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

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

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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.

Original languageEnglish
Pages (from-to)3356-3372
Number of pages17
JournalJournal of Clinical Investigation
Volume119
Issue number11
DOIs
Publication statusPublished - Nov 2 2009

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Semaphorin-3A
Angiogenesis Inhibitors
Transgenic Mice
Growth
Neoplasms
Carcinogenesis
Semaphorins
Vascular Tissue Neoplasms
Islet Cell Adenoma
Pericytes
Blood Vessels
Apoptosis

ASJC Scopus subject areas

  • Medicine(all)

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Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. / Maione, Federica; Molla, Fabiola; Meda, Claudia; Latini, Roberto; Zentilin, Lorena; Giacca, Mauro; Seano, Giorgio; Serini, Guido; Bussolino, Federico; Giraudo, Enrico.

In: Journal of Clinical Investigation, Vol. 119, No. 11, 02.11.2009, p. 3356-3372.

Research output: Contribution to journalArticle

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AU - Latini, Roberto

AU - Zentilin, Lorena

AU - Giacca, Mauro

AU - Seano, Giorgio

AU - Serini, Guido

AU - Bussolino, Federico

AU - Giraudo, Enrico

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