Skip to main content

Advertisement

SpringerLink
Log in

Epigenetic contributions to cancer metastasis

  • Review
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

The molecular basis of cancer encompasses both genetic and epigenetic alterations. These epigenetic changes primarily involve global DNA methylation changes in the form of widespread loss of methylation along with concurrent hypermethylation events in gene regulatory regions that can repress tissue-specific gene expression. Increasingly, the importance of these epigenetic changes to the metastatic process is being realized. Cells may acquire an epi-genotype that permits their dissemination from the primary tumour mass or the ability to survive and proliferate at a secondary tissue site. These epigenetic changes may be cancer-type specific, or in some cases may involve a common target gene providing a selective advantage to multiple metastatic cell types. In this review, I examine the growing volume of literature related to the epigenetic contributions to cancer metastasis. I discuss the functional importance of these epigenetic phenomena and how new epigenetic biomarkers may permit the identification of diagnostic signatures of metastasis and the development of new cancer therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  2. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572

    Article  PubMed  CAS  Google Scholar 

  3. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254

    Article  PubMed  CAS  Google Scholar 

  4. Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458

    Article  PubMed  CAS  Google Scholar 

  5. Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7:834–846

    Article  PubMed  CAS  Google Scholar 

  6. Allan AL, Vantyghem SA, Tuck AB et al (2006) Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis 26:87–98

    PubMed  CAS  Google Scholar 

  7. Welch DR (2004) Microarrays bring new insights into understanding of breast cancer metastasis to bone. Breast Cancer Res 6:61–64

    Article  PubMed  CAS  Google Scholar 

  8. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298

    Article  PubMed  CAS  Google Scholar 

  9. Bernstein BE, Meissner A, Lander ES (2007) The mammalian epigenome. Cell 128:669–681

    Article  PubMed  CAS  Google Scholar 

  10. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128:683–692

    Article  PubMed  CAS  Google Scholar 

  11. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  PubMed  CAS  Google Scholar 

  12. Rodenhiser D, Mann M (2006) Epigenetics and human disease: translating basic biology into clinical applications. CMAJ 174:341–348

    PubMed  Google Scholar 

  13. Bird A (2007) Perceptions of epigenetics. Nature 447:396–398

    Article  PubMed  CAS  Google Scholar 

  14. Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128:707–719

    Article  PubMed  CAS  Google Scholar 

  15. Esteller M, Corn PG, Baylin SB et al (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229

    PubMed  CAS  Google Scholar 

  16. Hoffmann MJ, Schulz WA (2005) Causes and consequences of DNA hypomethylation in human cancer. Biochem Cell Biol 83:296–321

    Article  PubMed  CAS  Google Scholar 

  17. Brena RM, Costello JF (2007) Genome-epigenome interactions in cancer. Hum Mol Genet 16(Spec No 1):R96–R105

    Article  PubMed  CAS  Google Scholar 

  18. Li LC (2007) Epigenetics of prostate cancer. Front Biosci 12:3377–3397

    Article  PubMed  CAS  Google Scholar 

  19. Agrawal A, Murphy RF, Agrawal DK (2007) DNA methylation in breast and colorectal cancers. Mod Pathol 20:711–721

    Article  PubMed  CAS  Google Scholar 

  20. Wilson AS, Power BE, Molloy PL (2007) DNA hypomethylation and human diseases. Biochim Biophys Acta 1775:138–162

    PubMed  CAS  Google Scholar 

  21. Miremadi A, Oestergaard MZ, Pharoah PD et al (2007) Cancer genetics of epigenetic genes. Hum Mol Genet 16(Spec No 1):R28–R49

    Article  PubMed  CAS  Google Scholar 

  22. Szyf M (2007) The dynamic epigenome and its implications in toxicology. Toxicol Sci 100:7–23

    Article  PubMed  CAS  Google Scholar 

  23. Dolinoy DC, Jirtle RL (2008) Environmental epigenomics in human health and disease. Environ Mol Mutagen 49:4–8

    Article  PubMed  CAS  Google Scholar 

  24. Kim YI (2004) Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 13:511–519

    PubMed  CAS  Google Scholar 

  25. Steeg PS, Ouatas T, Halverson D et al (2003) Metastasis suppressor genes: basic biology and potential clinical use. Clin Breast Cancer 4:51–62

    Article  PubMed  CAS  Google Scholar 

  26. Palmieri D, Horak CE, Lee JH et al (2006) Translational approaches using metastasis suppressor genes. J Bioenerg Biomembr 38:151–161

    Article  PubMed  CAS  Google Scholar 

  27. Stark AM, Tongers K, Maass N et al (2005) Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases. J Cancer Res Clin Oncol 131:191–198

    Article  PubMed  CAS  Google Scholar 

  28. Shevde LA, Samant RS, Goldberg SF et al (2002) Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1. Exp Cell Res 273:229–239

    Article  PubMed  CAS  Google Scholar 

  29. Uzawa K, Ono K, Suzuki H et al (2002) High prevalence of decreased expression of KAI1 metastasis suppressor in human oral carcinogenesis. Clin Cancer Res 8:828–835

    PubMed  CAS  Google Scholar 

  30. Harms JF, Welch DR, Miele ME (2003) KISS1 metastasis suppression and emergent pathways. Clin Exp Metastasis 20:11–18

    Article  PubMed  CAS  Google Scholar 

  31. Gildea JJ, Seraj MJ, Oxford G et al (2002) RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res 62:6418–6423

    PubMed  CAS  Google Scholar 

  32. Goncharuk VN, del-Rosario A, Kren L et al (2004) Co-downregulation of PTEN, KAI-1, and nm23-H1 tumor/metastasis suppressor proteins in non-small cell lung cancer. Ann Diagn Pathol 8:6–16

    Article  PubMed  Google Scholar 

  33. van’t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  PubMed  Google Scholar 

  34. Wang Y, Klijn JG, Zhang Y et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671–679

    PubMed  CAS  Google Scholar 

  35. Weigelt B, Hu Z, He X et al (2005) Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res 65:9155–9158

    Article  PubMed  CAS  Google Scholar 

  36. Buyse M, Loi S, van’t Veer L et al (2006) Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98:1183–1192

    PubMed  CAS  Google Scholar 

  37. Eccles S, Paon L, Sleeman J (2007) Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms. Clin Exp Metastasis 24:619–636

    Article  PubMed  CAS  Google Scholar 

  38. Steeg PS (2005) New insights into the tumor metastatic process revealed by gene expression profiling. Am J Pathol 166:1291–1294

    PubMed  CAS  Google Scholar 

  39. Minn AJ, Gupta GP, Siegel PM et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524

    Article  PubMed  CAS  Google Scholar 

  40. Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537–549

    Article  PubMed  CAS  Google Scholar 

  41. Woelfle U, Cloos J, Sauter G et al (2003) Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 63:5679–5684

    PubMed  CAS  Google Scholar 

  42. Hao X, Sun B, Hu L et al (2004) Differential gene and protein expression in primary breast malignancies and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. Cancer 100:1110–1122

    Article  PubMed  CAS  Google Scholar 

  43. Kwon HC, Kim SH, Roh MS et al (2004) Gene expression profiling in lymph node-positive and lymph node-negative colorectal cancer. Dis Colon Rectum 47:141–152

    Article  PubMed  Google Scholar 

  44. Bandyopadhyay A, Elkahloun A, Baysa SJ et al (2005) Development and gene expression profiling of a metastatic variant of the human breast cancer MDA-MB-435 cells. Cancer Biol Ther 4:168–174

    Article  PubMed  CAS  Google Scholar 

  45. Van den Eynden GG, Van Laere SJ, Van der Auwera I et al (2007) Differential expression of hypoxia and (lymph)angiogenesis-related genes at different metastatic sites in breast cancer. Clin Exp Metastasis 24:13–23

    Article  PubMed  CAS  Google Scholar 

  46. Roepman P, de Koning E, van Leenen D et al (2006) Dissection of a metastatic gene expression signature into distinct components. Genome Biol 7:R117

    Article  PubMed  CAS  Google Scholar 

  47. Ramaswamy S, Ross KN, Lander ES et al (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33:49–54

    Article  PubMed  CAS  Google Scholar 

  48. Clark SJ, Harrison J, Paul CL et al (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22:2990–2997

    Article  PubMed  CAS  Google Scholar 

  49. Nixdorf S, Grimm MO, Loberg R et al (2004) Expression and regulation of MIM (Missing In Metastasis), a novel putative metastasis suppressor gene, and MIM-B, in bladder cancer cell lines. Cancer Lett 215:209–220

    Article  PubMed  CAS  Google Scholar 

  50. Guo H, Lin Y, Zhang H et al (2007) Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells. BMC Mol Biol 8:110

    Article  PubMed  CAS  Google Scholar 

  51. Wendt MK, Cooper AN, Dwinell MB (2008) Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene 27:1461–1471

    Article  PubMed  CAS  Google Scholar 

  52. Shi B, Vinyals A, Alia P et al (2006) Differential expression of MHC class II molecules in highly metastatic breast cancer cells is mediated by the regulation of the CIITA transcription Implication of CIITA in tumor and metastasis development. Int J Biochem Cell Biol 38:544–562

    Article  PubMed  CAS  Google Scholar 

  53. Pakneshan P, Szyf M, Farias-Eisner R et al (2004) Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis. J Biol Chem 279:31735–31744

    Article  PubMed  CAS  Google Scholar 

  54. Nam JS, Ino Y, Kanai Y et al (2004) 5-aza-2′-deoxycytidine restores the E-cadherin system in E-cadherin-silenced cancer cells and reduces cancer metastasis. Clin Exp Metastasis 21:49–56

    Article  PubMed  CAS  Google Scholar 

  55. Skliris GP, Munot K, Bell SM et al (2003) Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol 201:213–220

    Article  PubMed  CAS  Google Scholar 

  56. Rivenbark AG, Livasy CA, Boyd CE et al (2007) Methylation-dependent silencing of CST6 in primary human breast tumors and metastatic lesions. Exp Mol Pathol 83:188–197

    Article  PubMed  CAS  Google Scholar 

  57. Fabianowska-Majewska K, Kordek R, Krawczyk B (2006) Studies on the methylation status of CpG sequences located in promoters of selected tumour suppressor genes in breast cancer cells. Nucleosides Nucleotides Nucleic Acids 25:1025–1028

    Article  PubMed  CAS  Google Scholar 

  58. Nimmrich I, Sieuwerts AM, Meijer-van Gelder ME et al (2007) DNA hypermethylation of PITX2 is a marker of poor prognosis in untreated lymph node-negative hormone receptor-positive breast cancer patients. Breast Cancer Res Treat. doi:10.1007/s10549-007-9800-8

  59. Veeck J, Chorovicer M, Naami A et al (2008) The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation. Oncogene 27:865–876

    Article  PubMed  CAS  Google Scholar 

  60. Umetani N, Mori T, Koyanagi K et al (2005) Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer. Oncogene 24:4721–4727

    Article  PubMed  CAS  Google Scholar 

  61. Murata H, Khattar NH, Gu L et al (2005) Roles of mismatch repair proteins hMSH2 and hMLH1 in the development of sporadic breast cancer. Cancer Lett 223:143–150

    Article  PubMed  CAS  Google Scholar 

  62. Takahashi Y, Miyoshi Y, Takahata C et al (2005) Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. Clin Cancer Res 11:1380–1385

    Article  PubMed  CAS  Google Scholar 

  63. Osanai T, Takagi Y, Toriya Y et al (2005) Inverse correlation between the expression of O6-methylguanine-DNA methyl transferase (MGMT) and p53 in breast cancer. Jpn J Clin Oncol 35:121–125

    Article  PubMed  Google Scholar 

  64. Li X, Cowell JK, Sossey-Alaoui K (2004) CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer. Oncogene 23:1474–1480

    Article  PubMed  CAS  Google Scholar 

  65. Yang D, Thangaraju M, Greeneltch K et al (2007) Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells. Cancer Res 67:3301–3309

    Article  PubMed  CAS  Google Scholar 

  66. Hu XC, Wong IH, Chow LW (2003) Tumor-derived aberrant methylation in plasma of invasive ductal breast cancer patients: clinical implications. Oncol Rep 10:1811–1815

    PubMed  CAS  Google Scholar 

  67. Lui EL, Loo WT, Zhu L et al (2005) DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Biomed Pharmacother 59(Suppl 2):S363–S365

    Article  PubMed  CAS  Google Scholar 

  68. Mehrotra J, Vali M, McVeigh M et al (2004) Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin Cancer Res 10:3104–3109

    Article  PubMed  CAS  Google Scholar 

  69. Shinozaki M, Hoon DS, Giuliano AE et al (2005) Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis. Clin Cancer Res 11:2156–2162

    Article  PubMed  CAS  Google Scholar 

  70. Mimori K, Kataoka A, Yoshinaga K et al (2005) Identification of molecular markers for metastasis-related genes in primary breast cancer cells. Clin Exp Metastasis 22:59–67

    Article  PubMed  CAS  Google Scholar 

  71. Cavalli LR, Urban CA, Dai D et al (2003) Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors. Cancer Genet Cytogenet 146:33–40

    Article  PubMed  CAS  Google Scholar 

  72. Caldeira JR, Prando EC, Quevedo FC et al (2006) CDH1 promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer. BMC Cancer 6:48

    Article  PubMed  CAS  Google Scholar 

  73. Nakayama H, Sano T, Motegi A et al (2005) Increasing 14-3-3 sigma expression with declining estrogen receptor alpha and estrogen-responsive finger protein expression defines malignant progression of endometrial carcinoma. Pathol Int 55:707–715

    Article  PubMed  CAS  Google Scholar 

  74. Hong SM, Choi J, Ryu K et al (2006) Promoter hypermethylation of the p16 gene and loss of its protein expression is correlated with tumor progression in extrahepatic bile duct carcinomas. Arch Pathol Lab Med 130:33–38

    PubMed  CAS  Google Scholar 

  75. Kim BH, Cho NY, Choi M et al (2007) Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas. Arch Pathol Lab Med 131:923–930

    PubMed  CAS  Google Scholar 

  76. Wendt MK, Johanesen PA, Kang-Decker N et al (2006) Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 25:4986–4997

    Article  PubMed  CAS  Google Scholar 

  77. Semba S, Itoh N, Ito M et al (2002) Down-regulation of PIK3CG, a catalytic subunit of phosphatidylinositol 3-OH kinase, by CpG hypermethylation in human colorectal carcinoma. Clin Cancer Res 8:3824–3831

    PubMed  CAS  Google Scholar 

  78. Lee M, Sup Han W, Kyoung Kim O et al (2006) Prognostic value of p16INK4a and p14ARF gene hypermethylation in human colon cancer. Pathol Res Pract 202:415–424

    Article  PubMed  CAS  Google Scholar 

  79. Umetani N, Fujimoto A, Takeuchi H et al (2004) Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. Oncogene 23:8292–8300

    Article  PubMed  CAS  Google Scholar 

  80. Ebert MP, Mooney SH, Tonnes-Priddy L et al (2005) Hypermethylation of the TPEF/HPP1 gene in primary and metastatic colorectal cancers. Neoplasia 7:771–778

    Article  PubMed  CAS  Google Scholar 

  81. Tang M, Torres-Lanzas J, Lopez-Rios F et al (2006) Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung. Int J Cancer 119:2603–2606

    Article  PubMed  CAS  Google Scholar 

  82. Fu L, Qin YR, Xie D et al (2007) Characterization of a novel tumor-suppressor gene PLC delta 1 at 3p22 in esophageal squamous cell carcinoma. Cancer Res 67:10720–10726

    Article  PubMed  CAS  Google Scholar 

  83. Onda T, Uzawa K, Nakashima D et al (2007) Lin-7C/VELI3/MALS-3: an essential component in metastasis of human squamous cell carcinoma. Cancer Res 67:9643–9648

    Article  PubMed  CAS  Google Scholar 

  84. Ito S, Ohga T, Saeki H et al (2007) Promoter hypermethylation and quantitative expression analysis of CDKN2A (p14ARF and pl6INK4a) gene in esophageal squamous cell carcinoma. Anticancer Res 27:3345–3353

    PubMed  CAS  Google Scholar 

  85. Zhang C, Li K, Wei L et al (2007) p300 expression repression by hypermethylation associated with tumour invasion and metastasis in oesophageal squamous cell carcinoma. J Clin Pathol 60:1249–1253

    Article  PubMed  CAS  Google Scholar 

  86. Liu WT, Jiao HL, Yang YL et al (2007) Correlation of E-cadherin hypermethylation to tumorigenesis and development of gastric cancer. Ai Zheng 26:1199–1203

    PubMed  CAS  Google Scholar 

  87. Yi Kim D, Kyoon Joo J, Kyu Park Y et al (2007) E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol 96:429–435

    Article  PubMed  CAS  Google Scholar 

  88. Wang J, Li G, Ma H et al (2007) Differential expression of EphA7 receptor tyrosine kinase in gastric carcinoma. Hum Pathol 38:1649–1656

    Article  PubMed  CAS  Google Scholar 

  89. Kim SK, Jang HR, Kim JH et al (2006) The epigenetic silencing of LIMS2 in gastric cancer and its inhibitory effect on cell migration. Biochem Biophys Res Commun 349:1032–1040

    Article  PubMed  CAS  Google Scholar 

  90. Chan AW, Chan MW, Lee TL et al (2005) Promoter hypermethylation of Death-associated protein-kinase gene associated with advance stage gastric cancer. Oncol Rep 13:937–941

    PubMed  CAS  Google Scholar 

  91. Wei D, Gong W, Kanai M et al (2005) Drastic down-regulation of Kruppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res 65:2746–2754

    Article  PubMed  CAS  Google Scholar 

  92. Ebert MP, Yu J, Hoffmann J et al (2003) Loss of beta-catenin expression in metastatic gastric cancer. J Clin Oncol 21:1708–1714

    Article  PubMed  CAS  Google Scholar 

  93. Oshimo Y, Kuraoka K, Nakayama H et al (2004) Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma. Int J Cancer 112:1003–1009

    Article  PubMed  CAS  Google Scholar 

  94. Wang S, Ding YB, Chen GY et al (2004) Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma. World J Gastroenterol 10:1815–1818

    PubMed  CAS  Google Scholar 

  95. Chen J, Rocken C, Klein-Hitpass L et al (2004) Microarray analysis of gene expression in metastatic gastric cancer cells after incubation with the methylation inhibitor 5-aza-2’-deoxycytidine. Clin Exp Metastasis 21:389–397

    Article  PubMed  CAS  Google Scholar 

  96. Taniguchi H, Yamamoto H, Akutsu N et al (2007) Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer. J Pathol 213:131–139

    Article  PubMed  CAS  Google Scholar 

  97. Nakamura M, Ishida E, Shimada K et al (2005) Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas. Lab Invest 85:165–175

    Article  PubMed  CAS  Google Scholar 

  98. Smiraglia DJ, Smith LT, Lang JC et al (2003) Differential targets of CpG island hypermethylation in primary and metastatic head and neck squamous cell carcinoma (HNSCC). J Med Genet 40:25–33

    Article  PubMed  CAS  Google Scholar 

  99. Lee MN, Tseng RC, Hsu HS et al (2007) Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin Cancer Res 13:832–838

    Article  PubMed  CAS  Google Scholar 

  100. Harden SV, Tokumaru Y, Westra WH et al (2003) Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clin Cancer Res 9:1370–1375

    PubMed  CAS  Google Scholar 

  101. Chakraborty AK, Sousa Jde F, Chakraborty D et al (2006) GnT-V expression and metastatic phenotypes in macrophage-melanoma fusion hybrids is down-regulated by 5-Aza-dC: evidence for methylation sensitive, extragenic regulation of GnT-V transcription. Gene 374:166–173

    Article  PubMed  CAS  Google Scholar 

  102. Lung HL, Bangarusamy DK, Xie D et al (2005) THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene 24:6525–6532

    PubMed  CAS  Google Scholar 

  103. Kudo Y, Kitajima S, Ogawa I et al (2004) Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous beta-catenin. Clin Cancer Res 10:5455–5463

    Article  PubMed  CAS  Google Scholar 

  104. Ishida E, Nakamura M, Ikuta M et al (2005) Promotor hypermethylation of p14ARF is a key alteration for progression of oral squamous cell carcinoma. Oral Oncol 41:614–622

    Article  PubMed  CAS  Google Scholar 

  105. Makarla PB, Saboorian MH, Ashfaq R et al (2005) Promoter hypermethylation profile of ovarian epithelial neoplasms. Clin Cancer Res 11:5365–5369

    Article  PubMed  CAS  Google Scholar 

  106. House MG, Guo M, Efron DT et al (2003) Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior. J Gastrointest Surg 7:1004–1014. Discussion 1014

    Article  PubMed  Google Scholar 

  107. Pulukuri SM, Patibandla S, Patel J et al (2007) Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors. Oncogene 26:5229–5237

    Article  PubMed  CAS  Google Scholar 

  108. Zhu X, Leav I, Leung YK et al (2004) Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 164:2003–2012

    PubMed  CAS  Google Scholar 

  109. Kelavkar UP, Harya NS, Hutzley J et al (2007) DNA methylation paradigm shift: 15-lipoxygenase-1 upregulation in prostatic intraepithelial neoplasia and prostate cancer by atypical promoter hypermethylation. Prostaglandins Other Lipid Mediat 82:185–197

    Article  PubMed  CAS  Google Scholar 

  110. Bastian PJ, Ellinger J, Wellmann A et al (2005) Diagnostic and prognostic information in prostate cancer with the help of a small set of hypermethylated gene loci. Clin Cancer Res 11:4097–4106

    Article  PubMed  CAS  Google Scholar 

  111. Yegnasubramanian S, Kowalski J, Gonzalgo ML et al (2004) Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res 64:1975–1986

    Article  PubMed  CAS  Google Scholar 

  112. Kasahara T, Bilim V, Hara N et al (2006) Homozygous deletions of the INK4a/ARF locus in renal cell cancer. Anticancer Res 26:4299–4305

    PubMed  CAS  Google Scholar 

  113. Yamada D, Kikuchi S, Williams YN et al (2006) Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. Int J Cancer 118:916–923

    Article  PubMed  CAS  Google Scholar 

  114. Boltze C, Schneider-Stock R, Quednow C et al (2003) Silencing of the maspin gene by promoter hypermethylation in thyroid cancer. Int J Mol Med 12:479–484

    PubMed  CAS  Google Scholar 

  115. van der Velden PA, Zuidervaart W, Hurks MH et al (2003) Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. Int J Cancer 106:472–479

    Article  PubMed  CAS  Google Scholar 

  116. Gonzalez-Gomez P, Bello MJ, Alonso ME et al (2003) Frequent death-associated protein-kinase promoter hypermethylation in brain metastases of solid tumors. Oncol Rep 10:1031–1033

    PubMed  CAS  Google Scholar 

  117. Tan SH, Ida H, Goh BC et al (2006) Analyses of promoter hypermethylation for RUNX3 and other tumor suppressor genes in nasopharyngeal carcinoma. Anticancer Res 26:4287–4292

    PubMed  CAS  Google Scholar 

  118. Pellise M, Castells A, Gines A et al (2004) Detection of lymph node micrometastases by gene promoter hypermethylation in samples obtained by endosonography- guided fine-needle aspiration biopsy. Clin Cancer Res 10:4444–4449

    Article  PubMed  CAS  Google Scholar 

  119. Yamashita K, Park HL, Kim MS et al (2006) PGP9.5 methylation in diffuse-type gastric cancer. Cancer Res 66:3921–3927

    Article  PubMed  CAS  Google Scholar 

  120. Driouch K, Landemaine T, Sin S et al (2007) Gene arrays for diagnosis, prognosis and treatment of breast cancer metastasis. Clin Exp Metastasis 24:575–585

    Article  PubMed  CAS  Google Scholar 

  121. Takayama T, Miyanishi K, Hayashi T et al (2006) Colorectal cancer: genetics of development and metastasis. J Gastroenterol 41:185–192

    Article  PubMed  CAS  Google Scholar 

  122. Segditsas S, Tomlinson I (2006) Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25:7531–7537

    Article  PubMed  CAS  Google Scholar 

  123. Vogiatzi P, Vindigni C, Roviello F et al (2007) Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis. J Cell Physiol 211:287–295

    Article  PubMed  CAS  Google Scholar 

  124. Jee CD, Lee HS, Bae SI et al (2005) Loss of caspase-1 gene expression in human gastric carcinomas and cell lines. Int J Oncol 26:1265–1271

    PubMed  CAS  Google Scholar 

  125. Nelson WG, Yegnasubramanian S, Agoston AT et al (2007) Abnormal DNA methylation, epigenetics, and prostate cancer. Front Biosci 12:4254–4266

    Article  PubMed  CAS  Google Scholar 

  126. Yu J, Yu J, Rhodes DR et al (2007) A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res 67:10657–10663

    Article  PubMed  CAS  Google Scholar 

  127. Beke L, Nuytten M, Van Eynde A et al (2007) The gene encoding the prostatic tumor suppressor PSP94 is a target for repression by the Polycomb group protein EZH2. Oncogene 26:4590–4595

    Article  PubMed  CAS  Google Scholar 

  128. Chen H, Tu SW, Hsieh JT (2005) Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J Biol Chem 280:22437–22444

    Article  PubMed  CAS  Google Scholar 

  129. Vire E, Brenner C, Deplus R et al (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874

    Article  PubMed  CAS  Google Scholar 

  130. Berezovska OP, Glinskii AB, Yang Z et al (2006) Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle 5:1886–1901

    PubMed  CAS  Google Scholar 

  131. Cho KS, Oh HY, Lee EJ et al (2007) Identification of enhancer of zeste homolog 2 expression in peripheral circulating tumor cells in metastatic prostate cancer patients: a preliminary study. Yonsei Med J 48:1009–1014

    Article  PubMed  CAS  Google Scholar 

  132. Choi IS, Estecio MR, Nagano Y et al (2007) Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors). Mod Pathol 20:802–810

    Article  PubMed  CAS  Google Scholar 

  133. Schulz WA, Elo JP, Florl AR et al (2002) Genomewide DNA hypomethylation is associated with alterations on chromosome 8 in prostate carcinoma. Genes Chromosomes Cancer 35:58–65

    Article  PubMed  CAS  Google Scholar 

  134. Shukeir N, Pakneshan P, Chen G et al (2006) Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. Cancer Res 66:9202–9210

    Article  PubMed  CAS  Google Scholar 

  135. Nakamura N, Takenaga K (1998) Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin Exp Metastasis 16:471–479

    Article  PubMed  CAS  Google Scholar 

  136. Rosty C, Ueki T, Argani P et al (2002) Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation. Am J Pathol 160:45–50

    PubMed  CAS  Google Scholar 

  137. Xie R, Loose DS, Shipley GL et al (2007) Hypomethylation-induced expression of S100A4 in endometrial carcinoma. Mod Pathol 20:1045–1054

    Article  PubMed  CAS  Google Scholar 

  138. Lindsey JC, Lusher ME, Anderton JA et al (2007) Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma. Br J Cancer 97:267–274

    Article  PubMed  CAS  Google Scholar 

  139. Arisawa T, Tahara T, Shibata T et al (2007) Promoter hypomethylation of protease-activated receptor 2 associated with carcinogenesis in the stomach. J Gastroenterol Hepatol 22:943–948

    Article  PubMed  CAS  Google Scholar 

  140. Honda T, Tamura G, Waki T et al (2004) Demethylation of MAGE promoters during gastric cancer progression. Br J Cancer 90:838–843

    Article  PubMed  CAS  Google Scholar 

  141. Jung EJ, Kim MA, Lee HS et al (2005) Expression of family A melanoma antigen in human gastric carcinoma. Anticancer Res 25:2105–2111

    PubMed  CAS  Google Scholar 

  142. Gupta A, Godwin AK, Vanderveer L et al (2003) Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 63:664–673

    PubMed  CAS  Google Scholar 

  143. Bariol C, Suter C, Cheong K et al (2003) The relationship between hypomethylation and CpG island methylation in colorectal neoplasia. Am J Pathol 162:1361–1371

    PubMed  CAS  Google Scholar 

  144. Sadikovic B, Andrews J, Carter D et al (2008) Genome-wide H3K9 histone acetylation profiles are altered in benzopyrene treated MCF7 breast cancer cells. J Biol Chem 283:4051–4060

    Article  PubMed  CAS  Google Scholar 

  145. Sigalotti L, Fratta E, Coral S et al (2007) Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. J Cell Physiol 212:330–344

    Article  PubMed  CAS  Google Scholar 

  146. Oh BK, Kim H, Park HJ et al (2007) DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. Int J Mol Med 20:65–73

    PubMed  CAS  Google Scholar 

  147. Momparler RL (2005) Epigenetic therapy of cancer with 5-aza-2′-deoxycytidine (decitabine). Semin Oncol 32:443–451

    Article  PubMed  CAS  Google Scholar 

  148. Cho CY, Wang JH, Chang HC et al (2007) Epigenetic inactivation of the metastasis suppressor RECK enhances invasion of human colon cancer cells. J Cell Physiol 213:65–69

    Article  PubMed  CAS  Google Scholar 

  149. Kassis ES, Zhao M, Hong JA et al (2006) Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. J Thorac Cardiovasc Surg 131:298–306

    Article  PubMed  CAS  Google Scholar 

  150. Winquist E, Knox J, Ayoub JP et al (2006) Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study. Invest New Drugs 24:159–167

    Article  PubMed  CAS  Google Scholar 

  151. Lin RK, Hsu CH, Wang YC (2007) Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells. Anticancer Drugs 18:1157–1164

    PubMed  CAS  Google Scholar 

  152. Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50

    Article  PubMed  CAS  Google Scholar 

  153. Joseph J, Mudduluru G, Antony S et al (2004) Expression profiling of sodium butyrate (NaB)-treated cells: identification of regulation of genes related to cytokine signaling and cancer metastasis by NaB. Oncogene 23:6304–6315

    Article  PubMed  CAS  Google Scholar 

  154. Lin KT, Yeh SH, Chen DS et al (2005) Epigenetic activation of alpha4, beta2 and beta6 integrins involved in cell migration in trichostatin A-treated Hep3B cells. J Biomed Sci 12:803–813

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I gratefully acknowledge financial support by grant #016506 from the Canadian Breast Cancer Research Alliance, with special funding support from the Canadian Breast Cancer Foundation and the Cancer Research Society. I also acknowledge funding support from the London Regional Cancer Program Small Grants Competition and the Lawson Health Research Institute Internal Research Fund. Finally, I thank my colleagues and the trainees and staff in my lab for stimulating discussions and critique during preparation of this review.

Author information

Authors and Affiliations

  1. Departments of Biochemistry, Oncology and Paediatrics, University of Western Ontario, London, Ontario, Canada

    David I. Rodenhiser

  2. The London Regional Cancer Program, London Health Sciences Centre and the EpiGenWestern Research Group at the Children’s Health Research Institute, London, Ontario, Canada

    David I. Rodenhiser

  3. Room A4-134 Victoria Research Laboratories, London Health Sciences Centre, 790 Commissioners Rd. East, London, Ontario, Canada, N6A 4L6

    David I. Rodenhiser

Authors
  1. David I. Rodenhiser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David I. Rodenhiser.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodenhiser, D.I. Epigenetic contributions to cancer metastasis. Clin Exp Metastasis 26, 5–18 (2009). https://doi.org/10.1007/s10585-008-9166-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-008-9166-2

Keywords

Search

Navigation