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 6

Sema3A inhibits basal and sunitinib-induced expression and activation of Met TK receptor.

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Sema3A inhibits basal and sunitinib-induced expression and activation of...
(A) Protein analysis showed greater total Met and phospho-Met in RIP-Tag2 tumors treated with sunitinib compared with controls; notably, both were reduced by Sema3A, either alone or in combination with sunitinib. Vinculin protein was used as loading control. (B) Protein levels of phospho-Met, normalized to total Met. (C–F) Presence and localization of Met and phospho-Met in RIP-Tag2 tumors treated with sunitinib, Sema3A, and the combination compared with controls, as evaluated by colocalization of anti-Met or anti–phospho-Met Abs with Meca32. Shown are (C and E) representative confocal microscopy, representative of 5 fields per mouse, and (D and F) quantification by MFI (n = 8 per treatment group). (C and D) Total Met was present in a subset of tumor blood vessels and in cancer cells in basal conditions and was highly expressed in both vessels and tumor cells after sunitinib treatment (arrows); combined Sema3A and sunitinib reduced Met both in vessels and tumor cells. (E and F) Phospho-Met was present in some tumor vessels (arrows) and in cancer cells in basal conditions, but increased mainly in tumor cells in sunitinib-treated animals. Notably, Sema3A alone or combined with sunitinib inhibited both total and phospho-Met. *P < 0.05, **P < 0.01, unpaired Mann-Whitney U test. Scale bars: 50 μm.