1. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models
- Author
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Guido Serini, Enrico Giraudo, Claudia Meda, Roberto Latini, Federica Maione, Lorena Zentilin, Giorgio Seano, Fabiola Molla, Mauro Giacca, Federico Bussolino, F., Maione, F., Molla, C., Meda, R., Latini, L., Zentilin, Giacca, Mauro, G., Seano, G., Serini, F., Bussolino, and E., Giraudo
- Subjects
blood supply/physiopathology, Neovascularization ,Pathology ,Angiogenic Switch ,Angiogenesis ,genetics/metabolism ,genetics/metabolism, Uterine Cervical Neoplasm ,Uterine Cervical Neoplasms ,Angiogenesis Inhibitors ,Inbred C57BL ,blood supply/physiopathology, Angiogenesis Inhibitor ,medicine.disease_cause ,Transgenic ,Neovascularization ,Mice ,Cell Movement ,Neoplasms ,Class 3 Semaphorins ,blood supply/physiopathology ,tumor vessel normalization ,Neovascularization, Pathologic ,Integrin beta1 ,General Medicine ,Adenoma, Islet Cell ,Adenoma ,Islet Cell ,blood supply/physiopathology, Angiogenesis Inhibitors ,metabolism, Animals, Antigens ,CD29 ,metabolism, Cell Hypoxia, Cell Movement, Disease Models ,Animal, Female, Gene Expression Regulation ,Neoplastic, Humans, Mice, Mice ,Inbred C57BL, Mice ,Transgenic, Neoplasms ,Pathologic ,metabolism, Semaphorin-3A ,genetics/metabolism, Uterine Cervical Neoplasms ,Cell Hypoxia ,Angiogenesis inhibitor ,Gene Expression Regulation, Neoplastic ,Female ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Mice, Transgenic ,metabolism, Animals, Antigen ,Biology ,Transgenic, Neoplasm ,tumor angiogenesis ,transgenic mouse model of tumorigenesis ,Semaphorin ,medicine ,Animals ,Humans ,Antigens ,Neoplastic ,Animal ,SEMA3A ,Semaphorin-3A ,metabolism, Cell Hypoxia, Cell Movement, Disease Model ,Mice, Inbred C57BL ,Disease Models, Animal ,Gene Expression Regulation ,Tumor progression ,Disease Models ,Cancer research ,Carcinogenesis ,metabolism - 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.
- Published
- 2009