Skip to main content Accessibility help
×
Home
  • Print publication year: 2011
  • Online publication date: June 2012

8 - Metastasis Genes: Epigenetics

from GENES

Summary

Metastasis is the sequence of interrelated steps by which primary tumor cells acquire the capability to invade adjacent tissue, enter the systemic circulation (intravasate), translocate through the vasculature, arrest in distant capillaries, extravasate into the surrounding tissue parenchyma, and, finally, proliferate from micrometastases into macroscopic secondary tumors [1, 2]. This metastatic process is the cause of 90 percent of deaths in patients with solid tumors [1, 2]. Therefore, unraveling the inner mechanisms of the pathogenesis of metastasis at systemic, cellular, and molecular levels has become a major goal of cancer research [1, 2].

In recent years, the contribution of epigenetics to the field of cancer has been of paramount importance, because cancer is both a genetic and an epigenetic disease [3] and because epigenetic alterations are also involved in the metastatic process [4]. Thus, cancer cells have to gain an epigenotype to disseminate from the primary tumor mass or to survive and proliferate at a secondary tissue site [4].

We are still in the early stages of deciphering the timing and hierarchy of these epigenetic lesions; we need to know how epigenetic mechanisms operate in normal and cancer cells to understand the epigenetic changes that occur in metastasis. This information will allow us to identify new metastasis-related genes, to discover new epigenetic biomarkers that may help identify the diagnostic signatures of metastasis, and to develop new cancer therapies based on epigenetic drugs [5].

References
Fidler, IJ (2003) The pathogenesis of cancer metastasis: the “seed and soil” hypothesis revisited. Nature Rev Cancer. 3: 453–458.
Gupta, GP, Massague, J (2006) Cancer metastasis: building a framework. Cell. 127: 679–695.
Esteller, M (2008) Epigenetics in cancer. N Engl J Med. 358: 1148–1159.
Rodenhiser, DI (2009) Epigenetic contributions to cancer metastasis. Clin Exp Metastasis. 26: 5–18. Epub ahead of print.
Chambers, AF, Groom, AC, MacDonald, IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2: 563–572.
Egger, G, Liang, G, Aparicio, A, Jones, PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature. 429: 457–463.
Jones, PA, Laird, PW (1999) Cancer epigenetics comes of age. Nat Genet. 21: 163–167.
Esteller, M (2005) Aberrant DNA methylation as a cancerinducing mechanism. Annu Rev Pharmacol Toxicol. 45: 629–656.
Kaneda, M, Okano, M, Hata, K et al. (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature. 429: 900–903.
Klose, RJ, Bird, AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 31: 89–97.
Takai, D, Jones, PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99: 3740–3745.
Takai, D, Jones, PA (2003) The CpG island searcher: a new WWW resource. In Silico Biol. 3: 235–240.
Esteller, M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 4: 286–298.
Csankovszki, G, Nagy, A, Jaenisch, R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol. 153: 773–784.
Walsh, CP, Chaillet, JR, Bestor, TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet. 20: 116–117.
Bodey, B (2002) Cancer-testis antigens: promising targets for antigen directed antineoplastic immunotherapy. Expert Opin Biol Ther. 2: 577–584.
Futscher, BW, Oshiro, MM, Wozniak, RJ et al. (2002) Role for DNA methylation in the control of cell type specific maspin expression. Nat Genet. 31: 175–179.
Wang, Y, Fischle, W, Cheung, W, Jacobs, S, Khorasanizadeh, S, Allis, CD (2004) Beyond the double helix: writing and reading the histone code. Novartis Found Symp. 259: 3–17.
Peters, AH, Mermoud, JE, O'Carroll, D (2002) Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat Genet. 30: 77–80.
Sanders, SL, Portoso, M, Mata, J, Bähler, J, Allshire, RC, Kouzarides, T (2004) Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell. 119: 603–614.
Ballestar, E, Esteller, M (2002) The impact of chromatin in human cancer: linking DNA methylation to gene silencing. Carcinogenesis. 23: 1103–1109.
Esteller, M (2006) Epigenetics provides a new generation of oncogenes and tumor-suppressor genes. Br J Cancer. 94: 179–83.
Welch, DR (2004) Microarrays bring new insights into understanding of breast cancer metastasis to bone. Breast Cancer Res. 6: 61–64.
Hanahan, D, Weinberg, RA (2000) The hallmarks of cancer. Cell. 100: 57–70.
Bernstein, BE, Meissner, A, Lander, ES (2007) The mammalian epigenome. Cell. 128: 669–681.
Jones, PA, Baylin, SB (2007) The epigenomics of cancer. Cell. 128: 683–692.
Kouzarides, T (2007) Chromatin modifications and their function. Cell. 128: 693–705.
Herman, JG, Baylin, SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Eng J Med. 349: 2042–2054.
Feinberg, AP, Vogelstein, B (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 301: 89–92.
Fraga, MF, Herranz, M, Espada, J et al. (2004) A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 64: 5527–5534.
Fraga, MF, Rodríguez, R, Canal, MJ (2000) Rapid quantification of DNA methylation by high performance capillary electrophoresis. Electrophoresis. 21: 2990–2994.
Fraga, MF, Uriel, E, Borja, Diego L et al. (2002) High-performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues. Electrophoresis 23: 1677–1681.
Paz, MF, Fraga, MF, Avila, S et al. (2003) A systematic profile of DNA methylation in human cancer cell lines. Cancer Res. 63: 1114–1121.
Habib, M, Fares, F, Bourgeois, CA et al. (1999) DNA global hypomethylation in EBV-transformed interphase nuclei. Exp Cell Res. 249: 46–53.
Eden, A, Gaudet, F, Waghmare, A, Jaenisch, R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 300: 455.
Karpf, AR, Matsui, S (2005) Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer Res. 65: 8635–8639.
Cui, H, Cruz-Correa, M, Giardiello, FM et al. (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science. 299: 1753–1755.
Kaneda, A, Feinberg, AP (2005) Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res. 65: 11236–11240.
Feinberg, AP (1999) Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. Cancer Res. 59: Suppl:1743s–1746s.
Xu, GL, Bestor, TH, Bourc'his, D et al. (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 402: 187–191.
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.
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.
Feinberg, AP, Tycko, B (2004) The history of cancer epigenetics. Nat Rev Cancer. 4: 143–153.
Wu, H, Chen, Y, Liang, J et al. (2005) Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature. 438: 981–987.
Brueckner, B, Stresemann, C, Kuner, R et al. (2007) The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res. 67: 1419–1423.
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.
Lindsey, JC, Lusher, ME, Anderton, JA, Gilbertson, RJ, Ellison, DW, Clifford, SC (2007) Epigenetic deregulation of multiple S100 gene family members by differential hypomethylation and hypermethylation events in medulloblastoma. Br J Cancer. 97: 267–274.
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.
Xie, R, Loose, DS, Shipley, GL, Xie, S, Bassett, RL Jr, Broaddus, RR (2007) Hypomethylation-induced expression of S100A4 in endometrial carcinoma. Mod Pathol. 20: 1045–1054.
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.
Gupta, A, Godwin, AK, Vanderveer, L, Lu, A, Liu, J (2003) Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res. 63: 664–673.
Ballestar, E, Paz, MF, Valle, L et al. (2003) Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 22: 6335–6345.
Richon, VM, Sandhoff, TW, Rifkind, RA, Marks, PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 97: 10014–10019.
Mack, GS (2006) Epigenetic cancer therapy makes headway. J Natl Cancer Inst. 98: 1443–1444.
Fraga, MF, Ballestar, E, Villar-Garea, A et al. (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 37: 391–400.
Pogribny, IP, Ross, SA, Tryndyak, VP, Pogribna, M, Poirier, , Karpinets, TV (2006) Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4–20h2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats. Carcinogenesis. 27: 1180–1186.
Tryndyak, VP, Kovalchuk, O, Pogribny, IP (2006) Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4–20h2 histone methyltransferase and methyl-binding proteins. Cancer Biol Ther. 5: 65–70.
Greger, V, Passarge, E, Höpping, W, Messmer, E, Horsthemke, B (1989) Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 83: 155–158.
Sakai, T, Toguchida, J, Ohtani, N, Yandell, DW, Rapaport, JM, Dryja, TP (1991) Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am Hum Genet. 48: 880–888.
Herman, JG, Latif, F, Weng, Y et al. (1994) Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA. 91: 9700–9704.
Merlo, A, Herman, JG, Mao, L et al. (1995) 5′ CpG island methylation is associated with transcriptional silencing of the tumor suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1: 686–692.
Herman, JG, Merlo, A, Mao, L et al. (1995) Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 55: 4525–4530.
Gonzalez-Zulueta, M, Bender, CM, Yang, AS et al. (1995) Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 55: 4531–4535.
Esteller, M, Silva, JM, Dominguez, G et al. (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 92: 564–569.
Graff, JR, Herman, JG, Lapidus, RG et al. (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 55: 5195–5199.
Yoshiura, K, Kanai, Y, Ochiai, A, Shimoyama, Y, Sugimura, T, Hirohashi, S (1995) Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci U S A 92: 7416–7419.
Graff, JR, Gabrielson, E, Fujii, H, Baylin, SB, Herman, JG (2000) Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem. 275: 2727–2732.
Bolós, V, Peinado, H, Pérez-Moreno, MA, Fraga, MF, Esteller, M, Cano, A (2003) The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 116(Pt 3): 499–511.
Peinado, H, Ballestar, E, Esteller, M, Cano, A (2004) Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 24: 306–319.
Sato, M, Mori, Y, Sakurada, A, Fujimura, S, Horii, A (1998) The H-cadherin (CDH13) gene is inactivated in human lung cancer. Hum Genet. 103: 96–101.
Toyooka, KO, Toyooka, S, Virmani, AK et al. (2001) Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. Cancer Res 61: 4556–4560.
Miotto, E, Sabbioni, S, Veronese, A et al. (2004) Frequent aberrant methylation of the CDH4 gene promoter in human colorectal and gastric cancer. Cancer Res 64: 8156–8159.
Paz, MF, Wei, S, Cigudosa, JC et al. (2003) Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum Mol Genet. 12: 2209–2219.
Ropero, S, Setien, F, Espada, J et al. (2004) Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells. Hum Mol Genet. 13: 2753–2765.
Lin, H, Huber, R, Schlessinger, D, Morin, PJ (1999) Frequent silencing of the GPC3 gene in ovarian cancer cell lines. Cancer Res. 59: 807–810.
Miyamoto, K, Asada, K, Fukutomi, T et al. (2003) Methylation-associated silencing of heparan sulfate D-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers. Oncogene. 22: 274–280.
Overall, CM, Kleifeld, O (2006) Tumour microenvironment – opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 6: 227–239.
Esteller, M, Fraga, MF, Guo, M et al. (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet. 10: 3001–3007.
Bachman, KE, Herman, JG, Corn, PG et al. (1999) Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Res. 59: 798–802.
Ivanova, T, Vinokurova, S, Petrenko, A et al. (2004) Frequent hypermethylation of 5′ flanking region of TIMP-2 gene in cervical cancer. Int J Cancer. 108: 882–886.
Galm, O, Suzuki, H, Akiyama, Y et al. (2005) Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies. Oncogene. 24: 4799–4805.
Pulukuri, SM, Patibandla, S, Patel, J, Estes, N, Rao, JS (2007) Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors. Oncogene. 26: 5229–5237.
Konduri, SD, Srivenugopal, KS, Yanamandra, N, Dinh, DH, Olivero, WC, Gujrati, M, Foster, DC, Kisiel, W, Ali-Osman, F, Kondraganti, S, Lakka, SS, Rao, JS (2003) Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells. Oncogene 22: 4509–4516.
Sato, N, Parker, AR, Fukushima, N et al. (2005) Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma. Oncogene. 24: 850–858.
Suzuki, K, Kumanogoh, A, Kikutani, H (2008) Semaphorins and their receptors in immune cell interactions. Nat Immunol. 9: 17–23.
Ji, L, Minna, JD, Roth, JA (2005) 3p21.3 tumor suppressor cluster: prospects for translational applications. Future Oncol. 1: 79–92.
Tomizawa, Y, Sekido, Y, Kondo, M et al. (2001) Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A 98: 13954–13959.
Kuroki, T, Trapasso, F, Yendamuri, S et al. (2003) Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3B in non-small cell lung cancer. Cancer Res. 63: 3352–3355.
Dickinson, RE, Dallol, A, Bieche, I et al. (2004) Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers. Br J Cancer. 91: 2071–2078.
Kazerounian, S, Yee, KO, Lawler, J (2008) Thrombospondins in cancer. Cell Mol Life Sci. 65: 700–712.
Lawler, J, Detmar, M (2004) Tumor progression: the effects of thrombospondin-1 and -2. Int J Biochem Cell Biol. 36: 1038–1045.
Li, Q, Ahuja, N, Burger, PC, Issa, JP (1999) Methylation and silencing of the thrombospondin-1 promoter in human cancer. Oncogene. 18: 3284–3289.
Schéele, S, Nyström, A, Durbeej, M, Talts, JF, Ekblom, M, Ekblom, P (2007) Laminin isoforms in development and disease. J Mol Med. 85: 825–836.
Sathyanarayana, UG, Toyooka, S, Padar, A et al. (2003) Epigenetic inactivation of laminin-5-encoding genes in lung cancers. Clin Cancer Res. 9: 2665–2672.
He, L, Hannon, GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 5: 522–531.
Lu, J, Getz, G, Miska, EA et al. (2005) MicroRNA expression profiles classify human cancers. Nature. 435: 834–838.
Calin, GA, Dumitru, CD, Shimizu, M et al. (2002) Frequent deletions and downregulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 99: 15524–15529.
Takamizawa, J, Konishi, H, Yanagisawa, K et al. (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64: 3753–3756.
Cimmino, A, Calin, GA, Fabbri, M et al. (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102: 13944–13949.
Johnson, SM, Grosshans, H, Shingara, J et al. (2005) RAS is regulated by the let-7 MicroRNA family. Cell. 120: 635–647.
Hammond, SM (2006) MicroRNAs as oncogenes. Curr Opin Genet Dev. 16: 4–9.
Chan, JA, Krichevsky, AM, Kosik, KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65: 6029–6033.
He, L, Thomson, JM, Hemann, MT et al. (2005) A microRNA polycistron as a potential human oncogene. Nature. 435: 828–833.
Ma, L, Teruya-Feldstein, J, Weinberg, RA (2007) Tumor invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 449: 682–688.
Huang, Q, Gumireddy, K, Schrier, M et al. (2008) The microRNAs miR-373 and miR-520c promote tumor invasion and metastasis. Nat Cell Biol. 10: 202–210.
Tavazoie, SF, Alarcón, C, Oskarsson, T et al. (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 451: 147–152.
Lujambio, A, Esteller, M (2007) CpG island hypermethylation of tumor suppressor microRNAs in human cancer. Cell Cycle. 6: 1455–1459.
Saito, Y, Liang, G, Egger, G et al. (2006) Specific activation of microRNA-127 with downregulation of the protooncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 9: 435–443.
Lujambio, A, Ropero, S, Ballestar, E et al. (2007) Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res. 67: 1424–1429.
Lehmann, U, Hasemeier, B, Christgen, M et al. (2008) Epigenetic inactivation of microRNA gene hsa-mir-9–1 in human breast cancer. J Pathol. 214: 17–24.
Kozaki, K, Imoto, I, Mogi, S, Omura, K, Inazawa, J (2008) Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 68: 2094–2105.
Grady, WM, Parkin, RK, Mitchell, PS et al. (2008) Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene. 27: 3880–3888.
Yoo, CB, Jones, PA (2006) Epigenetic therapy of cancer: Past, present and future. Nat Rev Drug Discov. 5: 37–50.
Lujambio, A, Calin, GA, Villanueva, A et al. (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA. (in press) 105: 13556–13561.
Villar-Garea, A, Esteller, M (2004) Histone deacetylase inhibitors: understanding a new wave of anticancer agents. Int J Cancer. 112: 171–178.
Sadikovic, B, Andrews, J, Carter, D, Robinson, J, Rodenhiser, DI (2008) Genome-wide H3K9 histone acetylation profiles are altered in benzopyrene-treated MCF7 breast cancer cells. J Biol Chem. 283: 4051–4060.
Shukeir, N, Pakneshan, P, Chen, G, Szyf, M, Rabbani, SA (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.