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Roles of Matrix Metalloproteinases in Tumor Metastasis and Angiogenesis

  • Yoon, Sang-Oh (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Park, Soo-Jin (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Yun, Chang-Hyun (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Chung, An-Sik (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
  • Published : 2003.01.31

Abstract

Matrix metalloproteinases (MMPs), zinc dependent proteolytic enzymes, cleave extracellular matrix (ECM: collagen, laminin, firbronectin, etc) as well as non-matrix substrates (growth factors, cell surface receptors, etc). The deregulation of MMPs is involved in many diseases, such as tumor metastasis, rheumatoid arthritis, and periodontal disease. Metastasis is the major cause of death among cancer patients. In this review, we will focus on the roles of MMPs in tumor metastasis. The process of metastasis involves a cascade of linked, sequential steps that involve multiple host-tumor interactions. Specifically, MMPs are involved in many steps of tumor metastasis. These include tumor invasion, migration, host immune escape, extravasation, angiogenesis, and tumor growth. Therefore, without MMPs, the tumor cell cannot perform successful metastasis. The activities of MMPs are tightly regulated at the gene transcription levels, zymogen activation by proteolysis, and inhibition of active forms by endogenous inhibitors, tissue inhibitor of metalloproteinase (TIMP), and RECK. The detailed regulations of MMPs are described in this review.

Keywords

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  2. Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling vol.15, pp.4, 2011, https://doi.org/10.1111/j.1582-4934.2010.01049.x
  3. Gene Expression Profiling of Hairy Cell Leukemia Reveals a Phenotype Related to Memory B Cells with Altered Expression of Chemokine and Adhesion Receptors vol.199, pp.1, 2004, https://doi.org/10.1084/jem.20031175
  4. Different pattern of matrix metalloproteinases expression in alveolar versus embryonal rhabdomyosarcoma vol.39, pp.11, 2004, https://doi.org/10.1016/j.jpedsurg.2004.07.014
  5. Expression of Matrix Metalloproteinase 2 (MMP-2) and Tissue Inhibitor of Metalloproteinase 2 (TIMP-2) in Medullary Thyroid Carcinoma: Prognostic Implications vol.18, pp.8, 2008, https://doi.org/10.1089/thy.2007.0412
  6. Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinase-3 and -4 in normal ovary and ovarian carcinoma vol.16, pp.5, 2006, https://doi.org/10.1111/j.1525-1438.2006.00714.x
  7. Targeting of proangiogenic signalling pathways in chronic inflammation vol.12, pp.2, 2016, https://doi.org/10.1038/nrrheum.2015.164
  8. Matrix metalloproteinases (MMPs) and trophoblast invasion vol.50, pp.12, 2005, https://doi.org/10.1007/BF03183688
  9. Calcium in tumour metastasis: new roles for known actors vol.11, pp.8, 2011, https://doi.org/10.1038/nrc3105
  10. Inhibitive effect of celecoxib on the adhesion and invasion of human tongue squamous carcinoma cells to extracellular matrix via down regulation of MMP-2 expression vol.93, pp.3-4, 2010, https://doi.org/10.1016/j.prostaglandins.2010.08.001
  11. Expression of MMP2 and MMP9 (Gelatinases A and B) in Human Colon Cancer Cells vol.165, pp.5-6, 2011, https://doi.org/10.1007/s12010-011-9342-8
  12. Antimetastatic activity of pinosylvin, a natural stilbenoid, is associated with the suppression of matrix metalloproteinases vol.23, pp.8, 2012, https://doi.org/10.1016/j.jnutbio.2011.04.021
  13. The role of probiotics and natural bioactive compounds in modulation of the common molecular pathways in pathogenesis of atherosclerosis and cancer vol.67, pp.1, 2012, https://doi.org/10.2478/s11756-011-0155-6
  14. Platelet-derived microparticles promote invasiveness of prostate cancer cellsviaupregulation of MMP-2 production vol.124, pp.8, 2009, https://doi.org/10.1002/ijc.24016
  15. Prion protein modifies TGF-β induced signal transduction vol.349, pp.2, 2006, https://doi.org/10.1016/j.bbrc.2006.08.074
  16. Inhibition of matrix metalloproteinases related to metastasis by diosgenyl and pennogenyl saponins vol.137, pp.3, 2011, https://doi.org/10.1016/j.jep.2011.07.045
  17. Increased plasma levels of urokinase plasminogen activator and matrix metalloproteinase-9 in nonsmall cell lung cancer patients vol.354, pp.1-2, 2005, https://doi.org/10.1016/j.cccn.2004.11.011
  18. Enzyme-responsive nanomaterials for controlled drug delivery vol.6, pp.21, 2014, https://doi.org/10.1039/C4NR04249B
  19. Antimetastatic Effect of Halichondramide, a Trisoxazole Macrolide from the Marine Sponge Chondrosia corticata, on Human Prostate Cancer Cells via Modulation of Epithelial-to-Mesenchymal Transition vol.11, pp.7, 2013, https://doi.org/10.3390/md11072472
  20. Antimetastatic potentials of flavones on oral cancer cell via an inhibition of matrix-degrading proteases vol.53, pp.3, 2008, https://doi.org/10.1016/j.archoralbio.2007.09.001
  21. Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma – In vitro and in vivo studies vol.46, pp.3, 2010, https://doi.org/10.1016/j.oraloncology.2009.11.013
  22. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs vol.31, pp.sup1, 2016, https://doi.org/10.3109/14756366.2016.1161620
  23. Overexpression of matrix metalloproteinase (MMP)-1 and -9 in central giant cell lesions of the jaws: implications for clinical behavior vol.110, pp.6, 2010, https://doi.org/10.1016/j.tripleo.2010.06.024
  24. Significance of circulating matrix metalloproteinase-9 to tissue inhibitor of metalloproteinases-2 ratio as a predictor of disease progression in patients with metastatic renal cell carcinoma receiving sunitinib11This study was partially supported by Pfizer Inc. vol.32, pp.5, 2014, https://doi.org/10.1016/j.urolonc.2014.01.016
  25. Matrix metalloproteinases in urinary system tumours. Part I - Matrix metalloproteinases in renal cell carcinoma vol.7, pp.1, 2017, https://doi.org/10.5604/01.3001.0010.1878
  26. Flavokawain B induced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB231 and inhibited the metastatic potential of MDA-MB231 via the regulation of several tyrosine kinases In vitro vol.16, pp.1, 2016, https://doi.org/10.1186/s12906-016-1046-8
  27. Métalloprotéases de la matrice extracellulaire et cancers du tractus digestif vol.29, pp.4, 2005, https://doi.org/10.1016/S0399-8320(05)80799-7
  28. Serum matrix metalloproteinases and tympanosclerosis vol.125, pp.02, 2011, https://doi.org/10.1017/S002221511000201X
  29. S1P regulation of ovarian carcinoma invasiveness vol.103, pp.3, 2006, https://doi.org/10.1016/j.ygyno.2006.06.036
  30. Modulatory effect of hesperidin on benzo(a)pyrene induced experimental lung carcinogenesis with reference to COX-2, MMP-2 and MMP-9 vol.649, pp.1-3, 2010, https://doi.org/10.1016/j.ejphar.2010.09.017
  31. Pterostilbene suppresses oral cancer cell invasion by inhibiting MMP-2 expression vol.18, pp.10, 2014, https://doi.org/10.1517/14728222.2014.947962
  32. Cathepsin K in Melanoma Invasion vol.128, pp.9, 2008, https://doi.org/10.1038/jid.2008.63
  33. Stealth siRNA against CD147 inhibits hepatocellular carcinoma cell metastatic properties vol.63, pp.5, 2008, https://doi.org/10.2478/s11756-008-0132-x
  34. Dioscorea nipponica Makino inhibits migration and invasion of human oral cancer HSC-3 cells by transcriptional inhibition of matrix metalloproteinase-2 through modulation of CREB and AP-1 activity vol.50, pp.3-4, 2012, https://doi.org/10.1016/j.fct.2011.12.016
  35. A novel matrix metalloproteinase-2 inhibitor triazolylmethyl aziridine reduces melanoma cell invasion, angiogenesis and targets ERK1/2 phosphorylation vol.29, pp.6, 2014, https://doi.org/10.3109/14756366.2013.855207
  36. Effects of Raf Kinase Inhibitor Protein Expression on Suppression of Prostate Cancer Metastasis vol.95, pp.12, 2003, https://doi.org/10.1093/jnci/95.12.878
  37. The Role of Tissue Inhibitors of Metalloproteinases in Tumorigenesis and Metastasis vol.45, pp.3, 2008, https://doi.org/10.1080/10408360801973244
  38. Roles of Matrix Metalloproteinases on Intracellular Staphylococcus aureus Growth in Bronchial Epithelial Cell vol.64, pp.1, 2008, https://doi.org/10.4046/trd.2008.64.1.22
  39. The role of Twist1 in hepatocellular carcinoma angiogenesis: a clinical study vol.42, pp.6, 2011, https://doi.org/10.1016/j.humpath.2010.03.010
  40. RETRACTED ARTICLE: Signaling pathways in tumor vasculogenic mimicry vol.77, pp.9, 2012, https://doi.org/10.1134/S000629791209012X
  41. Host response modulation in the management of periodontal diseases vol.32, pp.s6, 2005, https://doi.org/10.1111/j.1600-051X.2005.00785.x
  42. Inhibitory effects of isoliquiritigenin on the migration and invasion of human breast cancer cells vol.17, pp.4, 2013, https://doi.org/10.1517/14728222.2013.756869
  43. 11-epi-Sinulariolide Acetate Reduces Cell Migration and Invasion of Human Hepatocellular Carcinoma by Reducing the Activation of ERK1/2, p38MAPK and FAK/PI3K/AKT/mTOR Signaling Pathways vol.12, pp.9, 2014, https://doi.org/10.3390/md12094783
  44. Effect of shRNA Mediated Down-Regulation of Annexin A2 on Biological Behavior of Human Lung Adencarcinoma Cells A549 vol.18, pp.2, 2012, https://doi.org/10.1007/s12253-011-9427-2
  45. Comparative study of stapled haemorrhoidectomy under local anaesthesia versus spinal anaesthesia vol.88, pp.2, 2016, https://doi.org/10.1007/s13126-016-0292-z
  46. Targeting tissue oxidative damage by means of cell signaling modulators: The antioxidant concept revisited vol.128, pp.2, 2010, https://doi.org/10.1016/j.pharmthera.2010.08.003
  47. Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms vol.109, pp.1, 2012, https://doi.org/10.1007/s11060-012-0871-y
  48. Glabridin inhibits migration and invasion by transcriptional inhibition of matrix metalloproteinase 9 through modulation of NF-κB and AP-1 activity in human liver cancer cells vol.171, pp.12, 2014, https://doi.org/10.1111/bph.12626
  49. Inhibitory Effects of Dried Longan (Euphoria longana Lam.) Seed Extract on Invasion and Matrix Metalloproteinases of Colon Cancer Cells vol.61, pp.15, 2013, https://doi.org/10.1021/jf3052863
  50. Matrix metalloproteinases in cancer: comparison of known and novel aspects of their inhibition as a therapeutic approach vol.5, pp.1, 2005, https://doi.org/10.1586/14737140.5.1.149
  51. Immunonutrition and cancer vol.551, pp.1-2, 2004, https://doi.org/10.1016/j.mrfmmm.2004.03.005
  52. A novel circular invasion assay mimics in vivo invasive behavior of cancer cell lines and distinguishes single-cell motility in vitro vol.8, pp.1, 2008, https://doi.org/10.1186/1471-2407-8-198
  53. Anti-metastatic properties of the leaves of Eriobotrya japonica vol.34, pp.3, 2011, https://doi.org/10.1007/s12272-011-0310-1
  54. Histone Deacetylase 7 Maintains Vascular Integrity by Repressing Matrix Metalloproteinase 10 vol.126, pp.2, 2006, https://doi.org/10.1016/j.cell.2006.05.040
  55. Dioscorea nipponica Attenuates Migration and Invasion by Inhibition of Urokinase-Type Plasminogen Activator through Involving PI3K/Akt and Transcriptional Inhibition of NF-κB and SP-1 in Hepatocellular Carcinoma vol.44, pp.01, 2016, https://doi.org/10.1142/S0192415X16500129
  56. Association of Promoter Polymorphisms in MMP2 and TIMP2 with Prostate Cancer Susceptibility in North India vol.43, pp.2, 2012, https://doi.org/10.1016/j.arcmed.2012.02.006
  57. Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy vol.266, pp.1, 2008, https://doi.org/10.1016/j.canlet.2008.02.044
  58. Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma vol.219, pp.3, 2009, https://doi.org/10.1002/path.2613
  59. Matrix metalloproteinase dysregulation in HIV infection: implications for therapeutic strategies vol.13, pp.11, 2007, https://doi.org/10.1016/j.molmed.2007.09.001
  60. Key Enzymes of the Extracellular Matrix in Colorectal Cancer vol.147, pp.3, 2009, https://doi.org/10.1007/s10517-009-0507-1
  61. Antimetastatic activities of Selaginella tamariscina (Beauv.) on lung cancer cells in vitro and in vivo vol.110, pp.3, 2007, https://doi.org/10.1016/j.jep.2006.10.010
  62. Novel chemotherapeutic agents for the treatment of glioblastoma multiforme vol.12, pp.12, 2003, https://doi.org/10.1517/13543784.12.12.1899
  63. Relationships between the level of matrix metalloproteinase-2 and tumor size of breast cancer vol.371, pp.1-2, 2006, https://doi.org/10.1016/j.cca.2006.02.026
  64. Menhaden oil administration to dogs treated with radiation for nasal tumors demonstrates lower levels of tissue eicosanoids vol.31, pp.12, 2011, https://doi.org/10.1016/j.nutres.2011.09.018
  65. Collagenase expression and activity in the stromal cells from giant cell tumour of bone vol.44, pp.5, 2009, https://doi.org/10.1016/j.bone.2009.01.393
  66. Prognostic significance of CLPTM1L expression and its effects on migration and invasion of human lung cancer cells vol.16, pp.3, 2016, https://doi.org/10.3233/CBM-160583
  67. Gene expression of the invasive phenotype of TNF-α-treated MCF-7 cells vol.63, pp.6, 2009, https://doi.org/10.1016/j.biopha.2009.04.032
  68. Effect of therapeutic levels of doxycycline and minocycline in the proliferation and differentiation of human bone marrow osteoblastic cells vol.52, pp.3, 2007, https://doi.org/10.1016/j.archoralbio.2006.10.005
  69. Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review vol.36, pp.1, 2015, https://doi.org/10.1007/s13277-014-2747-6
  70. Polymorphisms in tissue inhibitors of metalloproteinases-2 and -3 and breast cancer susceptibility and survival vol.125, pp.4, 2009, https://doi.org/10.1002/ijc.24405
  71. Fucoidan from Turbinaria conoides: A multifaceted ‘deliverable’ to combat pancreatic cancer progression vol.74, 2015, https://doi.org/10.1016/j.ijbiomac.2014.12.031
  72. Human kallikrein 13 involvement in extracellular matrix degradation vol.323, pp.3, 2004, https://doi.org/10.1016/j.bbrc.2004.08.206
  73. Apigenin and its impact on gastrointestinal cancers vol.57, pp.1, 2013, https://doi.org/10.1002/mnfr.201200424
  74. Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (pycnogenol) vol.36, pp.6, 2004, https://doi.org/10.1016/j.freeradbiomed.2003.12.017
  75. Human Kallikrein 6 Degrades Extracellular Matrix Proteins and May Enhance the Metastatic Potential of Tumour Cells vol.25, pp.4, 2004, https://doi.org/10.1159/000081102
  76. Metalloproteinases in juvenile angiofibroma—a collagen rich tumor vol.39, pp.2, 2008, https://doi.org/10.1016/j.humpath.2007.06.015
  77. Impact of MMP-3 and TIMP-3 gene polymorphisms on prostate cancer susceptibility in North Indian cohort vol.530, pp.2, 2013, https://doi.org/10.1016/j.gene.2013.06.087
  78. Inhibition of mast cell tryptase activity. A new therapeutic target against malignancy induced angiogenesis vol.1, pp.4, 2008, https://doi.org/10.1016/j.bihy.2008.04.005
  79. Prognostic significance of expression of matrix metalloproteinase in colorectal adenocarcinomas and their metastases vol.143, pp.4, 2007, https://doi.org/10.1007/s10517-007-0155-2
  80. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation vol.25, pp.16, 2006, https://doi.org/10.1038/sj.onc.1209273
  81. Lonidamine Causes Inhibition of Angiogenesis-Related Endothelial Cell Functions vol.6, pp.5, 2004, https://doi.org/10.1593/neo.04133
  82. Drug resistance associated with antiangiogenesis therapy vol.19, pp.5, 2009, https://doi.org/10.1016/j.semcancer.2009.05.006
  83. Antimetastatic effects of Terminalia catappa L. on oral cancer via a down-regulation of metastasis-associated proteases vol.48, pp.4, 2010, https://doi.org/10.1016/j.fct.2010.01.019
  84. Decrease of phosphorylated proto-oncogeneCREBat Ser 133 site inhibits growth and metastatic activity of renal cell cancer vol.19, pp.7, 2015, https://doi.org/10.1517/14728222.2015.1053208
  85. Metaloproteasas de la matriz extracelular como marcadores moleculares en cáncer gástrico vol.134, pp.3, 2010, https://doi.org/10.1016/j.medcli.2009.09.031
  86. In vitro and in vivo antimetastatic effects of Terminalia catappa L. leaves on lung cancer cells vol.45, pp.7, 2007, https://doi.org/10.1016/j.fct.2006.12.028
  87. Genetic Polymorphism of MMP2 Gene and Susceptibility to Prostate Cancer vol.46, pp.7, 2015, https://doi.org/10.1016/j.arcmed.2015.08.004
  88. Selaginella tamariscina extract suppresses TPA-induced invasion and metastasis through inhibition of MMP-9 in human nasopharyngeal carcinoma HONE-1 cells vol.13, pp.1, 2013, https://doi.org/10.1186/1472-6882-13-234
  89. Radioactive Smart Probe for Potential Corrected Matrix Metalloproteinase Imaging vol.23, pp.11, 2012, https://doi.org/10.1021/bc3001968
  90. Role of the β1-integrin subunit in the adhesion, extravasation and migration of T24 human bladder carcinoma cells vol.22, pp.2, 2005, https://doi.org/10.1007/s10585-005-4335-z
  91. S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac vol.110, pp.2, 2008, https://doi.org/10.1016/j.ygyno.2008.04.013
  92. Reactive Oxygen Species as Signaling Molecules in Cardiovascular Differentiation of Embryonic Stem Cells and Tumor-Induced Angiogenesis vol.7, pp.11-12, 2005, https://doi.org/10.1089/ars.2005.7.1423
  93. Medullary thyroid carcinoma and biomarkers: past, present and future vol.266, pp.1, 2009, https://doi.org/10.1111/j.1365-2796.2009.02106.x
  94. Expression of membrane type 1 matrix metalloproteinase in medullary thyroid carcinoma: Prognostic implications 2010, https://doi.org/10.1002/hed.21146
  95. Bufalin Inhibits NCI-H460 Human Lung Cancer Cell Metastasis In Vitro by Inhibiting MAPKs, MMPs, and NF-κB Pathways vol.43, pp.06, 2015, https://doi.org/10.1142/S0192415X15500718
  96. Clinical Significance of Wnt/β-Catenin Signalling and Androgen Receptor Expression in Prostate Cancer vol.31, pp.1, 2013, https://doi.org/10.5534/wjmh.2013.31.1.36
  97. Matrix metalloproteinase-1 expression enhances tumorigenicity as well as tumor-related angiogenesis and is inversely associated with TIMP-4 expression in a model of glioblastoma vol.106, pp.3, 2012, https://doi.org/10.1007/s11060-011-0691-5
  98. Role of MUC20 overexpression as a predictor of recurrence and poor outcome in colorectal cancer vol.11, pp.1, 2013, https://doi.org/10.1186/1479-5876-11-151
  99. Alendronate inhibits cell invasion and MMP-2 secretion in human chondrosarcoma cell line vol.28, pp.8, 2007, https://doi.org/10.1111/j.1745-7254.2007.00607.x
  100. Recombinant human adiponectin suppresses invasion and motility of breast carcinama cells MDA-MB-231 by regulation of matrix metalloproteinases and tissue inhibitors vol.136, 2008, https://doi.org/10.1016/j.jbiotec.2008.07.214
  101. Impact of proteolytic enzymes in colorectal cancer development and progression vol.20, pp.37, 2014, https://doi.org/10.3748/wjg.v20.i37.13246
  102. Maslinic acid inhibits the metastatic capacity of DU145 human prostate cancer cells: possible mediation via hypoxia-inducible factor-1α signalling vol.109, pp.02, 2013, https://doi.org/10.1017/S0007114512000967
  103. Effect of Eupatorium japonicum Extract on the Metastasis, Invasion and Adhesion of MDA-MB-231 Human Breast Cancer Cells vol.43, pp.2, 2011, https://doi.org/10.9721/KJFST.2011.43.2.213
  104. Chemopreventive effect of chalcone derivative, L2H17, in colon cancer development vol.15, pp.1, 2015, https://doi.org/10.1186/s12885-015-1901-x
  105. Atrial extracellular matrix remodelling in patients with atrial fibrillation vol.12, pp.1, 2007, https://doi.org/10.1111/j.1582-4934.2008.00219.x
  106. Natural products as a gold mine for selective matrix metalloproteinases inhibitors vol.20, pp.13, 2012, https://doi.org/10.1016/j.bmc.2012.04.063
  107. Coexpressed High Levels of VEGF-C and Active MMP-9 Are Associated With Lymphatic Spreading and Local Invasiveness of Papillary Thyroid Carcinoma vol.146, pp.5, 2016, https://doi.org/10.1093/ajcp/aqw184
  108. Effect of Black Tea Polyphenol on Cell-ECM Interaction and MMP vol.08, pp.04, 2017, https://doi.org/10.4236/ajps.2017.84058
  109. ROS-major mediators of extracellular matrix remodeling during tumor progression vol.61, 2013, https://doi.org/10.1016/j.fct.2013.06.013
  110. Hexane–ethanol extract of Glycyrrhiza uralensis containing licoricidin inhibits the metastatic capacity of DU145 human prostate cancer cells vol.104, pp.09, 2010, https://doi.org/10.1017/S0007114510002114
  111. Role of Prolactin and Vasoinhibins in the Regulation of Vascular Function in Mammary Gland vol.13, pp.1, 2008, https://doi.org/10.1007/s10911-008-9067-7
  112. Melatonin inhibits MMP-9 transactivation and renal cell carcinoma metastasis by suppressing Akt-MAPKs pathway and NF-κB DNA-binding activity vol.60, pp.3, 2016, https://doi.org/10.1111/jpi.12308
  113. Redox balance dynamically regulates vascular growth and remodeling vol.23, pp.7, 2012, https://doi.org/10.1016/j.semcdb.2012.05.003
  114. Deregulation of Collagen Metabolism in Human Stomach Cancer vol.71, pp.6, 2004, https://doi.org/10.1159/000081726
  115. HIF-1αmRNA gene expression levels in improved diagnosis of early stages of prostate cancer vol.13, pp.7-8, 2008, https://doi.org/10.1080/13547500802591992
  116. Nobiletin inhibits invasion and migration of human nasopharyngeal carcinoma cell lines by involving ERK1/2 and transcriptional inhibition of MMP-2 vol.19, pp.3, 2015, https://doi.org/10.1517/14728222.2014.992875
  117. The Aqueous Extract of Prunella vulgaris Suppresses Cell Invasion and Migration in Human Liver Cancer Cells by Attenuating Matrix Metalloproteinases vol.40, pp.03, 2012, https://doi.org/10.1142/S0192415X12500486
  118. Suppression of Cell Growth, Migration and Drug Resistance by Ethanolic Extract of Antrodia cinnamomea in Human Lung Cancer A549 Cells and C57BL/6J Allograft Tumor Model vol.19, pp.3, 2018, https://doi.org/10.3390/ijms19030791
  119. Anti-Metastatic Effects of Antrodan with and without Cisplatin on Lewis Lung Carcinomas in a Mouse Xenograft Model vol.19, pp.6, 2018, https://doi.org/10.3390/ijms19061565
  120. Yifei Tongluo, a Chinese Herbal Formula, Suppresses Tumor Growth and Metastasis and Exerts Immunomodulatory Effect in Lewis Lung Carcinoma Mice vol.24, pp.4, 2019, https://doi.org/10.3390/molecules24040731