Imatinib Reduces the Vasculogenic Potential of Plastic Tumor Cells
Yvette W.J. Paulis, Domenica Dinnes, Patricia M.M.B. Soetekouw, Peter J. Nelson, Stefan Burdach, Robert P. Loewe, Vivianne C.G. Tjan-Heijnen, Irene von Luettichau and Arjan W. Griffioen
Pages 64-71 (8)
Aggressive tumor cells can obtain the ability to form vascular-like structures that may contribute to blood circulation.
This process is referred to as vasculogenic mimicry (VM). The occurrence of VM networks is associated with
increased tumor malignancy and poor prognosis. In addition, this process is speculated to contribute to resistance to angiostatic
therapy. Various signaling molecules involved in the formation of vasculogenic structures have been identified
and phosphorylation events have been shown to be required for VM network formation. Here, we show by microarray
analysis that highly aggressive VM positive (VM+) Ewing sarcoma cells show increased expression of c-Kit tyrosine
kinase. This result urged us to investigate the effect of the c-Kit targeting compound imatinib (Gleevec®, STI571) on the
process of VM. It was found that treatment of VM+ tumor cells with imatinib reduced VM network formation in 3-
dimensional cultures on Matrigel and collagen. This diminished capacity to form networks was associated with reduced
expression of VE-cadherin and MMP-2, proteins described to be essential for VM, and reduced phosphorylation of
EphA2. The data presented here demonstrate the potential of clinically used imatinib as a possible drug to target VM.
Imatinib, tumor cell plasticity, tyrosine kinase, vasculogenesis, vasculogenic mimicry
VU University Medical Center, Dept. of Medical Oncology - Angiogenesis Laboratory, De Boelelaan 1117, 1081 HV Amsterdam.