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

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

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 1

Gene expression profile of Sema3s and their receptors during RipTag2 and HPV/E2 tumorigenesis.

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Gene expression profile of Sema3s and their receptors during RipTag2 and...
(A and B) Real-time RT-PCR revealed that Sema3a, Sema3f, and, to a lesser extent, Sema3e transcripts were strongly upregulated both in angiogenic islets (A) of RipTag2 mice (A) and in CIN-3 of HPV/E2 mice (B) and downregulated in tumors (T) and SCC, as compared with normal islets (N) and E2-treated normal cervix (N/E2), respectively. (C and D) Compared with that in normal stages, Nrp1 and Nrp2 expression increased in both angiogenic islets and tumors (C) as well as in CIN-3 and SCC (D). (E and F) Compared with that in normal islets and E2-treated normal cervix, Plxna1, Plxnd1, and Plxnb1 mRNA was upregulated in both angiogenic islets and tumors (E) in addition to CIN-3 and SCC (F). In contrast, Plxna2 transcript increased in angiogenic islets and CIN-3 and decreased in tumors and SCC. Normalized relative quantification (RQ) values are compared with normal stages and are mean ± SD of 4 experiments. Sema3A transcript was present in sizeable amounts (pg per 100 ng of total RNA) in normal islets (Sema3A, 46 pg) and in normal cervix (Sema3A, 53 pg; see Supplemental Methods). Values were normalized to the endogenous Gus housekeeping gene. Total RNA derived from pools of islets or tissue lesions of 10 mice per stage (20 mice for normal islets). H, hyperplastic islets; CIN-1, -2, and -3, low, moderate, and high CIN, respectively.