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 3

Sema3A impairs basal and sunitinib-elicited tumor hypoxia and HIF-1α expression.

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Sema3A impairs basal and sunitinib-elicited tumor hypoxia and HIF-1α exp...
(A) Tumor hypoxia was assessed by means of pimonidazole adduct immunostaining (arrows) in serial sections of tumors of RIP-Tag2 mice treated for 4 weeks with sunitinib, Sema3A, and the combination compared with control. Representative images were derived from serial section analysis in each animal (n = 15 per treatment group). (B) Quantification of hypoxic tumors, expressed as percent of pimonidazole density area per tumor, per animal. Combined Sema3A and sunitinib reduced hypoxic area 84% compared with sunitinib alone; Sema3A decreased hypoxic area 90% compared with controls. (C) Western blot analysis of HIF-1α, CA9, and vinculin (as protein loading control) in tumors isolated from RIP-Tag2 mice treated as indicated. (D) Relative levels of HIF-1α and CA9 protein expression, normalized to vinculin (n = 12 per treatment group). Combined Sema3A and sunitinib diminished HIF-1α expression and CA9 amount 91% and 60%, respectively, compared with sunitinib alone; Sema3A decreased CA9 expression 55% compared with control. *P < 0.05, **P < 0.01, unpaired Mann-Whitney U test. Scale bars: 50 μm.