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

Research output: Contribution to journalArticle

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

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
Pages (from-to)894-908
Number of pages15
JournalJournal of the National Cancer Institute
Volume102
Issue number12
DOIs
StatePublished - Jun 1 2010

PMID: 20463307

PMCID: PMC2886094

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Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. / Penack, Olaf; Henke, Erik; Suh, David; King, Chris G.; Smith, Odette M.; Na, Il Kang; Holland, Amanda M.; Ghosh, Arnab; Lu, Sydney X.; Jenq, Robert R.; Liu, Chen; Murphy, George F.; Lu, Theresa T.; May, Chad; Scheinberg, David A.; Gao, Ding Cheng; Mittal, Vivek; Heller, Glenn; Benezra, Robert; Van Den Brink, Marcel R M.

In: Journal of the National Cancer Institute, Vol. 102, No. 12, 01.06.2010, p. 894-908.

Research output: Contribution to journalArticle

Harvard

Penack, O, Henke, E, Suh, D, King, CG, Smith, OM, Na, IK, Holland, AM, Ghosh, A, Lu, SX, Jenq, RR, Liu, C, Murphy, GF, Lu, TT, May, C, Scheinberg, DA, Gao, DC, Mittal, V, Heller, G, Benezra, R & Van Den Brink, MRM 2010, 'Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth' Journal of the National Cancer Institute, vol. 102, no. 12, pp. 894-908. https://doi.org/10.1093/jnci/djq172

APA

Penack, O., Henke, E., Suh, D., King, C. G., Smith, O. M., Na, I. K., ... Van Den Brink, M. R. M. (2010). Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. Journal of the National Cancer Institute, 102(12), 894-908. https://doi.org/10.1093/jnci/djq172

Vancouver

Penack O, Henke E, Suh D, King CG, Smith OM, Na IK et al. Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. Journal of the National Cancer Institute. 2010 Jun 1;102(12):894-908. https://doi.org/10.1093/jnci/djq172

Author

Penack, Olaf ; Henke, Erik ; Suh, David ; King, Chris G. ; Smith, Odette M. ; Na, Il Kang ; Holland, Amanda M. ; Ghosh, Arnab ; Lu, Sydney X. ; Jenq, Robert R. ; Liu, Chen ; Murphy, George F. ; Lu, Theresa T. ; May, Chad ; Scheinberg, David A. ; Gao, Ding Cheng ; Mittal, Vivek ; Heller, Glenn ; Benezra, Robert ; Van Den Brink, Marcel R M. / Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. In: Journal of the National Cancer Institute. 2010 ; Vol. 102, No. 12. pp. 894-908.

BibTeX

@article{05c43a4f74394e5db1e05413dc3d96b0,
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.",
author = "Olaf Penack and Erik Henke and David Suh and King, {Chris G.} and Smith, {Odette M.} and Na, {Il Kang} and Holland, {Amanda M.} and Arnab Ghosh and Lu, {Sydney X.} and Jenq, {Robert R.} and Chen Liu and Murphy, {George F.} and Lu, {Theresa T.} and Chad May and Scheinberg, {David A.} and Gao, {Ding Cheng} and Vivek Mittal and Glenn Heller and Robert Benezra and {Van Den Brink}, {Marcel R M}",
year = "2010",
month = "6",
day = "1",
doi = "10.1093/jnci/djq172",
language = "English",
volume = "102",
pages = "894--908",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "12",

}

RIS

TY - JOUR

T1 - Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth

AU - Penack, Olaf

AU - Henke, Erik

AU - Suh, David

AU - King, Chris G.

AU - Smith, Odette M.

AU - Na, Il Kang

AU - Holland, Amanda M.

AU - Ghosh, Arnab

AU - Lu, Sydney X.

AU - Jenq, Robert R.

AU - Liu, Chen

AU - Murphy, George F.

AU - Lu, Theresa T.

AU - May, Chad

AU - Scheinberg, David A.

AU - Gao, Ding Cheng

AU - Mittal, Vivek

AU - Heller, Glenn

AU - Benezra, Robert

AU - Van Den Brink, Marcel R M

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77953689269&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953689269&partnerID=8YFLogxK

U2 - 10.1093/jnci/djq172

DO - 10.1093/jnci/djq172

M3 - Article

VL - 102

SP - 894

EP - 908

JO - Journal of the National Cancer Institute

T2 - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 12

ER -

ID: 3374409