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.
authors.affiliation: Department of Hematology and Oncology, Charité, Campus Benjamin Franklin, 12200 Berlin, Germany. olaf.penack@charite.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Penack
authors.forename: Erik
authors.initials: E
authors.lastname: Henke
authors.forename: David
authors.initials: D
authors.lastname: Suh
authors.forename: Chris G
authors.initials: CG
authors.lastname: King
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: Il-Kang
authors.initials: IK
authors.lastname: Na
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Holland
authors.forename: Arnab
authors.initials: A
authors.lastname: Ghosh
authors.forename: Sydney X
authors.initials: SX
authors.lastname: Lu
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Lu
authors.forename: Chad
authors.initials: C
authors.lastname: May
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: Ding Cheng
authors.initials: DC
authors.lastname: Gao
authors.forename: Vivek
authors.initials: V
authors.lastname: Mittal
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015820:Cadherins / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D014184:Transplantation, Homologous; D000099152:Cadherin 5
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5; C550191:E4G10 antibody
references.citation: Science. 2008 Jan 11;319(5860):195-8
references.pmid: 18187653
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: Oncol Rep. 2006 May;15(5):1163-8
references.pmid: 16596180
references.citation: Nat Med. 2001 Nov;7(11):1194-201
references.pmid: 11689883
references.citation: J Immunol. 2007 May 15;178(10):6482-94
references.pmid: 17475878
references.citation: Bone Marrow Transplant. 2006 Jul;38(2):149-56
references.pmid: 16751784
references.citation: J Clin Invest. 1999 Jan;103(1):3-4
references.pmid: 9884327
references.citation: Clin Cancer Res. 2008 Apr 1;14(7):2210-9
references.pmid: 18381963
references.citation: Cancer Res. 2005 May 1;65(9):3643-55
references.pmid: 15867359
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18111-6
references.pmid: 16326806
references.citation: Transl Oncol. 2008 Dec;1(4):195-201
references.pmid: 19043530
references.citation: Cell Tissue Kinet. 1980 Jan;13(1):91-104
references.pmid: 7371061
references.citation: Clin Cancer Res. 2008 Apr 1;14(7):2128-36
references.pmid: 18381954
references.citation: Nat Biotechnol. 2008 Apr;26(4):453-61
references.pmid: 18376399
references.citation: Clin Cancer Res. 2008 Feb 1;14(3):892-900
references.pmid: 18245553
references.citation: Cancer Res. 2002 May 1;62(9):2567-75
references.pmid: 11980651
references.citation: Science. 2006 Sep 22;313(5794):1785-7
references.pmid: 16990548
references.citation: N Engl J Med. 2005 Dec 15;353(24):2613-6; author reply 2613-6
references.pmid: 16363023
references.citation: Cancer Cell. 2008 Mar;13(3):193-205
references.pmid: 18328424
references.citation: Nat Rev Cancer. 2008 Aug;8(8):579-91
references.pmid: 18596824
references.citation: Science. 1997 Feb 14;275(5302):964-7
references.pmid: 9020076
references.citation: Nat Rev Mol Cell Biol. 2004 Apr;5(4):261-70
references.pmid: 15071551
references.citation: Gut. 2007 Jun;56(6):855-62
references.pmid: 17170016
references.citation: J Clin Oncol. 2005 Feb 10;23(5):1011-27
references.pmid: 15585754
references.citation: J Exp Med. 2009 Sep 28;206(10):2101-10
references.pmid: 19737867
references.citation: J Immunol. 2005 Sep 1;175(5):2890-9
references.pmid: 16116175
references.citation: Br J Cancer. 2007 Oct 8;97(7):877-82
references.pmid: 17848952
references.citation: Blood. 1997 Oct 15;90(8):3204-13
references.pmid: 9376604
references.citation: PLoS One. 2007 Mar 07;2(3):e267
references.pmid: 17342201
references.citation: Blood. 2003 Oct 1;102(7):2555-61
references.pmid: 12775571
references.citation: Cell Cycle. 2008 Aug 15;7(16):2452-5
references.pmid: 18719382
references.citation: Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):223-32
references.pmid: 18162609
references.citation: Radiat Res. 1991 May;126(2):237-43
references.pmid: 1708892
references.citation: Strahlenther Onkol. 2008 Jan;184(1):1-7
references.pmid: 18188516
references.citation: Br J Radiol. 1985 May;58(689):443-51
references.pmid: 4063693
references.citation: PLoS One. 2007 Dec 19;2(12):e1338
references.pmid: 18092003
references.citation: Lab Invest. 1984 Dec;51(6):624-34
references.pmid: 6209468
references.citation: Genes Dev. 2007 Jun 15;21(12):1546-58
references.pmid: 17575055
references.citation: Blood. 2008 Sep 1;112(5):2139-48
references.pmid: 18483397
references.citation: Int J Radiat Biol Relat Stud Phys Chem Med. 1987 Oct;52(4):635-41
references.pmid: 2444545
references.citation: Arthritis Rheum. 2007 Jun;56(6):1817-26
references.pmid: 17530710
references.citation: Leukemia. 2007 Sep;21(9):1901-6
references.pmid: 17597808
references.citation: J Invest Dermatol. 1986 Apr;86(4):371-5
references.pmid: 3528309
references.citation: Blood. 1996 Oct 15;88(8):3230-9
references.pmid: 8963063
references.citation: Am J Pathol. 2008 Jul;173(1):265-77
references.pmid: 18535184
references.citation: Blood. 2005 Jun 1;105(11):4337-44
references.pmid: 15701713
references.citation: Int J Radiat Biol. 2001 Dec;77(12):1185-93
references.pmid: 11747543
references.citation: Biol Blood Marrow Transplant. 2008 Dec;14(12):1408-16
references.pmid: 19041064
references.citation: N Engl J Med. 2008 May 8;358(19):2039-49
references.pmid: 18463380
references.citation: Acta Morphol Neerl Scand. 1976 Sep;14(3):201-14
references.pmid: 1007968
references.citation: Blood. 2005 Nov 1;106(9):3322-30
references.pmid: 16037386
references.citation: Blood. 2004 Jan 1;103(1):13-9
references.pmid: 12958072
references.citation: Blood. 2001 Oct 1;98(7):2256-65
references.pmid: 11568014
references.citation: Nat Med. 2006 Sep;12(9):1039-47
references.pmid: 16936725
references.citation: PLoS One. 2008 May 28;3(5):e2275
references.pmid: 18509530
references.citation: Nature. 2005 Dec 15;438(7070):967-74
references.pmid: 16355214
references.citation: Lab Invest. 1987 Jan;56(1):85-95
references.pmid: 3540451
references.citation: Blood. 2006 Apr 1;107(7):2774-6
references.pmid: 16339405