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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis

  • You, Weon-Kyoo (Cardiovascular Research Institute, Comprehensive Cancer Center, Department of Anatomy, University of California) ;
  • McDonald, Donald M. (Cardiovascular Research Institute, Comprehensive Cancer Center, Department of Anatomy, University of California)
  • Published : 2008.12.31
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Abstract

Angiogenesis in tumors is driven by multiple growth factors that activate receptor tyrosine kinases. An important driving force of angiogenesis in solid tumors is signaling through vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). Angiogenesis inhibitors that target this signaling pathway are now in widespread use for the treatment of cancer. However, when used alone, inhibitors of VEGF/VEGFR signaling do not destroy all blood vessels in tumors and do not slow the growth of most human cancers. VEGF/VEGFR signaling inhibitors are, therefore, used in combination with chemotherapeutic agents or radiation therapy. Additional targets for inhibiting angiogenesis would be useful for more efficacious treatment of cancer. One promising target is the signaling pathway of hepatocyte growth factor (HGF) and its receptor (HGFR, also known as c-Met), which plays important roles in angiogenesis and tumor growth. Inhibitors of this signaling pathway have been shown to inhibit angiogenesis in multiple in vitro and in vivo models. The HGF/c-Met signaling pathway is now recognized as a promising target in cancer by inhibiting angiogenesis, tumor growth, invasion, and metastasis.

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  1. Comprehensive Molecular Analyses of Lung Adenocarcinoma with Regard to the Epidermal Growth Factor Receptor, K-ras, MET, and Hepatocyte Growth Factor Status vol.5, pp.5, 2010, https://doi.org/10.1097/JTO.0b013e3181d0a4db
  2. The ERK1/2-Hepatocyte Nuclear Factor 4α Axis Regulates HumanABCC6Gene Expression in Hepatocytes vol.285, pp.30, 2010, https://doi.org/10.1074/jbc.M110.105593
  3. c-Met expression is associated with time to recurrence in patients with glioblastoma multiforme vol.18, pp.1, 2011, https://doi.org/10.1016/j.jocn.2010.05.010
  4. Breaking down the evidence for bevacizumab in advanced cervical cancer: past, present and future vol.2, pp.1, 2015, https://doi.org/10.1186/s40661-015-0015-0
  5. Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development vol.61, pp.5, 2015, https://doi.org/10.18097/pbmc20156105579
  6. Monitoring the Longitudinal Intra-tumor Physiological Impulse Response to VEGFR2 Blockade in Breast Tumors Using DCE-CT vol.13, pp.6, 2011, https://doi.org/10.1007/s11307-010-0441-7
  7. Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches vol.34, pp.1, 2015, https://doi.org/10.1007/s10555-014-9538-9
  8. Overproduction of recombinant human hepatocyte growth factor in Chinese hamster ovary cells vol.70, pp.2, 2010, https://doi.org/10.1016/j.pep.2009.10.004
  9. Anti-angiogenic activity of water extract from Euphorbia pekinensis Rupr vol.206, 2017, https://doi.org/10.1016/j.jep.2017.05.033
  10. Hepatocyte Growth Factor Induces a Proangiogenic Phenotype and Mobilizes Endothelial Progenitor Cells by Activating Nox2 vol.15, pp.4, 2011, https://doi.org/10.1089/ars.2010.3533
  11. New agents for prostate cancer vol.25, pp.9, 2014, https://doi.org/10.1093/annonc/mdu038
  12. Importance of Fibroblast Growth Factor Receptor in Neovascularization and Tumor Escape from Antiangiogenic Therapy vol.10, pp.2, 2012, https://doi.org/10.1016/j.clgc.2012.01.010
  13. The third line of treatment for metastatic prostate cancer patients: Option or strategy? vol.95, pp.3, 2015, https://doi.org/10.1016/j.critrevonc.2015.04.010
  14. MET/HGF Signaling Pathway in Ovarian Carcinoma: Clinical Implications and Future Direction vol.2012, 2012, https://doi.org/10.1155/2012/960327
  15. Recent advances in the discovery of small molecule c-Met kinase inhibitors 2017, https://doi.org/10.1016/j.ejmech.2017.08.044
  16. JNK/P38 Mitogen-activated Protein Kinase Used for Hepatocyte Growth Factor–induced Proliferation, Differentiation, and Migration in Human Dental Papilla Cells vol.38, pp.9, 2012, https://doi.org/10.1016/j.joen.2012.06.011
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  20. Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes vol.10, pp.2, 2016, https://doi.org/10.1021/acsnano.5b06189
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  22. Inhibition of blood vessel formation in tumors by IL-18-polarized M1 macrophages vol.21, pp.3, 2016, https://doi.org/10.1111/gtc.12329
  23. Head neck squamous cell carcinoma c-Met+ cells display cancer stem cell properties and are responsible for cisplatin-resistance and metastasis vol.129, pp.10, 2011, https://doi.org/10.1002/ijc.25927
  24. Progress in emerging therapies for advanced prostate cancer vol.39, pp.3, 2013, https://doi.org/10.1016/j.ctrv.2012.09.005
  25. Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells vol.11, pp.1, 2017, https://doi.org/10.1186/s12918-017-0439-8
  26. A novel three-dimensional bone chip organ culture vol.17, pp.6, 2013, https://doi.org/10.1007/s00784-012-0833-y
  27. Decreased Serum Level of miR-146a as Sign of Chronic Inflammation in Type 2 Diabetic Patients vol.9, pp.12, 2014, https://doi.org/10.1371/journal.pone.0115209
  28. Anti-tumor effect of β-elemene in murine hepatocellular carcinoma cell line H22 depends on the level of c-Met downregulation vol.2, pp.2, 2012, https://doi.org/10.1016/j.bionut.2012.01.005
  29. New molecularly targeted therapies against advanced hepatocellular carcinoma: From molecular pathogenesis to clinical trials and future directions vol.45, pp.10, 2015, https://doi.org/10.1111/hepr.12459
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  31. Targeted Therapies for Prostate Cancer vol.33, pp.7, 2015, https://doi.org/10.3109/07357907.2015.1033105
  32. Isolation and epithelial co-culture of mouse renal peritubular endothelial cells vol.15, pp.1, 2014, https://doi.org/10.1186/s12860-014-0040-6
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  34. Hepatocyte Growth Factor and Lung Fibrosis vol.9, pp.3, 2012, https://doi.org/10.1513/pats.201202-018AW
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  37. The absolute bioavailability investigation of LS177 in rats using ultra-performance liquid chromatography-tandem mass spectrometry vol.7, pp.9, 2015, https://doi.org/10.1002/dta.1779
  38. The c-Met receptor: Implication for targeted therapies in colorectal cancer vol.39, pp.5, 2017, https://doi.org/10.1177/1010428317699118
  39. CoMFA and CoMSIA studies on 6,7-disubstituted-4-phenoxyquinoline derivatives as c-Met kinase inhibitors and anticancer agents vol.24, pp.12, 2015, https://doi.org/10.1007/s00044-015-1450-5
  40. Plasma and cerebrospinal fluid pharmacokinetics of MP470 in non-human primates vol.67, pp.4, 2011, https://doi.org/10.1007/s00280-010-1380-3
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  42. Impact of the small molecule Met inhibitor BMS-777607 on the metastatic process in a rodent tumor model with constitutive c-Met activation vol.29, pp.3, 2012, https://doi.org/10.1007/s10585-011-9447-z
  43. Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay vol.10, pp.2, 2012, https://doi.org/10.1039/C1OB06186K
  44. Halofuginone inhibits phosphorylation of SMAD-2 reducing angiogenesis and leukemia burden in an acute promyelocytic leukemia mouse model vol.34, pp.1, 2015, https://doi.org/10.1186/s13046-015-0181-2
  45. What Can Ecology Teach Us About Cancer? vol.4, pp.5, 2011, https://doi.org/10.1593/tlo.11154
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  48. Protective effects of HGF gene-expressing human mesenchymal stem cells in acetaminophen-treated hepatocytes vol.33, pp.5-6, 2015, https://doi.org/10.3109/08977194.2015.1080695
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  50. In vitro models for the evaluation of angiogenic potential in bone engineering vol.32, pp.1, 2011, https://doi.org/10.1038/aps.2010.143
  51. Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity vol.286, pp.8, 2011, https://doi.org/10.1074/jbc.M110.183277
  52. The angiogenic process as a therapeutic target in cancer vol.81, pp.10, 2011, https://doi.org/10.1016/j.bcp.2011.02.016
  53. Targeting MET in cancer: rationale and progress vol.12, pp.2, 2012, https://doi.org/10.1038/nrc3205
  54. MET and VEGF: synergistic targets in castration-resistant prostate cancer vol.13, pp.10, 2011, https://doi.org/10.1007/s12094-011-0719-5
  55. NK4 therapy: a new approach to target angiogenesis and inflammation in rheumatoid arthritis vol.15, pp.5, 2013, https://doi.org/10.1186/ar4320
  56. Molecular Targeted Therapy for Hepatocellular Carcinoma: Present Status and Future Directions vol.38, pp.7, 2015, https://doi.org/10.1248/bpb.b15-00231
  57. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients With Medullary Thyroid Cancer vol.29, pp.19, 2011, https://doi.org/10.1200/JCO.2010.32.4145
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  60. Hepatocyte Growth Factor Family Negatively Regulates Hepatic Gluconeogenesis via Induction of Orphan Nuclear Receptor Small Heterodimer Partner in Primary Hepatocytes vol.284, pp.42, 2009, https://doi.org/10.1074/jbc.M109.022244
  61. Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function vol.286, pp.18, 2011, https://doi.org/10.1074/jbc.M110.212597
  62. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion vol.5, pp.3, 2016, https://doi.org/10.5966/sctm.2015-0166
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  64. Gene-expression profiling of microdissected breast cancer microvasculature identifies distinct tumor vascular subtypes vol.14, pp.4, 2012, https://doi.org/10.1186/bcr3246
  65. Role of c-Met/Phosphatidylinositol 3-Kinase (PI3k)/Akt Signaling in Hepatocyte Growth Factor (HGF)-mediated Lamellipodia Formation, Reactive Oxygen Species (ROS) Generation, and Motility of Lung Endothelial Cells vol.289, pp.19, 2014, https://doi.org/10.1074/jbc.M113.527556
  66. A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth vol.29, pp.5, 2013, https://doi.org/10.3892/or.2013.2329
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  70. VEGF-A/HGF induce Prox-1 expression in the chick embryo chorioallantoic membrane lymphatic vasculature vol.10, pp.3, 2010, https://doi.org/10.1007/s10238-009-0085-6
  71. Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth vol.29, pp.38, 2010, https://doi.org/10.1038/onc.2010.267
  72. Effect of lanthanum chloride on growth of breast cancer cells and regulation of c-met transcription vol.3, pp.3, 2009, https://doi.org/10.1007/s11684-009-0053-2
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  75. MACC1 induces metastasis in ovarian carcinoma by upregulating hepatocyte growth factor receptor c-MET vol.8, pp.2, 2014, https://doi.org/10.3892/ol.2014.2184
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  78. Aptamer-based search for correlates of plasma and serum water T2: implications for early metabolic dysregulation and metabolic syndrome vol.6, pp.1, 2018, https://doi.org/10.1186/s40364-018-0143-x