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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

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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 4

Sema3A alone or in combination with sunitinib enhances pericyte coverage, reduces blood vessel leakage, improves tissue perfusion, and increases doxorubicin delivery to tumors.

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Sema3A alone or in combination with sunitinib enhances pericyte coverage...
(A and B) As assessed by confocal analysis of Meca32 immunostaining, vessel density in RIP-Tag2 tumors after a 4-week regression trial was reduced 89% in sunitinib-treated tumors, 60% in Sema3A and sunitinib–treated tumors, and 47% Sema3A-treated tumors compared with controls. (A and C–F) Pericyte coverage, as evaluated by confocal colocalization analysis of Meca32 with NG2 (A, arrows, and C) or with α-SMA (D), PDGFR-β (E), or desmin (F). Combined Sema3A and sunitinib enhanced pericyte coverage 62% (NG2), 72% (α-SMA), 84% (PDGFR-β), and 69% (desmin) compared with sunitinib alone; Sema3A increased pericyte coverage 45% (NG2), 47% (α-SMA), 40% (PDGFR-β), and 43% (desmin) compared with controls. (G) In tumors treated with Sema3A alone or in combination with sunitinib, FITC-lectin perfused vessels (arrows) were increased compared with sunitinib-treated and control insulinomas. (H) FITC-dextran extravasation (arrows) decreased in tumors treated with Sema3A alone or in combination with sunitinib compared with sunitinib-treated and control insulinomas. Results are from 5 fields per mouse (n = 12 per treatment group). (I) Amount of doxorubicin (DXR) present in tumors, expressed as μg equivalent/g tumor. Combined Sema3A and sunitinib enhanced doxorubicin 87% compared with sunitinib alone; Sema3A enhanced doxorubicin 83% compared with controls. *P < 0.05, **P < 0.01, unpaired Mann-Whitney U test. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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