Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice

Federica Maione, Stefania Capano, Donatella Regano, Lorena Zentilin, Mauro Giacca, Oriol Casanovas, Federico Bussolino, Guido Serini, Enrico Giraudo

Research output: Contribution to journalArticle

108 Citations (Scopus)

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/E 2 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.

Original languageEnglish
Pages (from-to)1832-1848
Number of pages17
JournalJournal of Clinical Investigation
Volume122
Issue number5
DOIs
Publication statusPublished - May 1 2012

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Semaphorin-3A
Neoplasms
Neuroendocrine Tumors
Carcinoma
Epithelial-Mesenchymal Transition
Hypoxia
Receptor Protein-Tyrosine Kinases
Pharmaceutical Preparations
Vascular Endothelial Growth Factor A
Tyrosine
Animal Models
Neoplasm Metastasis

ASJC Scopus subject areas

  • Medicine(all)

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Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. / Maione, Federica; Capano, Stefania; Regano, Donatella; Zentilin, Lorena; Giacca, Mauro; Casanovas, Oriol; Bussolino, Federico; Serini, Guido; Giraudo, Enrico.

In: Journal of Clinical Investigation, Vol. 122, No. 5, 01.05.2012, p. 1832-1848.

Research output: Contribution to journalArticle

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AU - Capano, Stefania

AU - Regano, Donatella

AU - Zentilin, Lorena

AU - Giacca, Mauro

AU - Casanovas, Oriol

AU - Bussolino, Federico

AU - Serini, Guido

AU - Giraudo, Enrico

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