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 9

Sema3A blocks DC101-induced cancer invasion and metastatic dissemination.

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Sema3A blocks DC101-induced cancer invasion and metastatic dissemination...
(A) Total tumor volume of RIP-Tag2 mice in a 4-week regression trial (from 12 to 16 weeks of age). Treatment with DC101, DC101 plus Sema3A, and Sema3A reduced tumor burden 60%, 79%, and 68%, respectively, compared with LacZ-injected, purified rat IgG–treated RIP-Tag2 controls. (B) Percent encapsulated IT, IC1, and IC2 carcinomas. Combined treatment with Sema3A and DC101 decreased IC2 carcinoma incidence 67% compared with DC101 alone. (C) DC101-treated tumors displayed highly invasive tumors (arrows), as shown by SV40 T-antigen immunostaining. (D–G) Analysis of peripancreatic LN (D and E) and liver (F and G) metastasis formation. Shown is (D and F) representative SV40 T-antigen immunostaining, derived from serial sections analysis of each animal, and (E and G) quantification of metastasis incidence per animal (n = 15 per group). Combined Sema3A and DC101 decreased LN and liver metastasis incidence 64% and 75%, respectively, compared with DC101. Sema3A treatment reduced LN and liver metastasis incidence 62% and 50%, respectively, compared with controls. *P < 0.05, **P < 0.01, unpaired Mann-Whitney U test. Scale bars: 50 μm.