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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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 10

Sema3A impairs DC101-induced hypoxia and improves tumor blood vessel function.

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Sema3A impairs DC101-induced hypoxia and improves tumor blood vessel fun...
(A) Tumor hypoxia, assessed by pimonidazole adduct immunostaining (arrows) in tumors from mice treated as indicated for 4 weeks. (B) Quantification of hypoxic tumors, expressed as percent pimonidazole density area per tumor, per animal. Sema3A and DC101 combined decreased hypoxia 88% compared with DC101 alone; Sema3A decreased hypoxia 90% compared with controls. (C) Vessel density, as assessed by confocal microscopy of Meca32 immunostaining, was reduced 75%, 73%, and 50% by treatment with DC101, DC101 plus Sema3A, and Sema3A, respectively, compared with controls. (D–H) Pericyte coverage, as evaluated by confocal colocalization (arrows) of Meca32 with NG2 (D and E) or with α-SMA (F), PDGFR-β (G), or desmin (H) and expressed as percent colocalization of pericyte markers on tumor ECs. Combined Sema3A and DC101 enhanced pericyte coverage 56% (NG2), 59% (PDGFR-β), and 48% (desmin) compared with DC101. Sema3A increased pericyte coverage 45% (NG2), 47% (PDGFR-β), and 40% (desmin) compared with controls. DC101 increased α-SMA+ pericyte coverage 46% versus controls. (I) Increased incidence of FITC-lectin–perfused vessels (arrows) in Sema3A-treated (alone or in combination with DC101) tumors compared with DC101-treated and control insulinomas. (J) Decreased FITC-dextran extravasation (arrows) in Sema3A-treated (alone or in combination with DC101) tumors compared with DC101-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.