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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 7

Sema3A halts sunitinib-elicited tumor invasion and metastasis formation in HPV16/E2 mice.

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Sema3A halts sunitinib-elicited tumor invasion and metastasis formation ...
(A) Total tumor volume of HPV16/E2 mice in a 4-week regression trial (from 5 to 6 months of age) revealed that sunitinib, Sema3A combined with sunitinib, and Sema3A alone reduced tumor burden 58%, 76%, and 53%, respectively, compared with LacZ-injected, vehicle-treated HPV16/E2 controls. (B and C) Liver and lung metastases (arrows), as assessed by oncogene E7 immunostaining. (D and E) Combined Sema3A and sunitinib decreased lung (D) and liver (E) metastasis incidence 67% and 70%, respectively, compared with sunitinib; Sema3A reduced lung and liver metastasis incidence 84% and 74%, respectively, compared with controls. (F and G) Combined Sema3A and sunitinib diminished the number (F) and volume (G) of liver metastases 82% and 94%, respectively, compared with sunitinib; Sema3A reduced liver metastasis number and volume 60% and 92%, respectively, compared with controls. Representative images were derived from serial section analysis of each animal (n = 12 per treatment group). *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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