Delta-like ligand 4 plays a critical role in pericyte/vascular smooth muscle cell formation during vasculogenesis and tumor vessel expansion in Ewing's sarcoma.
OBJECTIVE
Bone marrow (BM) cells contribute to tumor vessel formation that supports the growth of Ewing's sarcoma. These BM cells migrate into the tumor and differentiate into endothelial cells and pericytes. We investigated whether delta-like ligand 4 (DLL4) played a role in the formation of BM-derived pericytes/vascular smooth muscle cells (vSMC) during tumor vessel formation.


METHODS
Using immunohistochemistry, we examined the expression pattern of DLL4 in 14 patient samples and two xenograft mouse models of Ewing's sarcoma. We then used intratumor injections of short hairpin RNA to inhibit DLL4 expression in Ewing's sarcoma tumors in mice, and evaluated the effect on BM-derived pericytes/vSMCs.


RESULTS
DLL4 was expressed by perivascular cells in 12 of 14 human samples and in BM-derived pericytes/vSMCs in both A4573 and TC71 xenograft tumors. Inhibition of DLL4 expression by short hairpin RNA correlated with the decreased numbers of BM-derived cells in tumor vessels and the decreased numbers of alpha-SMA(+), desmin(+), and NG2(+) pericytes/vSMCs, as well as increased tumor hypoxia.


CONCLUSIONS
DLL4 is important for the formation of BM-derived pericytes/vSMCs during vasculogenesis in Ewing's sarcoma. DLL4 may be a therapeutic target for treatment of Ewing's sarcoma by inhibition of blood vessel formation.
Schadler
Keri L
KL
Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Zweidler-McKay
Patrick A
PA
Guan
Hui
H
Kleinerman
Eugenie S
ES
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000098:blood supply* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1