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A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours

Benjamin Beck, Gregory Driessens, Steven Goossens UGent, Khalil Kass Youssef, Anna Kuchnio, Amélie Caauwe, Panagiota A Sotiropoulou, Sonja Loges, Gaelle Lapouge and Aurélie Candi, et al. (2011) NATURE. 478(7369). p.399-403
abstract
Angiogenesis is critical during tumour initiation and malignant progression(1). Different strategies aimed at blocking vascular endothelial growth factor (VEGF) and its receptors have been developed to inhibit angiogenesis in cancer patients(2). It has become increasingly clear that in addition to its effect on angiogenesis, other mechanisms including a direct effect of VEGF on tumour cells may account for the efficiency of VEGF-blockade therapies(3). Cancer stem cells (CSCs) have been described in various cancers including squamous tumours of the skin(4,5). Here we use a mouse model of skin tumours to investigate the impact of the vascular niche and VEGF signalling on controlling the stemness (the ability to self renew and differentiate) of squamous skin tumours during the early stages of tumour progression. We show that CSCs of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking VEGFR2 caused tumour regression not only by decreasing the microvascular density, but also by reducing CSC pool size and impairing CSC renewal properties. Conditional deletion of Vegfa in tumour epithelial cells caused tumours to regress, whereas VEGF overexpression by tumour epithelial cells accelerated tumour growth. In addition to its well-known effect on angiogenesis, VEGF affected skin tumour growth by promoting cancer stemness and symmetric CSC division, leading to CSC expansion. Moreover, deletion of neuropilin-1 (Nrp1), a VEGF co-receptor expressed in cutaneous CSCs, blocked VEGF's ability to promote cancer stemness and renewal. Our results identify a dual role for tumour-cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for CSCs, and by directly affecting CSCs through Nrp1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of Nrp1 in normal epidermis prevents skin tumour initiation. These results may have important implications for the prevention and treatment of skin cancers.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
CANCER, CELLS, VEGF-A, MOUSE SKIN, ENDOTHELIAL-GROWTH-FACTOR, ANGIOGENESIS, NEUROPILIN-1, CATENIN, MICE, DIFFERENTIATION
journal title
NATURE
Nature
volume
478
issue
7369
pages
399 - 403
Web of Science type
Article
Web of Science id
000296021100049
JCR category
MULTIDISCIPLINARY SCIENCES
JCR impact factor
36.28 (2011)
JCR rank
1/54 (2011)
JCR quartile
1 (2011)
ISSN
0028-0836
DOI
10.1038/nature10525
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1942027
handle
http://hdl.handle.net/1854/LU-1942027
date created
2011-11-10 15:26:29
date last changed
2012-06-26 14:32:27
@article{1942027,
  abstract     = {Angiogenesis is critical during tumour initiation and malignant progression(1). Different strategies aimed at blocking vascular endothelial growth factor (VEGF) and its receptors have been developed to inhibit angiogenesis in cancer patients(2). It has become increasingly clear that in addition to its effect on angiogenesis, other mechanisms including a direct effect of VEGF on tumour cells may account for the efficiency of VEGF-blockade therapies(3). Cancer stem cells (CSCs) have been described in various cancers including squamous tumours of the skin(4,5). Here we use a mouse model of skin tumours to investigate the impact of the vascular niche and VEGF signalling on controlling the stemness (the ability to self renew and differentiate) of squamous skin tumours during the early stages of tumour progression. We show that CSCs of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking VEGFR2 caused tumour regression not only by decreasing the microvascular density, but also by reducing CSC pool size and impairing CSC renewal properties. Conditional deletion of Vegfa in tumour epithelial cells caused tumours to regress, whereas VEGF overexpression by tumour epithelial cells accelerated tumour growth. In addition to its well-known effect on angiogenesis, VEGF affected skin tumour growth by promoting cancer stemness and symmetric CSC division, leading to CSC expansion. Moreover, deletion of neuropilin-1 (Nrp1), a VEGF co-receptor expressed in cutaneous CSCs, blocked VEGF's ability to promote cancer stemness and renewal. Our results identify a dual role for tumour-cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for CSCs, and by directly affecting CSCs through Nrp1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of Nrp1 in normal epidermis prevents skin tumour initiation. These results may have important implications for the prevention and treatment of skin cancers.},
  author       = {Beck, Benjamin and Driessens, Gregory and Goossens, Steven and Youssef, Khalil Kass and Kuchnio, Anna and Caauwe, Am{\'e}lie and Sotiropoulou, Panagiota A and Loges, Sonja and Lapouge, Gaelle and Candi, Aur{\'e}lie and Mascre, Guilhem and Drogat, Benjamin and Dekoninck, Sophie and Haigh, Jody and Carmeliet, Peter and Blanpain, C{\'e}dric},
  issn         = {0028-0836},
  journal      = {NATURE},
  keyword      = {CANCER,CELLS,VEGF-A,MOUSE SKIN,ENDOTHELIAL-GROWTH-FACTOR,ANGIOGENESIS,NEUROPILIN-1,CATENIN,MICE,DIFFERENTIATION},
  language     = {eng},
  number       = {7369},
  pages        = {399--403},
  title        = {A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours},
  url          = {http://dx.doi.org/10.1038/nature10525},
  volume       = {478},
  year         = {2011},
}

Chicago
Beck, Benjamin, Gregory Driessens, Steven Goossens, Khalil Kass Youssef, Anna Kuchnio, Amélie Caauwe, Panagiota A Sotiropoulou, et al. 2011. “A Vascular Niche and a VEGF-Nrp1 Loop Regulate the Initiation and Stemness of Skin Tumours.” Nature 478 (7369): 399–403.
APA
Beck, Benjamin, Driessens, G., Goossens, S., Youssef, K. K., Kuchnio, A., Caauwe, A., Sotiropoulou, P. A., et al. (2011). A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. NATURE, 478(7369), 399–403.
Vancouver
1.
Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. NATURE. 2011;478(7369):399–403.
MLA
Beck, Benjamin, Gregory Driessens, Steven Goossens, et al. “A Vascular Niche and a VEGF-Nrp1 Loop Regulate the Initiation and Stemness of Skin Tumours.” NATURE 478.7369 (2011): 399–403. Print.