Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis.
A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent
Gioelli, Noemi;Maione, Federica;Camillo, Chiara;Valdembri, Donatella;Morello, Noemi;Cagnoni, Gabriella;QIU, Yaqi;Giacca, Mauro;Giustetto, Maurizio;CASCONE, ILARIA;Tamagnone, Luca;Giraudo, Enrico
Co-last
;Serini, Guido
Co-last
2018-01-01
Abstract
Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis.File | Dimensione | Formato | |
---|---|---|---|
Gioelli et al_Sci Transl Med_2018 (1).pdf
Accesso riservato
Descrizione: Sci Trans Med 2018_RISERVATO
Tipo di file:
PDF EDITORIALE
Dimensione
5.16 MB
Formato
Adobe PDF
|
5.16 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Sci Trans Med_articolo.pdf
Accesso aperto
Descrizione: Sci Trans Med 2018_APERTO
Tipo di file:
POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione
1.28 MB
Formato
Adobe PDF
|
1.28 MB | Adobe PDF | Visualizza/Apri |
Science Transaltion Medicine 2018.pdf
Accesso riservato
Tipo di file:
PDF EDITORIALE
Dimensione
2.35 MB
Formato
Adobe PDF
|
2.35 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.