Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice
Federica Maione, … , Guido Serini, Enrico Giraudo
Federica Maione, … , Guido Serini, Enrico Giraudo
Published April 9, 2012
Citation Information: J Clin Invest. 2012;122(5):1832-1848. https://doi.org/10.1172/JCI58976.
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Research Article Oncology

Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice

Abstract

Cancer development, progression, and metastasis are highly dependent on angiogenesis. The use of antiangiogenic drugs has been proposed as a novel strategy to interfere with tumor growth, but cancer cells respond by developing strategies to escape these treatments. In particular, animal models show that antiangiogenic drugs currently used in clinical settings reduce tumor tissue oxygenation and trigger molecular events that foster cancer resistance to therapy. Here, we show that semaphorin 3A (Sema3A) expression overcomes the proinvasive and prometastatic resistance observed upon angiogenesis reduction by the small-molecule tyrosine inhibitor sunitinib in both pancreatic neuroendocrine tumors (PNETs) in RIP-Tag2 mice and cervical carcinomas in HPV16/E2 mice. By improving cancer tissue oxygenation and extending the normalization window, Sema3A counteracted sunitinib-induced activation of HIF-1α, Met tyrosine kinase receptor, epithelial-mesenchymal transition (EMT), and other hypoxia-dependent signaling pathways. Sema3A also reduced tumor hypoxia and halted cancer dissemination induced by DC101, a specific inhibitor of the VEGF pathway. As a result, reexpressing Sema3A in cancer cells converts metastatic PNETs and cervical carcinomas into benign lesions. We therefore suggest that this strategy could be developed to safely harnesses the therapeutic potential of the antiangiogenic treatment.

Authors

Federica Maione, Stefania Capano, Donatella Regano, Lorena Zentilin, Mauro Giacca, Oriol Casanovas, Federico Bussolino, Guido Serini, Enrico Giraudo

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Figure 2

Sema3A blocks distal metastasis formation caused by antiangiogenic treatment.

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Sema3A blocks distal metastasis formation caused by antiangiogenic treat...
(A and B) SV40 T-antigen immunostaining (arrows) of peripancreatic LN and liver metastases (Met). Representative images were derived from serial section analysis in each animal (n = 30 per treatment group). (C and D) Metastasis incidence per animal. Combined Sema3A and sunitinib decreased LN and liver metastases 57% and 54%, respectively, compared with sunitinib alone. Sema3A reduced LN and liver metastases 62% and 50%, respectively, compared with controls. (E) LN metastasis volume. Combined Sema3A and sunitinib decreased LN volume 89% compared with sunitinib alone; Sema3A decreased LN volume 79% compared with controls. (F and G) Number (F) and volume (G) of liver metastases (n = 30 per treatment group). Combined Sema3A and sunitinib diminished the number and volume of liver metastases 88% and 91%, respectively, compared with sunitinib alone; Sema3A reduced liver metastasis number and volume 80% and 85%, respectively, compared with controls. (H) Survival trial in tumor-bearing RIP-Tag2 mice treated continuously with 40 mg/kg/d sunitinib, Sema3A, combined Sema3A and sunitinib, or LacZ beginning at 12 weeks (n = 20 per group). *P < 0.05, **P < 0.01, unpaired Mann-Whitney U test or log-rank test (for survival trials). Scale bars: 50 μm.