Title | Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Penack O, Henke E, Suh D, King CG, Smith OM, Na I-K, Holland AM, Ghosh A, Lu SX, Jenq RR, Liu C, Murphy GF, Lu TT, May C, Scheinberg DA, Gao DCheng, Mittal V, Heller G, Benezra R, van den Brink MRM |
Journal | J Natl Cancer Inst |
Volume | 102 |
Issue | 12 |
Pagination | 894-908 |
Date Published | 2010 Jun 16 |
ISSN | 1460-2105 |
Keywords | Angiogenesis Inhibitors, Animals, Antibodies, Monoclonal, Antigens, CD, Bone Marrow Transplantation, Cadherins, Female, Flow Cytometry, Fluorescent Antibody Technique, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Mice, Mice, Inbred C57BL, Neoplasms, Neovascularization, Pathologic, Transplantation, Homologous |
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. |
DOI | 10.1093/jnci/djq172 |
Alternate Journal | J Natl Cancer Inst |
PubMed ID | 20463307 |
PubMed Central ID | PMC2886094 |
Grant List | R01 AI079178 / AI / NIAID NIH HHS / United States R01 CA055349 / CA / NCI NIH HHS / United States P01-CA33049 / CA / NCI NIH HHS / United States R01 HL084815 / HL / NHLBI NIH HHS / United States R01 AI080455 / AI / NIAID NIH HHS / United States R01-HL095075 / HL / NHLBI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R01-HL069929 / HL / NHLBI NIH HHS / United States R01-CA107096 / CA / NCI NIH HHS / United States R01-AI080455 / AI / NIAID NIH HHS / United States |