Home LiteratureArticle Details
PMID: 25704811 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2.

Cell reports ·Vol. 10 ·No. 7 ·2015-02-24 ·Pages 1066-81

Keskin D, Kim J, Cooke VG, Wu CC, Sugimoto H, Gu C, De Palma M, Kalluri R, LeBleu VS

Abstract

Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis. Furthermore, depletion of pericytes in post-natal retinal blood vessels resulted in abnormal and leaky vasculature. Tumor transcriptome profiling and biological validation revealed that angiopoietin signaling is a key regulatory pathway associated with pericyte targeting. Indeed, pericyte targeting in established mouse tumors increased angiopoietin-2 (ANG2/Angpt2) expression. Depletion of pericytes, coupled with targeting of ANG2 signaling, restored vascular stability in multiple model systems and decreased tumor growth and metastasis. Importantly, ANGPT2 expression correlated with poor outcome in patients with breast cancer. These results emphasize the potential utility of therapeutic regimens that target pericytes and ANG2 signaling in metastatic breast cancer.

MeSH Terms
Angiopoietin-2/immunology,metabolism Animals Antibodies/immunology,pharmacology Antigens/genetics,metabolism Breast Neoplasms/pathology Cell Hypoxia Cell Line, Tumor Cell Proliferation/drug effects Epithelial-Mesenchymal Transition Female Imatinib Mesylate/pharmacology Lung Neoplasms/pathology,secondary Mice Mice, Inbred BALB C Mice, Knockout Neovascularization, Pathologic Pericytes/cytology,drug effects,metabolism Protein Kinase Inhibitors/pharmacology Proteoglycans/deficiency,genetics,metabolism Receptor, Platelet-Derived Growth Factor beta/deficiency,genetics,metabolism Retina/physiology Signal Transduction/drug effects
Chemicals
Angiopoietin-2 Antibodies Antigens Protein Kinase Inhibitors Proteoglycans chondroitin sulfate proteoglycan 4 Imatinib Mesylate Receptor, Platelet-Derived Growth Factor beta
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Keskin Doruk
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Kim Jiha
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Cooke Vesselina G
Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Wu Chia-Chin
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Sugimoto Hikaru
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Gu Chenghua
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
De Palma Michele
The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Kalluri Raghu
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: rkalluri@mdanderson.org.
LeBleu Valerie S
Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: vlebleu@mdanderson.org.
References (62)
62 references, click to expand
  1. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF.
    Oncogene. 1999 Sep 20;18(38):5356-62 PMID: 10498889
  2. Angiogenesis, metastasis, and endogenous inhibition.
    J Neurooncol. 2000 Oct-Nov;50(1-2):173-80 PMID: 11245277
  3. Pericyte requirement for anti-leak action of angiopoietin-1 and vascular remodeling in sustained inflammation.
    Am J Pathol. 2011 Jun;178(6):2897-909 PMID: 21550017
  4. The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism.
    J Cell Sci. 2005 Feb 15;118(Pt 4):771-80 PMID: 15687104
  5. Endothelial HIF-2α regulates murine pathological angiogenesis and revascularization processes.
    J Clin Invest. 2012 Apr;122(4):1427-43 PMID: 22426208
  6. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis.
    Cancer Cell. 2009 Mar 3;15(3):232-9 PMID: 19249681
  7. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis.
    J Natl Cancer Inst. 2012 Mar 21;104(6):461-75 PMID: 22343031
  8. Endothelial/pericyte interactions.
    Circ Res. 2005 Sep 16;97(6):512-23 PMID: 16166562
  9. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF.
    Development. 1998 May;125(9):1591-8 PMID: 9521897
  10. The mouse retina as an angiogenesis model.
    Invest Ophthalmol Vis Sci. 2010 Jun;51(6):2813-26 PMID: 20484600
  11. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade.
    Cell Rep. 2014 Aug 7;8(3):696-706 PMID: 25088418
  12. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.
    Science. 2005 Jan 7;307(5706):58-62 PMID: 15637262
  13. Pericytes and the pathogenesis of diabetic retinopathy.
    Diabetes. 2002 Oct;51(10):3107-12 PMID: 12351455
  14. Endothelial-mural cell signaling in vascular development and angiogenesis.
    Arterioscler Thromb Vasc Biol. 2009 May;29(5):630-8 PMID: 19164813
  15. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions.
    Angiogenesis. 2014 Jul;17(3):471-94 PMID: 24482243
  16. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth.
    Cancer Cell. 2014 Dec 8;26(6):880-95 PMID: 25490450
  17. Cross-talk between endothelial and breast cancer cells regulates reciprocal expression of angiogenic factors in vitro.
    J Cell Biochem. 2012 Apr;113(4):1142-51 PMID: 22095586
  18. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo.
    Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11205-10 PMID: 12163646
  19. Pericytes in the mature chorioallantoic membrane capillary plexus contain desmin and alpha-smooth muscle actin: relevance for non-sprouting angiogenesis.
    Histochem Cell Biol. 2008 Nov;130(5):1027-40 PMID: 18688635
  20. Anti-angiogenesis: new concept for therapy of solid tumors.
    Ann Surg. 1972 Mar;175(3):409-16 PMID: 5077799
  21. A novel angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to Pan-Angiopoietin-1/-2 inhibitors.
    PLoS One. 2013;8(2):e54923 PMID: 23405099
  22. Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis.
    Cancer Res. 2011 Sep 1;71(17):5717-27 PMID: 21778249
  23. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.
    Dev Cell. 2011 Aug 16;21(2):193-215 PMID: 21839917
  24. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis.
    Trends Mol Med. 2011 Jul;17(7):347-62 PMID: 21481637
  25. Dual targeting of endothelial cells and pericytes in antivascular therapy for ovarian carcinoma.
    Clin Cancer Res. 2007 Jul 15;13(14):4209-17 PMID: 17634550
  26. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1.
    Circ Res. 2003 Nov 28;93(11):1074-81 PMID: 14576200
  27. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.
    Cell. 1994 Oct 21;79(2):315-28 PMID: 7525077
  28. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis.
    Cancer Cell. 2009 Mar 3;15(3):220-31 PMID: 19249680
  29. Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching.
    Blood. 2010 Jun 17;115(24):5102-10 PMID: 20154215
  30. Involvement of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1alpha in breast cancer cell migration through human brain microvascular endothelial cells.
    Mol Cancer Res. 2004 Jun;2(6):327-38 PMID: 15235108
  31. Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102.
    Cancer Res. 2007 Aug 1;67(15):7358-67 PMID: 17671206
  32. Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells.
    J Cell Biol. 1987 Sep;105(3):1455-62 PMID: 3654761
  33. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo.
    Cancer Res. 2007 Dec 1;67(23):11244-53 PMID: 18056450
  34. Increased vascularization in mice overexpressing angiopoietin-1.
    Science. 1998 Oct 16;282(5388):468-71 PMID: 9774272
  35. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients.
    Endocr Relat Cancer. 2012 Apr;19(2):197-208 PMID: 22277193
  36. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system.
    Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77 PMID: 19234476
  37. Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives.
    Cancer Detect Prev. 2003;27(3):229-38 PMID: 12787731
  38. Pericytes and vascular stability.
    Exp Cell Res. 2006 Mar 10;312(5):623-9 PMID: 16303125
  39. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
    Cell. 1997 Jan 24;88(2):277-85 PMID: 9008168
  40. Involvement of chemokine receptors in breast cancer metastasis.
    Nature. 2001 Mar 1;410(6824):50-6 PMID: 11242036
  41. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors.
    J Clin Invest. 2003 May;111(9):1287-95 PMID: 12727920
  42. A role for VEGF as a negative regulator of pericyte function and vessel maturation.
    Nature. 2008 Dec 11;456(7223):809-13 PMID: 18997771
  43. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells.
    J Biol Chem. 1999 May 28;274(22):15732-9 PMID: 10336473
  44. The role of the Angiopoietins in vascular morphogenesis.
    Angiogenesis. 2009;12(2):125-37 PMID: 19449109
  45. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases.
    Nat Rev Drug Discov. 2011 Jun;10(6):417-27 PMID: 21629292
  46. The role of pericytes in blood-vessel formation and maintenance.
    Neuro Oncol. 2005 Oct;7(4):452-64 PMID: 16212810
  47. Angiopoietin-1 protects the adult vasculature against plasma leakage.
    Nat Med. 2000 Apr;6(4):460-3 PMID: 10742156
  48. Role of angiogenesis in tumor growth and metastasis.
    Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8 PMID: 12516034
  49. The Role of chemokine receptor CXCR4 in breast cancer metastasis.
    Am J Cancer Res. 2013;3(1):46-57 PMID: 23359227
  50. Angiogenesis and tumor metastasis.
    Annu Rev Med. 1998;49:407-24 PMID: 9509272
  51. Angiogenic switch of angiopietins-Tie2 system and its prognostic value in bladder cancer.
    Clin Cancer Res. 2008 Dec 15;14(24):8253-62 PMID: 19088043
  52. Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis.
    Blood. 2009 Jul 9;114(2):469-77 PMID: 19439736
  53. Desmin ensheathment ratio as an indicator of vessel stability: evidence in normal development and in retinopathy of prematurity.
    Am J Pathol. 2004 Oct;165(4):1301-13 PMID: 15466395
  54. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway.
    Cancer Cell. 2012 Jan 17;21(1):66-81 PMID: 22264789
  55. Pericytes in the microvasculature.
    Cardiovasc Res. 1996 Oct;32(4):687-98 PMID: 8915187
  56. Molecular mechanisms and clinical applications of angiogenesis.
    Nature. 2011 May 19;473(7347):298-307 PMID: 21593862
  57. Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth.
    Cancer Res. 2009 Feb 15;69(4):1324-33 PMID: 19208839
  58. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells.
    Cancer Cell. 2011 Apr 12;19(4):512-26 PMID: 21481792
  59. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1.
    Science. 1999 Dec 24;286(5449):2511-4 PMID: 10617467
  60. Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma.
    Clin Cancer Res. 2009 Feb 15;15(4):1384-92 PMID: 19228739
  61. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma.
    N Engl J Med. 1991 Jan 3;324(1):1-8 PMID: 1701519
  62. PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival.
    Nat Cell Biol. 2005 Sep;7(9):870-9 PMID: 16113679
Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2015.01.035
Email
rkalluri@mdanderson.org
vlebleu@mdanderson.org
Published
2015-02-24
Epub
2015-00-19
Pages
1066-81
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC4342328
Subset
IM
Grants
NCI NIH HHS · U54 CA163191 · United States
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · U01 CA151925 · United States
NCI NIH HHS · CA163191 · United States
NCI NIH HHS · P30CA016672 · United States
NCI NIH HHS · CA151925 · United States
NCI NIH HHS · CA155370 · United States
NCI NIH HHS · R01 CA125550 · United States
NCI NIH HHS · CA125550 · United States
NCI NIH HHS · R01 CA155370 · United States
NINDS NIH HHS · R01 NS064583 · United States
External Links
PubMed source DOI: 10.1016/j.celrep.2015.01.035 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2