cell news 2/2013
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werner risau prize
factor-independent (autocrine) cancer cell tyrosine kinase acti-
vity and growth
21
. This mode of abnormal vessel growth might
contribute to the excessive and deregulated angiogenesis that
is observed in tumors treated with Notch inhibitors
22,23
. Interes-
tingly, it was previously shown that inhibition of Notch stron-
gly impairs the growth of tumors, even the ones resistant to
anti-VEGF
22
, which is in agreement with our results and with
the idea that Notch can control blood vessel biology in a VEGF-
independent manner.
Anti-VEGF treatment of patients with cancer and age-related
macular degeneration was already shown to signifcantly im-
prove their condition. However many patients seem to respond
poorly to anti-VEGF treatment and there are many cases of
resistance
24,25
. According to our results probing the status of
vascular Notch or VEGFR3 activation might be very relevant.
This information could yield valuable clues for selecting suitable
therapeutic strategies that could reduce the resistance to cur-
rent anti-angiogenic therapies.
References
1 Libby, P. et al., Progress and challenges in translating the biology of atherosclerosis.
Nature 473 (7347), 317-325 (2011).
2 Carmeliet, P. et al., Molecular mechanisms and clinical applications of angiogenesis.
Nature 473 (7347), 298-307 (2011).
3 Lohela, M. et al., VEGFs and receptors involved in angiogenesis versus lymphangiogene-
sis. Curr Opin Cell Biol 21 (2), 154-165 (2009).
4 Benedito, R. et al., Notch as a hub for signalling in angiogenesis. Exp Cell Res 319 (9),
1281-1288 (2013).
5 Carmeliet, P. et al., Abnormal blood vessel development and lethality in embryos lacking
a single VEGF allele. Nature 380 (6573), 435-439 (1996).
6 Duarte, A. et al., Dosage-sensitive requirement for mouse Dll4 in artery development.
Genes Dev 18 (20), 2474-2478 (2004).
7 Krebs, L.T. et al., Notch signalling is essential for vascular morphogenesis in mice. Genes
Dev 14 (11), 1343-1352 (2000).
8 Phng, L.K. et al., Angiogenesis: a team effort coordinated by notch. Dev Cell 16 (2), 196-
208 (2009).
9 Taylor, K.L. et al., Notch activation during endothelial cell network formation in vitro
targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR
expression. Microvasc Res 64 (3), 372-383 (2002).
10 Harrington, L.S. et al., Regulation of multiple angiogenic pathways by Dll4 and Notch in
human umbilical vein endothelial cells. Microvasc Res 75 (2), 144-154 (2008).
11 Sainson, R.C. et al., Cell-autonomous notch signalling regulates endothelial cell bran-
ching and proliferation during vascular tubulogenesis. Faseb J 19 (8), 1027-1029 (2005).
12 Siekmann, A.F. et al., Notch signalling limits angiogenic cell behaviour in developing
zebrafsh arteries. Nature 445 (7129), 781-784 (2007).
13 Tammela, T. et al., Blocking VEGFR-3 suppresses angiogenic sprouting and vascular net-
work formation. Nature 454 (7204), 656-660 (2008).
14 Haiko, P. et al., Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D
is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol 28 (15),
4843-4850 (2008).
15 Dumont, D.J. et al., Cardiovascular failure in mouse embryos defcient in VEGF recep-
tor-3. Science 282 (5390), 946-949 (1998).
16 Kirkin, V. et al., Characterization of indolinones which preferentially inhibit VEGF-C- and
VEGF-D-induced activation of VEGFR-3 rather than VEGFR-2. Eur J Biochem 268 (21),
5530-5540 (2001).
17 Hogan, B.M. et al., Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafsh
intersegmental arteries. Development 136 (23), 4001-4009 (2009).
18 Pytowski, B. et al., Complete and specifc inhibition of adult lymphatic regeneration by a
novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 97 (1), 14-21 (2005).
19 Tammela, T. et al., VEGFR-3 controls tip to stalk conversion at vessel fusion sites by
reinforcing Notch signalling. Nat Cell Biol (2011).
20 Galvagni, F. et al., Endothelial cell adhesion to the extracellular matrix induces c-Src-
dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic
kinase activity. Circ Res 106 (12), 1839-1848 (2010).
21 Lemmon, M.A. et al., Cell signalling by receptor tyrosine kinases. Cell 141 (7), 1117-1134
(2010).
22 Noguera-Troise, I. et al., Blockade of Dll4 inhibits tumour growth by promoting non-
productive angiogenesis. Nature 444 (7122), 1032-1037 (2006).
23 Ridgway, J. et al., Inhibition of Dll4 signalling inhibits tumour growth by deregulating
angiogenesis. Nature 444 (7122), 1083-1087 (2006).
24 Lux, A. et al., Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular
lesions. Br J Ophthalmol 91 (10), 1318-1322 (2007).
25 Jubb, A.M. et al., Biomarkers to predict the clinical effcacy of bevacizumab in cancer.
Lancet Oncol 11 (12), 1172-1183 (2010).
Acknowledgements
This work was funded by the Max Planck Society, the University of Munster and the German
Research Foundation (programmes SFB 629 and SPP 1190). I would like to thank S.F. Rocha, M.
Woeste, M. Zamykal, M. Schiller, M. Ehling, M. Pitulescu, M. Nakayama and A. Siekmann for
the help with experiments and discussions, and G. Breier, T. Honjo and A. Duarte, for the foxed
Vegfr2, Rbpj and Dll4 mutant mice, respectively. I am also very grateful to Prof. Dr. Ralf Adams
for his continuous support and exceptional scientifc input. Finally I would like to thank my
current institution, CNIC (Centro Nacional de Investigaciones Cardiovasculares - Madrid, Spain)
for providing the right environment and resources to continue my research career.
Rui Benedito, PhD
Molecular Genetics of Angiogenesis Laboratory
Cardiovascular Development and Repair Department
Centro Nacional de Investigaciones Cardiovasculares
Melchor Fernández Almagro, 3 | E-28029 Madrid (Spain)
E-mail:
From left to right: Rupert Hallmann, Rui Benedito, Eugen Kerkhoff
09/2012 – present: Assistant Professor and Group Leader of the Molecular Genetics of Angiogenesis Laboratory, Cardiovascular
Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
07/2008 – 08/2012: Postdoctoral Research Scientist, Max-Planck Institute for Molecular Biomedicine, Department Tissue
Morphogenesis, Germany.
10/2006 - 07/2008: Postdoctoral Fellow, Vascular Development Lab, London Research Institute – Cancer Research UK, United Kingdom.
10/2002 - 10/2006: PhD in Molecular Medicine, Faculty of Veterinary Medicine, Technical University of Lisbon, Portugal.
10/2001 - 10/2002: Diploma Thesis at Faculty of Sciences, University of Lisbon, Portugal.
10/1997 - 10/2002: Graduation in Microbiology and Genetics at Faculty of Sciences, University of Lisbon, Portugal.
