Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice
Open Access
- 1 May 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (5), 1832-1848
- https://doi.org/10.1172/jci58976
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.Keywords
This publication has 53 references indexed in Scilit:
- Molecular mechanisms and clinical applications of angiogenesisNature, 2011
- A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesisBritish Journal of Cancer, 2010
- IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasionGenes & Development, 2010
- Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapiesDrug Resistance Updates, 2009
- Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant MetastasisCancer Cell, 2009
- Modes of resistance to anti-angiogenic therapyNature Reviews Cancer, 2008
- Regulation of hypoxia-inducible factor-1α by NF-κBBiochemical Journal, 2008
- VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospectsTrends in Molecular Medicine, 2007
- Prolyl hydroxylase-1 negatively regulates IκB kinase-β, giving insight into hypoxia-induced NFκB activityProceedings of the National Academy of Sciences of the United States of America, 2006
- Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesisProceedings of the National Academy of Sciences of the United States of America, 2006