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Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models
Federica Maione, … , Federico Bussolino, Enrico Giraudo
Federica Maione, … , Federico Bussolino, Enrico Giraudo
Published October 5, 2009
Citation Information: J Clin Invest. 2009;119(11):3356-3372. https://doi.org/10.1172/JCI36308.
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Research Article Oncology Article has an altmetric score of 4

Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models

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Abstract

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.

Authors

Federica Maione, Fabiola Molla, Claudia Meda, Roberto Latini, Lorena Zentilin, Mauro Giacca, Giorgio Seano, Guido Serini, Federico Bussolino, Enrico Giraudo

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Figure 6

Sema3A induces pericyte coverage of tumor blood vessel and promotes SMC migration.

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Sema3A induces pericyte coverage of tumor blood vessel and promotes SMC ...
(A) Fluorescence confocal microscopy brought to light an increase in pericyte coverage of tumor blood vessels after 4 weeks of AVV8-Sema3A treatment compared with controls. Pericyte coverage was evaluated by analysis of colocalization (arrows) of Meca-32 with NG2, α-SMA, or PDGFR-β. Arrowheads indicate pericytes in the immediate vicinity of ECs. Images are representative of 5 fields per mouse from a total of 10 mice per treatment group. Scale bars: 50 μm. (B–D) Percentage of colocalization of pericyte markers on tumor ECs; quantification analysis revealed an increase in pericyte coverage of 44% for NG2+ cells (B), 45% for SMA+ cells (C), and 40% for PDGFR-β+ cells (D) in AAV8-Sema3A–treated versus untreated tumors (**P < 0.001). Values are mean ± SD (n = 10 animals per treatment group). Pericyte colocalization was measured as fluorescence intensity ratio between red (NG2, SMA, and PDGFR-β) and green (Meca-32) channels (see Methods). (E) While the NG2 gene was upregulated, the Rgs5 gene, a marker of activated pericytes, was strongly downregulated in AAV8-Sema3A–treated tumors (4 weeks) compared with controls, as detected by real-time RT-PCR. (F) Human recombinant Sema3A inhibited EC motility and enhanced human SMC migration in chemotaxis assays. Relative cell migration is expressed as fold increase compared with control unstimulated cells. Values are mean ± SD of 4 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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