title: Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models.
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.affiliation: Department of Oncological Sciences, University of Torino School of Medicine, Candiolo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.forename: Fabiola
authors.initials: F
authors.lastname: Molla
authors.forename: Claudia
authors.initials: C
authors.lastname: Meda
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.forename: Lorena
authors.initials: L
authors.lastname: Zentilin
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
mesh_terms: D007516:Adenoma, Islet Cell / Q000098:blood supply / Q000503:physiopathology; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply* / Q000503:physiopathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D040121:Semaphorin-3A / Q000235:genetics* / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000503:physiopathology
chemical_list: D020533:Angiogenesis Inhibitors; D019012:Integrin beta1; D040121:Semaphorin-3A