Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth.
BACKGROUND Blood vessels are formed either by sprouting of resident tissue endothelial cells (angiogenesis) or by recruitment of bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs, vasculogenesis). Neovascularization has been implicated in tumor growth and inflammation, but its roles in graft-vs-host disease (GVHD) and in tumors after allogeneic BM transplantation (allo-BMT) were not known. METHODS We analyzed neovascularization, the contribution of endothelial cells and EPCs, and the ability of anti-vascular endothelial-cadherin antibody, E4G10, to inhibit neovascularization in mice with GVHD after allo-BMT using immunofluorescence microscopy and flow cytometry. We examined survival and clinical and histopathologic GVHD in mice (n = 10-25 per group) in which GVHD was treated with the E4G10 antibody using immunohistochemistry, flow cytometry, and cytokine immunoassay. We also assessed survival, the contribution of green fluorescent protein-marked EPCs to the tumor vasculature, and the ability of E4G10 to inhibit tumor growth in tumor-bearing mice (n = 20-33 per group) after allo-BMT using histopathology and bioluminescence imaging. All statistical tests were two-sided. RESULTS We found increased neovascularization mediated by vasculogenesis, as opposed to angiogenesis, in GVHD target tissues, such as liver and intestines. Administration of E4G10 inhibited neovascularization by donor BM-derived cells without affecting host vascularization, inhibited both GVHD and tumor growth, and increased survival (at 60 days post-BMT and tumor challenge with A20 lymphoma, the probability of survival was 0.29 for control antibody-treated allo-BMT recipients vs 0.7 for E4G10-treated allo-BMT recipients, 95% confidence interval = 0.180 to 0.640, P < .001). CONCLUSIONS Therapeutic targeting of neovascularization in allo-BMT recipients is a novel strategy to simultaneously ameliorate GVHD and inhibit posttransplant tumor growth, providing a new approach to improve the overall outcome of allogeneic hematopoietic stem cell transplantation.
Penack
Olaf
O
Department of Hematology and Oncology, Charité, Campus Benjamin Franklin, 12200 Berlin, Germany. olaf.penack@charite.de
Henke
Erik
E
Suh
David
D
King
Chris G
CG
Smith
Odette M
OM
Na
Il-Kang
IK
Holland
Amanda M
AM
Ghosh
Arnab
A
Lu
Sydney X
SX
Jenq
Robert R
RR
Liu
Chen
C
Murphy
George F
GF
Lu
Theresa T
TT
May
Chad
C
Scheinberg
David A
DA
Gao
Ding Cheng
DC
Mittal
Vivek
V
Heller
Glenn
G
Benezra
Robert
R
van den Brink
Marcel R M
MR
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015820:Cadherins / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014184:Transplantation, Homologous; D000099152:Cadherin 5
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5; C550191:E4G10 antibody
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