期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 122, 期 5, 页码 1832-1848出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI58976
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资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [5837, 9211, 10133, 9970]
- Regione Piemonte Ricerca Sanitaria Finalizzata
- Ricerca industriale e sviluppo precompetitivo
- Associazione Augusto per la Vita
- Compagnia di San Paolo
- Ministero della Salute Programma di Ricerca Finalizzata
- Programma Straordinario di Ricerca Oncologica
- Converging Technologies
- Fondazione Guido Berlucchi
- Fondazione Cassa di Risparmio Torino
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS
- Telethon Italy
- FIRC
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-1 alpha, 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.
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