Integrin/cytokine receptor interaction provides permissive signals leading to neoangiogenesis, and integrins are crucial for differentiation of endothelial progenitor cells (EPCs). It is known that the inflammatory interleukin-3 (IL-3), released in the tumoral microenvironment, contributes to both angiogenesis and vasculogenic processes. Herein, we generated IL-3 receptor beta common (IL-3Rβc) extracellular domain-derived fusion proteins (Fc) to elucidate the molecular mechanisms regulating these processes. Three different Fc were generated, containing the entire extracellular domain of IL-3Rβc (Fc1.4), a fragment corresponding to domains 1-3 (Fc1.3) and a fragment corresponding to domain 4 (Fc4), respectively. The ability of the fusion proteins to interfere with IL-3Rβc/β1 integrin interaction was assessed on endothelial cells (ECs), EPCs and murine-derived ECs. Pull-down experiments showed that Fc1.4 and Fc4 fusion proteins specifically interacted with β1 integrin. Fc4 and Fc1.4 fragments prevented IL-3-mediated EPC expansion, arterial morphogenesis and tumour-derived EC migration, without affecting cell adhesion. Fc4 in vivo inhibited the IL-3-mediated vasculogenic process, as well as inflammatory and tumour vascular growth. In conclusion, these data identify the β1 integrin-interacting domain in the juxta-membrane IL-3Rβc extracellular domain, and provide the rational for targeting this interaction to impair vascular growth.

Ihibition of beta 1 integrin and IL-3R beta common subunit interaction hinders tumor angiogenesis

DENTELLI, Patrizia;UBERTI, BARBARA;ROSSO, Arturo;CASTELLI, Ada;TROMBETTA, Antonella;OLGASI, CRISTINA;TOGLIATTO, Gabriele Maria;BARALE, CRISTINA;DEFILIPPI, Paola;BRIZZI, Maria Felice
2010

Abstract

Integrin/cytokine receptor interaction provides permissive signals leading to neoangiogenesis, and integrins are crucial for differentiation of endothelial progenitor cells (EPCs). It is known that the inflammatory interleukin-3 (IL-3), released in the tumoral microenvironment, contributes to both angiogenesis and vasculogenic processes. Herein, we generated IL-3 receptor beta common (IL-3Rβc) extracellular domain-derived fusion proteins (Fc) to elucidate the molecular mechanisms regulating these processes. Three different Fc were generated, containing the entire extracellular domain of IL-3Rβc (Fc1.4), a fragment corresponding to domains 1-3 (Fc1.3) and a fragment corresponding to domain 4 (Fc4), respectively. The ability of the fusion proteins to interfere with IL-3Rβc/β1 integrin interaction was assessed on endothelial cells (ECs), EPCs and murine-derived ECs. Pull-down experiments showed that Fc1.4 and Fc4 fusion proteins specifically interacted with β1 integrin. Fc4 and Fc1.4 fragments prevented IL-3-mediated EPC expansion, arterial morphogenesis and tumour-derived EC migration, without affecting cell adhesion. Fc4 in vivo inhibited the IL-3-mediated vasculogenic process, as well as inflammatory and tumour vascular growth. In conclusion, these data identify the β1 integrin-interacting domain in the juxta-membrane IL-3Rβc extracellular domain, and provide the rational for targeting this interaction to impair vascular growth.
Lost in translation: bridging the gap between cancer research and effective therapies
Roma
4-7 Ottobre 2010
Lost in translation: bridging the gap between cancer research and effective therapies
Società Italiana di Cancerologia
75
75
P.Dentelli; B.Uberti; A.Rosso; A.Castelli; A.Trombetta; C.Olgasi; G. Togliatto; C.Barale; P.Defilippi; M.F.Brizzi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/80017
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