Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeting the ANGPT–TIE2 pathway in malignancy

Key Points

  • The angiopoietin (ANGPT)–TIE system is crucial for the angiogenic switch in tumours, and together with vascular endothelial growth factor A (VEGFA) promotes the initiation of angiogenesis and maturation of new vessels. The ANGPT–TIE system is also involved in inflammation, metastasis and lymphangiogenesis.

  • ANGPT1 is a TIE2 agonist, and ANGPT2 functions as an antagonist or a partial agonist of TIE2 in different contexts. Both ANGPT1 and ANGPT2 have been shown to promote or inhibit tumorigenesis in various settings.

  • Agents specifically targeting ANGPT1 and ANGPT2 are currently in Phase II clinical trials and early reports suggest a promising anti-tumour activity and a safety profile distinct from those of anti-VEGFA agents.

  • Substantial combination benefit of targeting both the ANGPT2 and VEGFA pathways has been demonstrated preclinically.

Abstract

Angiopoietins (ANGPTs) are ligands of the endothelial cell receptor TIE2 and have crucial roles in the tumour angiogenic switch. Increased expression of ANGPT2 relative to ANGPT1 in tumours correlates with poor prognosis. The biological effects of the ANGPT–TIE system are context dependent, which brings into question what the best strategy is to target this pathway. This Review presents an encompassing picture of what we know about this important axis in tumour biology. The various options for therapeutic intervention are discussed to identify the best path forwards.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The ANGPT–TIE signalling pathways.
Figure 2: ANGPTs and angiogenesis.

References

  1. 1

    Abdollahi, A. & Folkman, J. Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist. Updat. 13, 16–28 (2010).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592–603 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Ebos, J. M., Lee, C. R. & Kerbel, R. S. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin. Cancer Res. 15, 5020–5025 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4

    Herbst, R. S. et al. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J. Clin. Oncol. 27, 3557–3565 (2009). First clinical report about the efficacy and distinct safety profile of the ANGPT1 and ANGPT2 trap AMG-386 in advanced solid tumours.

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997). First report about the identification of ANGPT2, the overexpression of ANGPT2 is shown to be embyronically lethal similar to the loss of ANGPT1 or TIE2.

    CAS  Article  Google Scholar 

  7. 7

    Yuan, H. T., Khankin, E. V., Karumanchi, S. A. & Parikh, S. M. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in endothelium. Mol. Cell. Biol. 29, 2011–2022 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Kim, H. Z., Jung, K., Kim, H. M., Cheng, Y. & Koh, G. Y. A designed angiopoietin-2 variant, pentameric COMP-Ang2, strongly activates Tie2 receptor and stimulates angiogenesis. Biochim. Biophys. Acta 1793, 772–780 (2009).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Kim, I. et al. Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Oncogene 19, 4549–4552 (2000).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Lee, H. J. et al. Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J. 18, 1200–1208 (2004).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Beaudet, M. J., Rueda, N., Kobinger, G. P., Villeneuve, J. & Vallieres, L. Construction of a ganciclovir-sensitive lentiviral vector to assess the influence of angiopoietin-3 and soluble Tie2 on glioma growth. J. Neurooncol. 18 Dec 2009 (doi: 10.1007/s11060-009-0095-y).

  12. 12

    Xu, Y., Liu, Y. J. & Yu, Q. Angiopoietin-3 inhibits pulmonary metastasis by inhibiting tumor angiogenesis. Cancer Res. 64, 6119–6126 (2004).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Olsen, M. W. et al. Angiopoietin-4 inhibits angiogenesis and reduces interstitial fluid pressure. Neoplasia 8, 364–372 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14

    Kim, K. L. et al. Interaction between Tie receptors modulates angiogenic activity of angiopoietin2 in endothelial progenitor cells. Cardiovasc. Res. 72, 394–402 (2006).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Milner, C. S., Hansen, T. M., Singh, H. & Brindle, N. P. Roles of the receptor tyrosine kinases Tie1 and Tie2 in mediating the effects of angiopoietin-1 on endothelial permeability and apoptosis. Microvasc. Res. 77, 187–191 (2009).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Saharinen, P. et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J. Cell Biol. 169, 239–243 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Barton, W. A. et al. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nature Struct. Mol. Biol. 13, 524–532 (2006). Identification of the interaction domains of ANGPT2 and TIE2, showing that small regions of ANGPT2 and TIE2 are responsible for binding.

    CAS  Article  Google Scholar 

  18. 18

    Kim, K. T. et al. Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2. J. Biol. Chem. 280, 20126–20131 (2005).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Jones, N. et al. A unique autophosphorylation site on Tie2/Tek mediates Dok-R. phosphotyrosine binding domain binding and function. Mol. Cell. Biol. 23, 2658–2668 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Jones, N. & Dumont, D. J. The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene 17, 1097–1108 (1998).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Jones, N. et al. Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J. Biol. Chem. 274, 30896–30905 (1999).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Seegar, T. C. M. et al. Tie1-Tie2 interactions mediate functional differences between angiopoietin ligands. Mol. Cell 37, 643–655 (2010). New data about the negative regulatory function of TIE1 towards TIE2.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Li, Z. et al. Embryonic stem cell tumor model reveals role of vascular endothelial receptor tyrosine phosphatase in regulating Tie2 pathway in tumor angiogenesis. Proc. Natl Acad. Sci. USA 106, 22399–22404 (2009).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Winderlich, M. et al. VE-PTP controls blood vessel development by balancing Tie-2 activity. J. Cell Biol. 185, 657–671 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Reiss, Y. et al. Angiopoietin-2 impairs revascularization after limb ischemia. Circ. Res. 101, 88–96 (2007).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Hansen, T. M., Singh, H., Tahir, T. A. & Brindle, N. P. Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface. Cell Signal. 22, 527–532 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Marron, M. B. et al. Regulated proteolytic processing of Tie1 modulates ligand responsiveness of the receptor-tyrosine kinase Tie2. J. Biol. Chem. 282, 30509–30517 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Yabkowitz, R. et al. Inflammatory cytokines and vascular endothelial growth factor stimulate the release of soluble tie receptor from human endothelial cells via metalloprotease activation. Blood 93, 1969–1979 (1999).

    CAS  PubMed  Google Scholar 

  29. 29

    Hu, B. & Cheng, S. Y. Angiopoietin-2: development of inhibitors for cancer therapy. Curr. Oncol. Rep. 11, 111–116 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Fiedler, U. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 103, 4150–4156 (2004).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Jang, C. et al. Angiopoietin-2 exocytosis is stimulated by sphingosine-1-phosphate in human blood and lymphatic endothelial cells. Arterioscler. Thromb. Vasc. Biol. 29, 401–407 (2009).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Goerge, T. et al. Secretion pores in human endothelial cells during acute hypoxia. J. Membr. Biol. 187, 203–211 (2002).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Rondaij, M. G., Bierings, R., Kragt, A., van Mourik, J. A. & Voorberg, J. Dynamics and plasticity of Weibel-Palade bodies in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26, 1002–1007 (2006).

    CAS  PubMed  Article  Google Scholar 

  34. 34

    Chung, Y. C., Hou, Y. C., Chang, C. N. & Hseu, T. H. Expression and prognostic significance of angiopoietin in colorectal carcinoma. J. Surg. Oncol. 94, 631–638 (2006).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Oka, N. et al. Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int. 95, 660–663 (2005).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Tanaka, F. et al. Expression of angiopoietins and its clinical significance in non-small cell lung cancer. Cancer Res. 62, 7124–7129 (2002).

    CAS  PubMed  Google Scholar 

  37. 37

    Dhiwakar, M., Malone, J. P., Kay, P. A., Robbins, K. T. & Ran, S. Use of angiopoietin-1 expression in squamous cell carcinoma of the head and neck to predict disease-free survival. J. Clin. Oncol. Abstr. 28, 5542 (2010).

    Article  Google Scholar 

  38. 38

    Hou, H. A. et al. Expression of angiopoietins and vascular endothelial growth factors and their clinical significance in acute myeloid leukemia. Leuk. Res. 32, 904–912 (2008).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Koenecke, C. et al. Shedding of the endothelial receptor tyrosine kinase Tie2 correlates with leukemic blast burden and outcome after allogeneic hematopoietic stem cell transplantation for AML. Ann. Hematol. 89, 459–467 (2010).

    CAS  PubMed  Article  Google Scholar 

  40. 40

    Loges, S. et al. Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival. J. Clin. Oncol. 23, 1109–1117 (2005).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Sfiligoi, C. et al. Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int. J. Cancer 103, 466–474 (2003).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Maffei, R. et al. Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia. Blood 9 Apr 2010 (doi:10.1182/blood-2009-11-252494).

  43. 43

    Mitsuhashi, N. et al. Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma. Hepatology 37, 1105–1113 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Ahmad, S. A. et al. The effects of angiopoietin-1 and -2 on tumor growth and angiogenesis in human colon cancer. Cancer Res. 61, 1255–1259 (2001).

    CAS  PubMed  Google Scholar 

  45. 45

    Ogawa, M. et al. Hepatic expression of ANG2 RNA in metastatic colorectal cancer. Hepatology 39, 528–539 (2004).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Anargyrou, K. et al. Normalization of the serum angiopoietin-1 to angiopoietin-2 ratio reflects response in refractory/resistant multiple myeloma patients treated with bortezomib. Haematologica 93, 451–454 (2008).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Srirajaskanthan, R. et al. Circulating angiopoietin-2 is elevated in patients with neuroendocrine tumours and correlates with disease burden and prognosis. Endocr. Relat. Cancer 16, 967–976 (2009).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Wong, M. P. et al. The angiopoietins, tie2 and vascular endothelial growth factor are differentially expressed in the transformation of normal lung to non-small cell lung carcinomas. Lung Cancer 29, 11–22 (2000).

    CAS  PubMed  Article  Google Scholar 

  49. 49

    Lind, A. J. et al. Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer. Prostate 62, 394–399 (2005).

    PubMed  Article  CAS  Google Scholar 

  50. 50

    Li, C. et al. Significance of a reversal expression of the angiopoietin-1 and 2 in oral squamous cell carcinoma. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 44, 412–418 (2009) (in Chinese).

    PubMed  Google Scholar 

  51. 51

    Hata, K. et al. Expression of the angopoietin-1, angopoietin-2, Tie2, and vascular endothelial growth factor gene in epithelial ovarian cancer. Gynecol. Oncol. 93, 215–222 (2004). Low ANGPT1/ANGPT2 ratio and increased VEGFA were found to be significantly associated with a poor prognosis in patients with ovarian cancer.

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Nasarre, P. et al. Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res. 69, 1324–1333 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Lobov, I. B., Brooks, P. C. & Lang, R. A. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc. Natl Acad. Sci. USA 99, 11205–11210 (2002).

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Bentley, K., Mariggi, G., Gerhardt, H. & Bates, P. A. Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis. PLoS Comput. Biol. 5, e1000549 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. 55

    Gerhardt, H. VEGF and endothelial guidance in angiogenic sprouting. Organogenesis 4, 241–246 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Benedito, R. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137, 1124–1135 (2009).

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Suchting, S. & Eichmann, A. Jagged gives endothelial tip cells an edge. Cell 137, 988–990 (2009).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Hellstrom, M., Phng, L. K. & Gerhardt, H. VEGF and Notch signaling: the yin and yang of angiogenic sprouting. Cell Adh. Migr. 1, 133–136 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Hellstrom, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60

    Hoey, T. et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5, 168–177 (2009).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Yan, M. & Plowman, G. D. Delta-like 4/Notch signaling and its therapeutic implications. Clin. Cancer Res. 13, 7243–7246 (2007).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    De Maziere, A., Parker, L., Van Dijk, S., Ye, W. & Klumperman, J. Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis. Dev. Dyn. 237, 580–591 (2008).

    PubMed  Article  Google Scholar 

  64. 64

    Parker, L. H. et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 428, 754–758 (2004). First report to demonstrate the role EGFL7 has in vascular lumen formation, linking it to tumour angiogenesis.

    CAS  Article  Google Scholar 

  65. 65

    Nikolic, I., Plate, K. H. & Schmidt, M. H. EGFL7 meets miRNA-126: an angiogenesis alliance. J. Angiogenes. Res. 2, 9 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66

    Wu, F. et al. Novel role for epidermal growth factor-like domain 7 in metastasis of human hepatocellular carcinoma. Hepatology 50, 1839–1850 (2009).

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Schmidt, M. H. et al. Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nature Cell Biol. 11, 873–880 (2009).

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Armulik, A., Abramsson, A. & Betsholtz, C. Endothelial/pericyte interactions. Circ. Res. 97, 512–523 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Gaengel, K., Genove, G., Armulik, A. & Betsholtz, C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 29, 630–638 (2009).

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Ramsauer, M. & D'Amore, P. A. Contextual role for angiopoietins and TGFβ1 in blood vessel stabilization. J. Cell Sci. 120, 1810–1817 (2007).

    CAS  PubMed  Article  Google Scholar 

  71. 71

    Hashizume, H. et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res. 70, 2213–2223 (2010). This paper clearly demonstrated the benefit of targeting both ANGPT2 and VEGFA on inhibiting tumour growth.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Med. 6, 460–463 (2000).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Vestweber, D., Winderlich, M., Cagna, G. & Nottebaum, A. F. Cell adhesion dynamics at endothelial junctions: VE-cadherin as a major player. Trends Cell Biol. 19, 8–15 (2009).

    CAS  PubMed  Article  Google Scholar 

  74. 74

    Mellberg, S. et al. Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis. FASEB J. 23, 1490–1502 (2009).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Nottebaum, A. F. et al. VE-PTP maintains the endothelial barrier via plakoglobin and becomes dissociated from VE-cadherin by leukocytes and by VEGF. J. Exp. Med. 205, 2929–2945 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Fachinger, G., Deutsch, U. & Risau, W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2. Oncogene 18, 5948–5953 (1999).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Baumer, S. et al. Vascular endothelial cell-specific phosphotyrosine phosphatase (VE-PTP) activity is required for blood vessel development. Blood 107, 4754–4762 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78

    Dominguez, M. G. et al. Vascular endothelial tyrosine phosphatase (VE-PTP)-null mice undergo vasculogenesis but die embryonically because of defects in angiogenesis. Proc. Natl Acad. Sci. USA 104, 3243–3248 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. 79

    Gavard, J., Patel, V. & Gutkind, J. S. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev. Cell 14, 25–36 (2008).

    CAS  PubMed  Article  Google Scholar 

  80. 80

    Falcon, B. L. et al. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am. J. Pathol. 175, 2159–2170 (2009). First report to show the differential effects of specifically blocking ANGPT1 or ANGPT2 in tumours.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Das, A. et al. Angiopoietin/Tek interactions regulate mmp-9 expression and retinal neovascularization. Lab. Invest. 83, 1637–1645 (2003).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Zhu, Y. et al. Angiopoietin-2 facilitates vascular endothelial growth factor-induced angiogenesis in the mature mouse brain. Stroke 36, 1533–1537 (2005).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Zhu, L. et al. Novel insights of the gastric gland organization revealed by chief cell specific expression of moesin. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G185–G195 (2009).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nature Cell Biol. 10, 527–537 (2008).

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Fukuhara, S. et al. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nature Cell Biol. 10, 513–526 (2008).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Fukuhara, S. et al. Tie2 is tied at the cell-cell contacts and to extracellular matrix by angiopoietin-1. Exp. Mol. Med. 41, 133–139 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87

    Gale, N. W. et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev. Cell 3, 411–423 (2002). First report of Angpt2 -knockout mice and the role of ANGPT2 in lymphangiogenesis.

    CAS  PubMed  Article  Google Scholar 

  88. 88

    Dellinger, M. et al. Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice. Dev. Biol. 319, 309–320 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89

    Fiedler, U. et al. Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation. Nature Med. 12, 235–239 (2006).

    CAS  PubMed  Article  Google Scholar 

  90. 90

    Kim, K. E. et al. In vivo actions of angiopoietins on quiescent and remodeling blood and lymphatic vessels in mouse airways and skin. Arterioscler. Thromb. Vasc. Biol. 27, 564–570 (2007).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Morisada, T. et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105, 4649–4656 (2005).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Tammela, T. et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105, 4642–4648 (2005).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Cao, Y. & Zhong, W. Tumor-derived lymphangiogenic factors and lymphatic metastasis. Biomed. Pharmacother. 61, 534–539 (2007).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Karkkainen, M. J. & Alitalo, K. Lymphatic endothelial regulation, lymphoedema, and lymph node metastasis. Semin. Cell Dev. Biol. 13, 9–18 (2002).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Jo, M. J. et al. Preoperative serum angiopoietin-2 levels correlate with lymph node status in patients with early gastric cancer. Ann. Surg. Oncol. 16, 2052–2057 (2009).

    PubMed  Article  Google Scholar 

  96. 96

    Gerhardt, H. & Semb, H. Pericytes: gatekeepers in tumour cell metastasis? J. Mol. Med. 86, 135–144 (2008).

    PubMed  Article  Google Scholar 

  97. 97

    Xian, X. et al. Pericytes limit tumor cell metastasis. J. Clin. Invest. 116, 642–651 (2006). This paper clearly demonstrated the role pericytes have in restricting tumour metastasis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98

    Imanishi, Y. et al. Angiopoietin-2 stimulates breast cancer metastasis through the α5β1 integrin-mediated pathway. Cancer Res. 67, 4254–4263 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Helfrich, I. et al. Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin. Cancer Res. 15, 1384–1392 (2009).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Park, J. H. et al. Serum angiopoietin-2 as a clinical marker for lung cancer. Chest 132, 200–206 (2007).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Tsutsui, S. et al. Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density. Breast Cancer Res. Treat 98, 261–266 (2006).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Hu, B. et al. Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc. Natl Acad. Sci. USA 100, 8904–8909 (2003).

    CAS  PubMed  Article  Google Scholar 

  103. 103

    Huang, Y. et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105

    Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124, 823–835 (2006).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    CAS  Article  Google Scholar 

  107. 107

    Marx, J. Cancer research. Inflammation and cancer: the link grows stronger. Science 306, 966–968 (2004).

    CAS  PubMed  Article  Google Scholar 

  108. 108

    Kobayashi, H. & Lin, P. C. Angiopoietin/Tie2 signaling, tumor angiogenesis and inflammatory diseases. Front. Biosci. (Elite Ed.) 10, 666–674 (2005).

    CAS  Article  Google Scholar 

  109. 109

    van Meurs, M. et al. Bench-to-bedside review: angiopoietin signalling in critical illness - a future target? Crit. Care 13, 207 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110

    Witzenbichler, B., Westermann, D., Knueppel, S., Schultheiss, H. P. & Tschope, C. Protective role of angiopoietin-1 in endotoxic shock. Circulation 111, 97–105 (2005).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Cho, C. H. et al. Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. Proc. Natl Acad. Sci. USA 101, 5553–5558 (2004).

    CAS  PubMed  Article  Google Scholar 

  112. 112

    Kim, S. R. et al. Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury. Exp. Mol. Med. 40, 320–331 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113

    Hughes, D. P., Marron, M. B. & Brindle, N. P. The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel nuclear factor-κB inhibitor ABIN-2. Circ. Res. 92, 630–636 (2003).

    CAS  PubMed  Article  Google Scholar 

  114. 114

    Tadros, A., Hughes, D. P., Dunmore, B. J. & Brindle, N. P. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Blood 102, 4407–4409 (2003).

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Kim, I., Moon, S. O., Park, S. K., Chae, S. W. & Koh, G. Y. Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression. Circ. Res. 89, 477–479 (2001).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Kim, I. et al. Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells. FASEB J. 16, 126–128 (2002).

    PubMed  Article  CAS  Google Scholar 

  117. 117

    Koutroubakis, I. E. et al. Potential role of soluble angiopoietin-2 and Tie-2 in patients with inflammatory bowel disease. Eur. J. Clin. Invest. 36, 127–132 (2006).

    CAS  PubMed  Article  Google Scholar 

  118. 118

    Scott, B. B. et al. Constitutive expression of angiopoietin-1 and -2 and modulation of their expression by inflammatory cytokines in rheumatoid arthritis synovial fibroblasts. J. Rheumatol. 29, 230–239 (2002).

    CAS  PubMed  Google Scholar 

  119. 119

    Kuroda, K., Sapadin, A., Shoji, T., Fleischmajer, R. & Lebwohl, M. Altered expression of angiopoietins and Tie2 endothelium receptor in psoriasis. J. Invest. Dermatol. 116, 713–720 (2001).

    CAS  PubMed  Article  Google Scholar 

  120. 120

    Bhandari, V. et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nature Med. 12, 1286–1293 (2006).

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Bhandari, V. & Elias, J. A. The role of angiopoietin 2 in hyperoxia-induced acute lung injury. Cell Cycle 6, 1049–1052 (2007).

    CAS  PubMed  Article  Google Scholar 

  122. 122

    Hashimoto, T. & Pittet, J. F. Angiopoietin-2: modulator of vascular permeability in acute lung injury? PLoS Med. 3, e113 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123

    Gallagher, D. C. et al. Angiopoietin 2 is a potential mediator of high-dose interleukin 2-induced vascular leak. Clin. Cancer Res. 13, 2115–2120 (2007).

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Parikh, S. M. et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 3, e46 (2006). This was the first report clearly linking increased circulating ANGPT2 to sepsis.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125

    van der Heijden, M., van Nieuw Amerongen, G. P., van Hinsbergh, V. W. & Groeneveld, A. J. The interaction of soluble Tie2 with angiopoietins and pulmonary vascular permeability in septic and non-septic critically ill patients. Shock 33, 263–268 (2009).

    Article  CAS  Google Scholar 

  126. 126

    McLean, K. & Buckanovich, R. J. Myeloid cells functioning in tumor vascularization as a novel therapeutic target. Transl. Res. 151, 59–67 (2008).

    CAS  PubMed  Article  Google Scholar 

  127. 127

    De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005). This was the first report of the presence of circulating TEMs and their role in tumour angiogenesis.

    CAS  Article  Google Scholar 

  128. 128

    Venneri, M. A. et al. Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109, 5276–5285 (2007).

    CAS  Article  PubMed  Google Scholar 

  129. 129

    Murdoch, C., Tazzyman, S., Webster, S. & Lewis, C. E. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J. Immunol. 178, 7405–7411 (2007).

    CAS  Article  PubMed  Google Scholar 

  130. 130

    Lewis, C. E., De Palma, M. & Naldini, L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 67, 8429–8432 (2007).

    CAS  PubMed  Article  Google Scholar 

  131. 131

    Williams, R. Discontinued drugs in 2007: oncology drugs. Expert Opin. Investig. Drugs 17, 1791–1816 (2008).

    CAS  PubMed  Article  Google Scholar 

  132. 132

    Hayes, A. J. et al. Expression and function of angiopoietin-1 in breast cancer. Br. J. Cancer 83, 1154–1160 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133

    Tian, S., Hayes, A. J., Metheny-Barlow, L. J. & Li, L. Y. Stabilization of breast cancer xenograft tumour neovasculature by angiopoietin-1. Br. J. Cancer 86, 645–651 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    Stoeltzing, O. et al. Angiopoietin-1 inhibits vascular permeability, angiogenesis, and growth of hepatic colon cancer tumors. Cancer Res. 63, 3370–3377 (2003).

    CAS  PubMed  Google Scholar 

  135. 135

    Hawighorst, T. et al. Activation of the tie2 receptor by angiopoietin-1 enhances tumor vessel maturation and impairs squamous cell carcinoma growth. Am. J. Pathol. 160, 1381–1392 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136

    Holopainen, T. et al. Angiopoietin-1 overexpression modulates vascular endothelium to facilitate tumor cell dissemination and metastasis establishment. Cancer Res. 69, 4656–4664 (2009).

    CAS  PubMed  Article  Google Scholar 

  137. 137

    Cao, Y. et al. Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res. 67, 3835–3844 (2007). Systemically overexpressed ANGPT2 leads to tumour vessel regression and inhibits tumour growth, casting doubt about the strategy to inhibit the ANGPT–TIE2 pathway.

    CAS  PubMed  Article  Google Scholar 

  138. 138

    Etoh, T. et al. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res. 61, 2145–2153 (2001).

    CAS  PubMed  Google Scholar 

  139. 139

    Kunz, P. et al. Angiopoietin-2 overexpression in morris hepatoma results in increased tumor perfusion and induction of critical angiogenesis-promoting genes. J. Nucl. Med. 47, 1515–1524 (2006).

    CAS  PubMed  Google Scholar 

  140. 140

    Hu, B. et al. Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the αvβ1 integrin and focal adhesion kinase signaling pathway. Cancer Res. 66, 775–783 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141

    Oliner, J. et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6, 507–516 (2004). First report about ANGPT1- and ANGPT2-specific peptibodies, demonstrating clear anti-tumour activity with agents targeting both ANGPT1 and ANGPT2.

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Huang, H. et al. Angiopoietin-2 specific CVX-060 inhibits tumor growth cooperatively with chemotherapy. AACR Annual Meeting Abstr. 2493 (2008).

    Google Scholar 

  143. 143

    Mita, A. C. et al. Phase 1 study of AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adults with advanced solid tumors. Clin. Cancer Res. 16, 3044–3056 (2010).

    CAS  PubMed  Article  Google Scholar 

  144. 144

    Karlan, B. Y. et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian carcinoma. J. Clin. Oncol. Abstr. 28, 5000 (2010).

    Article  Google Scholar 

  145. 145

    Rosen, L. S. et al. First-in-human dose-escalation safety and PK trial of a novel intravenous humanized monoclonal CovX body inhibiting angiopoietin 2. J. Clin. Oncol. Abstr. 28, 2524 (2010).

    Article  Google Scholar 

  146. 146

    Zhang, L. et al. Tumor-derived vascular endothelial growth factor up-regulates angiopoietin-2 in host endothelium and destabilizes host vasculature, supporting angiogenesis in ovarian cancer. Cancer Res. 63, 3403–3412 (2003).

    CAS  PubMed  Google Scholar 

  147. 147

    Yoshiji, H. et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut 54, 1768–1775 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148

    Chae, S. S. et al. Angiopoietin-2 interferes with anti-VEGFR-2- induced vessel normalization and survival benefit in mice bearing gliomas. Clin. Cancer Res. 25 May 2010 (doi:10.1158/1078-0432.CCR-09-3073).

  149. 149

    Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150

    Paez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220–231 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151

    Bullock, A. J. et al. Plasma angiopoietin-2 (ANG2) as an angiogenic biomarker in renal cell carcinoma (RCC). J. Clin. Oncol. Abstr. 28, 4630 (2010).

    Article  Google Scholar 

  152. 152

    Brown, J. L. et al. A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models. Mol. Cancer Ther. 9, 145–156 (2010). Clear combination benefit was reported when both ANGPT2 and VEGFA were blocked in a xenograft model.

    CAS  Article  PubMed  Google Scholar 

  153. 153

    Baehner, M. et al. Bispecific anti-human VEGF/angiopoietin 2 antibodies for treating cancer and vascular diseases. US Patent 2010040508 (2010).

  154. 154

    Niu, G. & Carter, W. B. Human epidermal growth factor receptor 2 regulates angiopoietin-2 expression in breast cancer via AKT and mitogen-activated protein kinase pathways. Cancer Res. 67, 1487–1493 (2007).

    CAS  PubMed  Article  Google Scholar 

  155. 155

    Carter, W. B. & Ward, M. D. HER2 regulatory control of angiopoietin-2 in breast cancer. Surgery 128, 153–158 (2000).

    CAS  PubMed  Article  Google Scholar 

  156. 156

    Fiedler, U. et al. Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats. J. Biol. Chem. 278, 1721–1727 (2003).

    CAS  PubMed  Article  Google Scholar 

  157. 157

    Partanen, J. et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol. Cell. Biol. 12, 1698–1707 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158

    Ziegler, S. F., Bird, T. A., Schneringer, J. A., Schooley, K. A. & Baum, P. R. Molecular cloning and characterization of a novel receptor protein tyrosine kinase from human placenta. Oncogene 8, 663–670 (1993).

    CAS  PubMed  Google Scholar 

  159. 159

    Yuan, H. T. et al. Activation of the orphan endothelial receptor Tie1 modifies Tie2-mediated intracellular signaling and cell survival. FASEB J. 21, 3171–3183 (2007).

    CAS  PubMed  Article  Google Scholar 

  160. 160

    Sarraf-Yazdi, S. et al. Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer. J. Surg. Res. 146, 16–23 (2008).

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Rodney Lappe.

Ethics declarations

Competing interests

All authors are employees of CovX, a division of Pfizer Inc.

Related links

Related links

DATABASES

ClinicalTrials.gov

NCT00875264

NCT01004822

National Cancer Institute Drug Dictionary

bevacizumab

carboplatin

CEP-11981

CVX-241

docetaxel

paclitaxel

sorafenib

sunitinib

trastuzumab

Glossary

Adaptive resistance

Tumours that adapt and evade anti-angiogenic therapy.

Intrinsic non-responsiveness

Tumours that are inherently non-responsive to anti-angiogenic therapy.

Mural cells

Vascular smooth muscle cells and pericytes, often used interchangeably with perivascular cells.

Weibel–Palade body

Storage granule of endothelial cells, including ANGPT2, von Willebrand factors, P-selectin and several other chemokines.

Angioblasts

Embryonic mesenchymal tissues from which blood cells and blood vessels are formed.

Adherens junction

Transmembrane clustered adhesive cadherin proteins at cell–cell contacts that connect with a complex network of cytoskeletal proteins through their cytoplasmic domain.

Tight junction

Also referred to as a zonula occludens, a site where the membranes of two cells join together forming a virtually impermeable barrier.

Gap junction

Specialized pores made of primarily homo-hexamers or hetero-hexamers of connexin proteins that allow small molecules and ions to pass between cells.

Allantois explant

Dissected from E8.0 to E8.5 animal embryo, cultured in vitro to study vasculogenesis and angiogenesis.

Peptibody

A biologically active peptide fused to either the N or C terminus of the Fc domain of immunoglobulin.

Chylous ascites

A milky chyle (fluid) that has leaked into the abdominal cavity.

Endotoxin shock

Septic shock induced by endotoxins of gram-negative bacteria.

Rolling leukocyte

White blood cell that moves more slowly in microvessels than red blood cells, and tends to attach and infiltrate vessel walls during inflammation.

CovX-Body

Specific covalent fusion between a biologically active pharmacophore, such as a peptide, and a monoclonal antibody through a specifically designed linker.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Huang, H., Bhat, A., Woodnutt, G. et al. Targeting the ANGPT–TIE2 pathway in malignancy. Nat Rev Cancer 10, 575–585 (2010). https://doi.org/10.1038/nrc2894

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing