Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing three different mouse models of multistep carcinogenesis, we have shown here that during angiogenesis semaphorin3A (Sema3A) is expressed in endothelial cells, 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 endothelial cells and then in tumor cells, resulting in reduced vascular density and branching, inhibition of tumor growth, and substantially extended survival. Further, long-term re-expression 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

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

MAIONE, FEDERICA;MEDA, CLAUDIA MARIA;SEANO, GIORGIO;SERINI, Guido;BUSSOLINO, Federico;GIRAUDO, Enrico
2009-01-01

Abstract

Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing three different mouse models of multistep carcinogenesis, we have shown here that during angiogenesis semaphorin3A (Sema3A) is expressed in endothelial cells, 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 endothelial cells and then in tumor cells, resulting in reduced vascular density and branching, inhibition of tumor growth, and substantially extended survival. Further, long-term re-expression 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
2009
119
11
3356
3372
Class 3 Semaphorins; tumor angiogenesis; tumor vessel normalization; transgenic mouse model of tumorigenesis
Maione F.; Molla F.; Meda C.; Latini R.; Zentilin R.; Giacca M.; Seano G.; Serini G.; Bussolino F.; Giraudo E.
File in questo prodotto:
File Dimensione Formato  
JCI36308.v2.pdf

Accesso riservato

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 6.5 MB
Formato Adobe PDF
6.5 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/61628
Citazioni
  • ???jsp.display-item.citation.pmc??? 92
  • Scopus 199
  • ???jsp.display-item.citation.isi??? 183
social impact