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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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 8

Endogenous Sema3A regulates the angiogenic switch during tumor progression.

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Endogenous Sema3A regulates the angiogenic switch during tumor progressi...
Sema3A inhibition increased the angiogenic activity of islet purified from 10.5-week-old RipTag2 mice in a collagen gel bioassay. (A) Angiogenic islets in the absence of ECs and (B) ECs without islets in a collagen gel. (C) Angiogenic islets in the absence (untreated control) (D) or presence of SM-216289 alone (E) or VEGF-blocking Ab alone (F) or both SM-216289 and VEGF-blocking Ab, were embedded into a 3D collagen matrix containing ECs. SM-216289 neutralized the inhibitory effect induced by an anti-VEGF Ab (arrows). Scale bars: 50 μm (A–F). (G) EC migration in the absence or presence of SM-216289 and Sema3A, Sema3E, or Sema3F. SM-216289 did not interfere with either Sema3E or Sema3F inhibitory activity. (H) SM-216289 or saline were locally administrated by osmotic minipumps in 8.5-week-old RipTag2 mice for 2 weeks. Gross pathology images of pancreatic islets and tumors from 10.5-week-old animals after 2 weeks of saline treatment showing angiogenic islets and small tumors (left panel) compared with a significantly enhanced tumor volume due to continuous inhibition of Sema3A (right panel). Scale bars: 800 μm (H). (I) Increased tumor incidence in SM-216289– versus saline-treated animals (by 50%). (J) Increased tumor volume in SM-216289–treated animals compared with controls (84%, ***P < 0.0001). (K) SM-216289 treatment enhanced the number of angiogenic islets compared with controls (36%, **P < 0.001). (L) In a PT, Sema3A overexpression delayed the angiogenic switch, as indicated by a 60% reduction in the number of angiogenic islets in AAV8-Sema3A–treated mice compared with controls (n = 12, ***P < 0.0001).