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

Olaf Penack, Erik Henke, David Suh, Chris G. King, Odette M. Smith, Il Kang Na, Amanda M. Holland, Arnab Ghosh, Sydney X. Lu, Robert R. Jenq, Chen Liu, George F. Murphy, Theresa T. Lu, Chad May, David A. Scheinberg, Ding Cheng Gao, Vivek Mittal, Glenn Heller, Robert Benezra, Marcel R.M. Van Den Brink

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)894-908
Number of pages15
JournalJournal of the National Cancer Institute
Volume102
Issue number12
DOIs
StatePublished - Jun 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth'. Together they form a unique fingerprint.

Cite this