Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature.
Federica Maione, Fabiola Molla, Claudia Meda, Roberto Latini, Lorena Zentilin, Mauro Giacca, Giorgio Seano, Guido Serini, Federico Bussolino, Enrico Giraudo
Title and authors | Publication | Year |
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Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by anti-angiogenic treatment in mice
Federica Maione, Stefania Capano, Donatella Regano, Lorena Zentilin, Mauro Giacca, Oriol Casanovas, Federico Bussolino, Guido Serini, Enrico Giraudo |
Journal of Clinical Investigation | 2012 |
Semaphorin 6A regulates angiogenesis by modulating VEGF signaling
M Segarra, H Ohnuki, D Maric, O Salvucci, X Hou, A Kumar, X Li, G Tosato |
Blood | 2012 |
Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
A Casazza, B Kigel, F Maione, L Capparuccia, O Kessler, E Giraudo, M Mazzone, G Neufeld, L Tamagnone |
EMBO Molecular Medicine | 2012 |
Neuropilins: expression and roles in the epithelium
JR Wild, CA Staton, K Chapple, BM Corfe |
International Journal of Experimental Pathology | 2012 |
Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease
S Goel, AH Wong, RK Jain |
Cold Spring Harbor Perspectives in Medicine | 2012 |
Semaphorins in Angiogenesis and Tumor Progression
G Neufeld, AD Sabag, N Rabinovicz, O Kessler |
Cold Spring Harbor Perspectives in Medicine | 2012 |
Recombinant Human Endostatin Normalizes Tumor Vasculature and Enhances Radiation Response in Xenografted Human Nasopharyngeal Carcinoma Models
F Peng, Z Xu, J Wang, Y Chen, Q Li, Y Zuo, J Chen, X Hu, Q Zhou, Y Wang, H Ma, Y Bao, M Chen |
PloS one | 2012 |
Semaphorin 3A Suppresses Tumor Growth and Metastasis in Mice Melanoma Model
G Chakraborty, S Kumar, R Mishra, TV Patil, GC Kundu |
PloS one | 2012 |
Semaphorin-3D and Semaphorin-3E Inhibit the Development of Tumors from Glioblastoma Cells Implanted in the Cortex of the Brain
AD Sabag, J Bode, D Fink, B Kigel, W Kugler, G Neufeld |
PloS one | 2012 |
Interplay of neuropilin-1 and semaphorin 3A after partial hepatectomy in rats
L Fu, T Kitamura, K Iwabuchi, S Ichinose, M Yanagida, H Ogawa, S Watanabe, T Maruyama, M Suyama, K Takamori |
World journal of gastroenterology : WJG | 2012 |
The VEGF Pathway in Cancer and Disease: Responses, Resistance, and the Path Forward
MW Kieran, R Kalluri, YJ Cho |
Cold Spring Harbor Perspectives in Medicine | 2012 |
Semaphorin3A, Neuropilin-1, and PlexinA1 Are Required for Lymphatic Valve Formation
K Bouvrée, I Brunet, R del Toro, E Gordon, C Prahst, B Cristofaro, T Mathivet, Y Xu, J Soueid, V Fortuna, N Miura, MS Aigrot, CH Maden, C Ruhrberg, JL Thomas, A Eichmann |
Circulation research | 2012 |
Double protection for weakened bones
M Zaidi, J Iqbal |
Nature | 2012 |
Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism.
Wong HK, Shimizu A, Kirkpatrick ND, Garkavtsev I, Chan AW, di Tomaso E, Klagsbrun M, Jain RK |
Neoplasia (New York, N.Y.) | 2012 |