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 8

Sema3A decreases basal and sunitinib-induced hypoxia in HPV16/E2 mice by normalizing the tumor vasculature.

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Sema3A decreases basal and sunitinib-induced hypoxia in HPV16/E2 mice by...
(A) Tumor hypoxia, assessed by pimonidazole adduct immunostaining in serial sections of tumors from HPV16/E2 mice treated as indicated for 4 weeks. (B) Quantification of hypoxic tumors, expressed as percent pimonidazole density area per tumor, per animal. Sema3A and sunitinib combined decreased hypoxia 92% compared with sunitinib alone; Sema3A decreased hypoxia 88% compared with controls. (C) Vessel density, as assessed by confocal analysis of Meca32 immunostaining, was reduced 67%, 62%, and 52% by treatment with sunitinib, sunitinib plus Sema3A, and Sema3A, respectively, compared with controls. (D–H) Pericyte coverage, as evaluated by confocal colocalization (arrows) of Meca32 with α-SMA (D and F) or with NG2 (E), PDGFR-β (G), or desmin (H) and expressed as percent colocalization of pericyte markers on tumor ECs. Combined Sema3A and sunitinib enhanced pericyte coverage 71% (NG2), 68% (α-SMA), 82% (PDGFR-β), and 69% (desmin) compared with sunitinib alone. Sema3A increased pericyte coverage 40% (NG2), 48% (α-SMA), 39% (PDGFR-β), and 32% (desmin) compared with controls. (I) Increased incidence of FITC-lectin–perfused vessels (arrows) in Sema3A-treated (alone or in combination with sunitinib) tumors compared with sunitinib-treated and control insulinomas. (J) Decreased FITC-dextran extravasation (arrows) in Sema3A-treated (alone or in combination with sunitinib) tumors compared with sunitinib-treated and control insulinomas. Results are from 5 fields per mouse (n = 8 per treatment group). *P < 0.05, **P < 0.01, unpaired Mann-Whitney U test. Scale bars: 50 μm.