Inhibition of β1 integrin and IL-3Rβ common subunit interaction hinders tumour angiogenesis.
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.
Uberti
B
B
Department of Internal Medicine, University of Turin, Turin, Italy.
Dentelli
P
P
Rosso
A
A
Defilippi
P
P
Brizzi
M F
MF
D000328:Adult; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement; D002478:Cells, Cultured; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013234:Stem Cells
D053648:Cytokine Receptor Common beta Subunit; D019012:Integrin beta1; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins