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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas

Authors: Dusan Djokovic, Alexandre Trindade, Joana Gigante, Mario Pinho, Adrian L. Harris, Antonio Duarte

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

In invasive malignancies, Dll4/Notch signaling inhibition enhances non-functional vessel proliferation and limits tumor growth by reducing its blood perfusion.

Methods

To assess the effects of targeted Dll4 allelic deletion in the incipient stages of tumor pathogenesis, we chemically induced skin papillomas in wild-type and Dll4+/− littermates, and compared tumor growth, their histological features, vascularization and the expression of angiogenesis-related molecules.

Results

We observed that Dll4 down-regulation promotes productive angiogenesis, although with less mature vessels, in chemically-induced pre-cancerous skin papillomas stimulating their growth. The increase in endothelial activation was associated with an increase in the VEGFR2 to VEGFR1 ratio, which neutralized the tumor-suppressive effect of VEGFR-targeting sorafenib. Thus, in early papillomas, lower levels of Dll4 increase vascularization through raised VEGFR2 levels, enhancing sensitivity to endogenous levels of VEGF, promoting functional angiogenesis and tumor growth.

Conclusion

Tumor promoting effect of low-dosage inhibition needs to be considered when implementing Dll4 targeting therapies.
Literature
1.
Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 2004;18:2474–8.CrossRefPubMedPubMedCentral
2.
Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 2004;18:2469–73.CrossRefPubMedPubMedCentral
3.
Claxton S, Fruttiger M. Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr Patterns. 2004;5:123–7.CrossRefPubMed
4.
Hellström M, Phng L-K, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445:776–80.CrossRefPubMed
5.
Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A. 2007;104:3219–24.CrossRefPubMedPubMedCentral
6.
Suchting S, Freitas C, Le Noble F, Benedito R, Bréant C, Duarte A, et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci U S A. 2007;104:3225–30.CrossRefPubMedPubMedCentral
7.
Trindade A, Djokovic D, Gigante J, Badenes M, Pedrosa A-R, Fernandes A-C, et al. Low-dosage inhibition of Dll4 signaling promotes wound healing by inducing functional neo-angiogenesis. PLoS One. 2012;7, e29863.CrossRefPubMedPubMedCentral
8.
Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444:1032–7.CrossRefPubMed
9.
Ridgway J, Zhang G, Wu Y, Stawicki S, Liang W-C, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444:1083–7.CrossRefPubMed
10.
Li J-L, Sainson RCA, Shi W, Leek R, Harrington LS, Preusser M, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 2007;67:11244–53.CrossRefPubMed
11.
Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, et al. Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood. 2007;109:4753–60.CrossRefPubMedPubMedCentral
12.
Djokovic D, Trindade A, Gigante J, Badenes M, Silva L, Liu R, et al. Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC Cancer. 2010;10:641.CrossRefPubMedPubMedCentral
13.
Haller BK, Bråve A, Wallgard E, Roswall P, Sunkari VG, Mattson U, et al. Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma. Oncogene. 2010;29:4276–86.CrossRefPubMed
14.
Hu G-H, Liu H, Lai P, Guo Z-F, Xu L, Yao X-D, et al. Delta-like ligand 4 (Dll4) predicts the prognosis of clear cell renal cell carcinoma, and anti-Dll4 suppresses tumor growth in vivo. Int J Clin Exp Pathol. 2014;7:2143–52.PubMedPubMedCentral
15.
Jubb AM, Soilleux EJ, Turley H, Steers G, Parker A, Low I, et al. Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer. Am J Pathol. 2010;176:2019–28.CrossRefPubMedPubMedCentral
16.
Chen H-T, Cai Q-C, Zheng J-M, Man X-H, Jiang H, Song B, et al. High expression of delta-like ligand 4 predicts poor prognosis after curative resection for pancreatic cancer. Ann Surg Oncol. 2012;19 Suppl 3:S464–74.CrossRefPubMed
17.
Zhang J-X, Cai M-B, Wang X-P, Duan L-P, Shao Q, Tong Z-T, et al. Elevated DLL4 expression is correlated with VEGF and predicts poor prognosis of nasopharyngeal carcinoma. Med Oncol. 2013;30:390.CrossRefPubMed
18.
Kalén M, Heikura T, Karvinen H, Nitzsche A, Weber H, Esser N, et al. Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion. PLoS One. 2011;6, e18709.CrossRefPubMedPubMedCentral
19.
Hoey T, Yen W-C, Axelrod F, Basi J, Donigian L, Dylla S, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009;5:168–77.CrossRefPubMed
20.
Yan M, Callahan CA, Beyer JC, Allamneni KP, Zhang G, Ridgway JB, et al. Chronic DLL4 blockade induces vascular neoplasms. Nature. 2010;463:E6–7.CrossRefPubMed
21.
Li J-L, Jubb AM, Harris AL. Targeting DLL4 in tumors shows preclinical activity but potentially significant toxicity. Future Oncol. 2010;6:1099–103.CrossRefPubMed
22.
Demehri S, Turkoz A, Kopan R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell. 2009;16:55–66.CrossRefPubMedPubMedCentral
23.
Gill M, Cohen J, Renwick N, Mones JM, Silvers DN, Celebi JT. Genetic similarities between Spitz nevus and Spitzoid melanoma in children. Cancer. 2004;101:2636–40.CrossRefPubMed
24.
Siegel DH, Mann JA, Krol AL, Rauen KA. Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. Br J Dermatol. 2012;166:601–7.CrossRefPubMedPubMedCentral
25.
Williams CK, Li J-L, Murga M, Harris AL, Tosato G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood. 2006;107:931–9.CrossRefPubMedPubMedCentral
26.
Trindade A, Kumar SR, Scehnet JS, Lopes-da-Costa L, Becker J, Jiang W, et al. Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood. 2008;112:1720–9.CrossRefPubMedPubMedCentral
27.
Larcher F, Robles AI, Duran H, Murillas R, Quintanilla M, Cano A, et al. Up-regulation of vascular endothelial growth factor/vascular permeability factor in mouse skin carcinogenesis correlates with malignant progression state and activated H-ras expression levels. Cancer Res. 1996;56:5391–6.PubMed
28.
Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A. 2002;99:11205–10.CrossRefPubMedPubMedCentral
29.
Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995;376:70–4.CrossRefPubMed
30.
Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res. 2004;59:51–71.CrossRefPubMed
31.
Foo SS, Turner CJ, Adams S, Compagni A, Aubyn D, Kogata N, et al. Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell. 2006;124:161–73.CrossRefPubMed
32.
33.
Adnane L, Trail PA, Taylor I, Wilhelm SM. Sorafenib (BAY 43–9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Meth Enzymol. 2006;407:597–612.CrossRefPubMed
34.
Sawamiphak S, Seidel S, Essmann CL, Wilkinson GA, Pitulescu ME, Acker T, et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature. 2010;465:487–91.CrossRefPubMed
Metadata
Title
Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas
Authors
Dusan Djokovic
Alexandre Trindade
Joana Gigante
Mario Pinho
Adrian L. Harris
Antonio Duarte
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1605-2

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