Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth Journal Article
| Authors: | Penack, O.; Henke, E.; Suh, D.; King, C. G.; Smith, O. M.; Na, I. K.; Holland, A. M.; Ghosh, A.; Lu, S. X.; Jenq, R. R.; Liu, C.; Murphy, G. F.; Lu, T. T.; May, C.; Scheinberg, D. A.; Gao, D. C.; Mittal, V.; Heller, G.; Benezra, R.; van den Brink, M. R. M. |
| Article Title: | Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth |
| 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. © 2010 The Author. |
| Keywords: | immunohistochemistry; survival; controlled study; treatment outcome; transplantation, homologous; unclassified drug; histopathology; angiogenesis inhibitor; nonhuman; flow cytometry; neoplasm; neoplasms; animal cell; mouse; animal; animals; mice; animal tissue; bone marrow; green fluorescent protein; animal experiment; animal model; allogenic bone marrow transplantation; hematopoietic stem cell transplantation; angiogenesis; neovascularization, pathologic; vascularization; mice, inbred c57bl; c57bl mouse; monoclonal antibody; endothelium cell; fluorescent antibody technique; cytokine; liver; immunology; antibodies, monoclonal; donor; probability; lymphoma; graft versus host reaction; allogeneic hematopoietic stem cell transplantation; immunoassay; antigens, cd; tumor growth; bone marrow transplantation; graft vs host disease; angiogenesis inhibitors; tumor vascularization; cadherin; cadherins; neovascularization (pathology); intestine; antibody; leukocyte antigen; bioluminescence; graft recipient; allotransplantation; immunofluorescence microscopy; host; growth inhibition; vascular endothelial cadherin; e4g10 antibody |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 102 |
| Issue: | 12 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2010-06-16 |
| Start Page: | 894 |
| End Page: | 908 |
| Language: | English |
| DOI: | 10.1093/jnci/djq172 |
| PUBMED: | 20463307 |
| PROVIDER: | scopus |
| PMCID: | PMC2886094 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: JNCIA" - "Source: Scopus" |
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