Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth

Item Type:	Article
Title:	Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth
Creators Name:	Penack, O. and Henke, E. and Suh, D. and King, C.G. and Smith, O.M. and Na, I.K. and Holland, A.M. and Ghosh, A. and Lu, S.X. and Jenq, R.R. and Liu, C. and Murphy, G.F. and Lu, T.T. and May, C. and Scheinberg, D.A. and Gao, D.C. and Mittal, V. and Heller, G. and Benezra, R. and van den Brink, M.R.M.
Abstract:	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.
Keywords:	Angiogenesis Inhibitors, Bone Marrow Transplantation, Cadherins, CD Antigens, Flow Cytometry, Fluorescent Antibody Technique, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Homologous Transplantation, Monoclonal Antibodies, Neoplasms, Pathologic Neovascularization, Animals, Mice
Source:	Journal of the National Cancer Institute
ISSN:	0027-8874
Publisher:	Oxford University Press
Volume:	102
Number:	12
Page Range:	894-908
Date:	16 June 2010
Official Publication:	https://doi.org/10.1093/jnci/djq172
PubMed:	View item in PubMed

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