Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature.
Federica Maione, Fabiola Molla, Claudia Meda, Roberto Latini, Lorena Zentilin, Mauro Giacca, Giorgio Seano, Guido Serini, Federico Bussolino, Enrico Giraudo
Title and authors | Publication | Year |
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Therapeutic Silencing of miR-214 Inhibits Tumor Progression in Multiple Mouse Models
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Molecular Therapy | 2018 |
A mechanism for semaphorin-induced apoptosis: DNA damage of endothelial and myogenic cells in primary cultures from skeletal muscle
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Oncotarget | 2018 |
Guidance Molecules in Vascular Smooth Muscle
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Frontiers in physiology | 2018 |
New and Old Genes Associated with Primary and Established Responses to Paclitaxel Treatment in Ovarian Cancer Cell Lines
M Świerczewska, A Klejewski, M Brązert, D Kaźmierczak, D Iżycki, M Nowicki, M Zabel, R Januchowski |
Molecules (Basel, Switzerland) | 2018 |
Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?
A Iyer, S Chapoval |
International journal of molecular sciences | 2018 |
Targeting Semaphorin 3C in Prostate Cancer with Small Molecules
CC Lee, RS Munuganti, JW Peacock, K Dalal, IZ Jiao, A Shepherd, L Liu, KJ Tam, CG Sedgwick, S Bhasin, KC Lee, L Gooding, B Vanderkruk, T Tombe, Y Gong, ME Gleave, A Cherkasov, CJ Ong |
Journal of the Endocrine Society | 2018 |