kruyt FAE, Losekoot N, Fukushima M, Griffioen AW, Thijssen VL, Peters GJ. Thymidine phosphorylase in cancer cells stimulates human endothelial cell migration and invasion by the secretion of angiogenic factors. Br J Cancer 2011; 104: 1185-1192.

Langenberg MHG, Witteveen PO, Roodhart J, Lolkema MP,  Verheul HMW,  Mergui-Roelvink M, Brendel E, Krätzschmar J, Loembé B, Nol-Boekel A,  Christensen O, Schellens JHM, Voest EE. Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors. Ann Oncol 2011;  22: 2508-2515.

Salomonsson E, Thijssen VL, Griffioen AW, Nilsson UJ, Leffler H. The anti-angiogenic peptide anginex greatly enhances galectin-1 binding affinity for glycoproteins. J Biol Chem 2011; 286:13801-13804.

Shapira A, Livney YD, Broxterman HJ, Assaraf YG. Nanomedicine for targeted cancer therapy: Towards the overcoming of drug resistance. Drug Resist. Updates 2011; 14:150-163.

Dings RP, Vang KB, Castermans K, Popescu F, Zhang Y, A Oude Egbrink MG, Mescher M, Farrar M, Griffioen AW, Mayo KH. Enhancement of T-cell mediated anti-tumor response: angiostatic adjuvant to immunotherapy against cancer. Clin Cancer Res 2011; 17:3134-3145.

Walraven M, Witteveen PO, Lolkema MP, van Hillegersberg R, Voest EE, Verheul HM. Antiangiogenic tyrosine kinase inhibition related gastrointestinal perforations: a case report and literature review. Angiogenesis 2011; 14:135-141.

Sabrkhany S, Griffioen AW, Egbrink MG. The role of blood platelets in tumor angiogenesis. Biochim Biophys Acta 2011; 1815: 189-196. 

Pardali E, van der Schaft DWJ, Wiercinska E, Gorter A, Hogendoorn PCW, Griffioen AW, ten Dijke P. Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma. Oncogene 2011; 30:334-345.

2010

Biere SS, van Weyenberg SJ, Verheul HM, Mulder CJ, Cuesta MA, van der Peet DL. [Non-metastasized oesophageal cancer.] [Article in Dutch] Ned Tijdsch Geneesk 2010;154(8):A820.

Snoeren N, Voest EE, Bergman AM, Dalesio O, Verheul HM, Tollenaar RA, van der Sijp JR, Schouten SB, Rinkes IH, van Hillegersberg R. A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment. BMC Cancer 2010 Oct 11;10:545.

Nowak-Sliwinska P, van Beijnum JR, van Berkel M, van den Bergh H, Griffioen AW. Vascular regrowth following photodynamic therapy in the chicken embryo chorioallantoic membrane. Angiogenesis 2010; 13:281-292.

Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L, Hackeng TM, Kiss R, Kloog Y, Poirier F, Griffioen AW. Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res. 2010; 70:6216-6224.

Boven E, Massard C, Armand JP, Tillier C, Hartog V, Brega NM, Countouriotis AM, Ruiz-Garcia A, Soria JC. A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours. Br J Cancer 2010; 103: 993-1000.

Dingemans AMC, van den Boogaart V, Vosse BA , van Suylen RJ , Griffioen AW, Thijssen VL. Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer. Molecular Cancer 2010 Jun 17; 9:152.

Piersma SR, Labots M, Verheul HM, Jiménez CR. Strategies for kinome profiling in cancer and potential clinical applications: chemical proteomics and array-based methods. Anal. Bioanal. Chem. 2010; 397:3163-3171.

Hammers HJ, Verheul HM, Salumbides B, Sharma R, Rudek M, Jaspers J, Shah P, Ellis L, Shen L, Paesante S, Dykema K, Furge K, Teh BT, Netto G, Pili R. Reversible epithelial to mesenchymal transition and acquired resistance to sunitinib in patients with renal cell carcinoma: evidence from a xenograft study. Mol Cancer Ther 2010; 9:1525-1535.

Casal C, Xavier Torres-Collado A, del Carmen Plaza-Calonge M, Martino-Echarri E, Ramón y Cajal S, Rojo F, Griffioen AW, Rodríguez-Manzaneque JC. ADAMTS1 contributes to the acquisition of an endothelial-like phenotype in plastic tumor cells. Cancer Res 2010; 70:4676-4686.

van Wijk XM, Oosterhof A, van den Broek SA, Griffioen AW, Ten Dam GB, Rutjes FP, van Delft FL, van Kuppevelt TH. A 4-deoxy analogue of N-acetyl-d-glucosamine inhibits heparan sulphate expression and growth factor binding in vitro. Exp Cell Res 2010; 316:2504-2512.

Strijkers GJ, Kluza E, Van Tilborg GA, van der Schaft DW, Griffioen AW, Mulder WJ, Nicolay K. Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis. Angiogenesis 2010; 13:161-173.

Langenberg MH, Witteveen PO, Roodhart JM, Verheul HM, Mergui-Roelvink M, van der Sar J, Brendel E, Laferriere N, Schellens JH, Voest EE. Phase I evaluation of telatinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan and capecitabine in patients with advanced solid tumors. Clin Cancer Res 2010; 16:2187-2197.

Paulis YW, Soetekouw PM, Verheul HM, Tjan-Heijnen VC, Griffioen AW.  Signalling pathways in vasculogenic mimicry. Biochem Biophys Acta 2010; 1806:18-28.

Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010; 13: 1-14.

Heusschen R, van Gink M, Griffioen AW, Thijssen VL. microRNAs in the tumor endothelium: novel controls on the angioregulatory switchboard. Biochim Biophys Acta 2010; 1805: 87-96.

Overkleeft EN, Goldschmeding R, van Reekum F, Voest EE, Verheul HM.
Nephrotic syndrome caused by the angiogenesis inhibitor sorafenib. Ann Oncol 2010; 21: 184-185.

Verheul HM, van Erp K, Homs MY, Yoon GS, van Der Groep P, Rogers C, Hansel DE, Netto GJ, Pili R. The Relationship of vascular endothelial growth factor and coagulation factor (fibrin and fibrinogen) expression in clear cell renal cell carcinoma. Urology 2010; 75: 608-614.

Nowak-Sliwinska P, Wagnieres G, Van den Bergh H, Griffioen AW. Angiostasis induced vascular normalization can improve photodynamic therapy. Cell Mol Life Sci 2010; 67:1559-1560; author reply 1561.

Martilla-Ichihara F, Castermans K, Auvinen K, Oude Egbrink MGA, Jalkanen S, Griffioen AW, Salmi M. Small molecule inhibitors of vascular adhesion protein-1 reduce the accumulation of myeloid cells into tumors and attenuate tumor growth in mice. J Immunol 2010; 184: 3164-3173.

Van Rooij, E, Fielitz, J, Sutherland, L.B., Thijssen, V.L., Crijns, H.J., Dimaio, M.J., Shelton, J, De Windt, L.J., Hill, J.A., Olson, E.N. Myocyte enhancer factor 2 and class II histone deacetylases control a gender-specific pathway of cardio-protection mediated by the estrogen receptor. Circ Res 106, 155-165, 2010.

Van Cruijsen H, Voest EE, Punt CJ, Hoekman K, Witteveen PO, Meijerink MR, Puchalski TA, Robertson J, Saunders O, Jürgensmeier JM, van Herpen CM, Giaccone G. Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. Eur J Cancer 2010; 46: 901-911.

Van der Veldt AA, de Boer MP, Boven E, Eringa EC, van den Eertwegh AJ, van Hinsbergh VW, Smulders YM, Serne EH. Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib. Anticancer Drugs 2010; 21: 439-446.

Van der Veldt AA, Meijerink MR, van den Eertwegh AJ, Haanen JB, Boven E. Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Br J Cancer 2010; 102: 803-809.

Banerji U, Camidge DR, Verheul HM, Agarwal R, Sarker D, Kaye SB, et al. The first-in-human study of the hydrogen sulfate capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): A phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 2010; 16: 1613-1623.

Vroling L, Lind JS, de Haas RR, Verheul HM, van Hinsbergh VW, Broxterman HJ and Smit EF. CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients. Br J Cancer 2010; 102: 268-275.

Kluza E, van der Schaft DW, Hautvast PA, Mulder WJ, Mayo KH, Griffioen AW, Strijkers GJ, Nicolay K. Synergistic targeting of alpha(v)beta(3) integrin and galectin-1 with heteromultivalent paramagnetic liposomes for combined MR imaging and treatment of angiogenesis. Nano Letters  2010; 10: 52-58.

Chen W, Jarzyna PA, Van Tilborg GA, Nguyen VA, Cormode DP, Klink A, Griffioen AW, Randolph GJ, Fisher EA, Mulder WJ, Fayad ZA. RGD-peptide funcionalized and reconstituted high density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe. FASEB J 2010; 24:1689-1699.

2009  

Van Erp NP, Eechoute K, van der Veldt AA, Haanen JB, Reyners AK, Mathijssen RH, Boven E, van der Straaten T, Baak-Pablo RF, Wessels JA, Guchelaar HJ, Gelderblom H. Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity. J Clin Oncol 2009; 27: 4406-4412.

Van der Vliet HJ, van der Peet DL, Verheul HM. Case 19-2009: Carcinoma of the gastroesophageal junction. New Engl J Med 2009; 361:1315; author reply 1315-1316, 2009.

Van Cruijsen H, van der Veldt A, Hoekman K. Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. Front. Bioscience 14: 2248-2268, 2009.

Broxterman HJ, Gotink KJ, Verheul HM. Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. Drug Resist Update 2009; 12:114-126.

Piersma SR, Broxterman HJ, Kapci M, de Haas RR, Hoekman K, Verheul HM, Jimenez CR. Proteomics of the TRAP-induced platelet releasate. J Proteomics 2009; 72: 91-109.

Witjes CD, Verhoef C, Verheul HM, Eskens FA. Systemic treatment in hepato-cellular carcinoma; 'A small step for man...'. Neth J Med 2009; 67: 86-90.

Vroling L, van der Veldt AA, de Haas RR, Haanen JB, Schuurhuis GJ, Kuik DJ, van Cruijsen H, Verheul HM, van den Eertwegh AJ, Hoekman K, Boven E, van Hinsbergh VW, Broxterman HJ. Increased numbers of small circulating endothelial cells in renal cell cancer patients treated with sunitinib. Angiogenesis 2009; 12: 69-79.

Van der Veldt AA, Boven E, Vroling L, Broxterman HJ, van den Eertwegh AJ, Haanen JG. Sunitinib-induced hemoglobin changes are related to the dosing schedule. J Clin Oncol 2009; 27: 1339-1340.

Tabruyn SP, Memet S, Ave P, Verhaeghe C, Struman I, Martial JA, Griffioen AW. NF-kB activation in endothelial cells is critical for the activity of angiostatic agents. Mol Cancer Ther 2009; 8: 2645-2654.

Griffioen AW, Vyth-Dreese F. Angiostasis as a way to improve immunotherapy. Thromb Haemost 2009; 101: 1025-1031.

Van Beijnum JR, Petersen K, Griffioen AW. Tumor endothelium is characterized by a matrix remodeling signature. Front Biosci 2009; 1: 216-225.

Griffioen AW. Lymphangiogenesis factors target for therapy? Blood 2009; 113: 4135-4136.

Mulder WJ, Castermans K, Van Beijnum JR, Oude Egbrink MG, Chin PT, Storm G, Strijkers GJ, Griffioen AW, Nicolay K. Multimodality molecular imaging of tumor angiogenesis using quantum dots. Angiogenesis 2009; 12: 17-24.

Baldewijns MM, Roskams T, Ballet V, Van den Eynden GG, Van Laere SJ, Van der Auwera I, Lerut E, De Bruïne AP, Thijssen VL, Vermeulen PB, Van Poppel H. Low frequency of lymph node metastasis in clear cell renal cell carcinoma is related to low lymphangiogenic activity. BJU Intern 2009; 103: 1626-1631.

Thijssen VL. One less concern. Nature 2009; 457: 628-628.

Eude-Le Parco I, Gendronneau G, N'Guyen T, Delacour D, Thijssen VL, Edelmann W, Peuchmaur M, Poirier F. Genetic assessment of the importance of galectin-3 in cancer initiation, progression and dissemination in mice. Glycobiology 2009; 19: 68-75.

2008 

Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T, Atadja P, Pili R., Pili R. Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 2008; 14: 3589-3597.

van Cruijsen H, van der Veldt AA, Vroling L, Oosterhoff D, Broxterman HJ, Scheper RJ, Giaccone G, Haanen JB, van den Eertwegh AJ, Boven E, Hoekman K, de Gruijl TD.Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival. Clin Cancer Res 2008; 14: 5884-5892.

VanTilborg GA, Mulder WJ, Van der Schaft  DW, Reutelingsperger CP,  Griffioen AW, Strijkers GJ, Nicolay, K. Improved molecular MR imaging of tumor angiogenesis by avidin-induced clearance of non-bound liposomes. Neoplasia 2008; 10: 1459-1469.

Castermans, K., Tabruyn, S.P., Zeng, R., Eppolito, C., Leonard, W.J., Shrikant, P.A., Griffioen, A.W. Angiostatic activity of the anti-tumor cytokine interleukin-21. Blood 2008; 112: 4940-4947.

Griffioen AW. Anti-angiogenesis; making the tumor vulnerable for the immune system. Cancer Immunol Immunother 2008; 57: 1553-1558.

Van Beijnum JR, Rousch M, Castermans K, Van der Linden E, Griffioen AW. Isolation of endothelial cells from fresh tissues. Nat. Protocols 2008; 3: 1085-1091.

Hillen F, Kaijzel EL, Castermans K, Oude Egbrink MG, Löwik CW, Griffioen AW. A transgenic Tie2-GFP athymic mouse model; a tool for vascular biology in xenograft tumors. Biochem Biophys Res Comm 2008; 368:364-367.

Griffioen AW. New entry in angiostatic cancer therapy. Blood 2008; 111:1755-1756.

Van Beijnum JR, Buurman WA, Griffioen AW. Convergence and amplification of TLR and RAGE signalling pathways via HMGB1. Angiogenesis 2008; 11: 91-99.

Tabruyn SP, Griffioen AW. NFkB: friend or foe in angiostatic therapy. Angiogenesis 2008; 11: 101-106.

Thijssen VL, Hulsmans S, Griffioen AW. The galectin profile of the endothelium; altered expression and localization in activated and tumor endothelial cells. Am J Pathol 2008; 172: 545-553.

Van Beijnum JR, Van der Linden E, Griffioen AW. Angiogenic profiling and comparison of immortalized endothelial cells for functional genomics. Exp Cell Res 2008; 314: 264-272.

Hillen F, Griffioen AW. Tumor vasculature; sprouting angiogenesis and beyond. Cancer Metast Rev 2008; 26: 489-502.


 


 


 

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