Chronic myeloid leukemia (CML) exosomes promote angiogenesis in a Src-dependent fashion in vitro and in vivo

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCI	CELLBIO-11

* FARE Award Winner

Authors

• M Mineo
• S Taverna
• A Flugy
• G De Leo
• R Alessandro
• EC Kohn

Abstract

Angiogenesis is newly recognized as a factor in CML progression. Exosomes are microvesicles that play an important role in cell-to-cell communication. The role of exosomes released by CML cells in angiogenesis is emerging; however, little is known about the mechanisms involved in this process. We isolated and characterized exosomes released by K562 CML cells and we demonstrated their ability to stimulate human vascular endothelial cells (HUVECs) tube differentiation on Matrigel. Next, we evaluated the effect on exosome behavior of imatinib and dasatinib, two tyrosine kinase inhibitors in use in CML treatment. K562 CML cell treatment with either imatinib or dasatinib reduced exosome release by 58% and 56%, respectively. Dasatinib treatment of HUVECs strongly reduced exosome-induced vascular differentiation. On the contrary, little effect was observed following treatment with imatinib. Vascularization of an exosome containing Matrigel plug in vivo was markedly inhibited by oral administration of dasatinib, but not imatinib. Immunofluorescence and immunoblot analysis showed that K562 exosomes induced a dasatinib-sensitive phosphorylation of Src and FAK and their downstream effectors, Erk and Akt. This credentials exosomes and angiogenesis as molecular targets in CML via activation of Src both in leukemia and its microenvironment.

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