Cancer Letters
Volume 198, Issue 1 , Pages 1-20 , 30 July 2003

Metastasis suppressor pathways—an evolving paradigm

  • Lalita A. Shevde

      Affiliations

    • Department of Pathology, 1670 University Boulevard, Volker Hall - G-038, The University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA
  • ,
  • Danny R. Welch

      Affiliations

    • Department of Pathology, 1670 University Boulevard, Volker Hall - G-038, The University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA
    • UAB-Comprehensive Cancer Center, The University fo Alabama at Birmingham, Birmingham, AL 35294, USA
    • Corresponding Author InformationCorresponding author. Address: Department of Pathology, 1670 University Boulevard, Volker Hall -G-038, The University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA. Tel.: +1-205-934-4612; fax: +1-205-934-1775

Received 5 April 2003 ,Accepted 16 April 2003.

References 

  1. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Metastasis: lymphangiogenesis and cancer metastasis. Nature Rev. Cancer. 2002;2:573–583
  2. Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer. 2003;3:55–63
  3. Welch DR, Tomasovic SP. Implications of tumor progression on clinical oncology. Clin. Exptl. Metastasis. 1985;3:151–188
  4. Nowell P. The clonal evolution of tumor cell populations. Science. 1976;194:23–28
  5. Luria SE, Delbruck M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics. 1943;28:491–511
  6. Bernards R, Weinberg RA. Metastasis genes: a progression puzzle. Nature (London). 2002;418:823
  7. Hahn WC, Weinberg RA. Rules for making human tumor cells. N. Engl. J. Med. 2002;347:1593–1603
  8. Liotta LA, Kohn EC. The microenvironment of the tumour–host interface. Nature (London). 2001;411:375–379
  9. Coussens LM, Werb Z. Inflammation and cancer. Nature (London). 2002;420:860–867
  10. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer. 2002;2:161–174
  11. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–573
  12. Folberg R, Hendrix MJC, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am. J. Pathol. 2000;156:361–381
  13. Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LMG, Pe'er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 1999;155:739–752
  14. Jain RK, Munn LL, Fukumura D. Dissecting tumour pathophysiology using intravital microscopy. Nature Rev. Cancer. 2002;2:266–276
  15. Kieda C, Paprocka M, Krawczenko A, Zalecki P, Dupuis P, Monsigny M, et al. New human microvascular endothelial cell lines with specific adhesion molecules phenotypes. Endothelium New York. 2002;9:247–261
  16. Laakkonen P, Porkka K, Hoffman JA, Ruoslahti E. A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nature Med. 2002;8:751–755
  17. Pasqualini R, Arap W, McDonald DM. Probing the structural and molecular diversity of tumor vasculature. Trends Mol. Med. 2002;8:563–571
  18. Ruoslahti E. Specialization of tumour vasculature. Nature Rev. Cancer. 2002;2:83–90
  19. Youngs SJ, Ali SA, Taub DD, Rees RC. Chemokines induce migrational responses in human breast carcinoma cell lines. Int. J. Cancer. 1997;71:257–266
  20. Nicolson GL. Cancer metastasis. Organ colonization and the cell-surface properties of malignant cells. Biochim. Biophys. Acta. 1982;695:113–176
  21. Müller A, Homey B, Soto H, Ge NF, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature (London). 2001;410:50–56
  22. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62:1832–1837
  23. Balkwill F. Chemokine biology in cancer. Seminars Immunol. 2003;15:49–55
  24. Chambers AF, MacDonald IC, Schmidt EE, Koop S, Morris VL, Khokha R, et al. Steps in tumor metastasis: new concepts from intravital videomicroscopy. Cancer Metastasis Rev. 1995;14:279–301
  25. Koop S, MacDonald IC, Luzzi K, Schmidt EE, Morris VL, Grattan M, et al. Fate of melanoma cells entering the microcirculation: over 80% survive and extravasate. Cancer Res. 1995;55:2520–2523
  26. Qiu HM, Orr FW, Jensen D, Wang HH, McIntosh AR, Hasinoff BB, et al. Arrest of B16 melanoma cells in the mouse pulmonary microcirculation induces endothelial nitric oxide synthase-dependent nitric oxide release that is cytotoxic to the tumor cells. Am. J. Pathol. 2003;162:403–412
  27. Al Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nature Med. 2000;6:100–102
  28. Chambers AF, Groom AC, MacDonald IC. Metastasis: dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer. 2002;2:563–572
  29. Weiss L. Metastatic inefficiency. Adv. Cancer Res. 1990;54:159–211
  30. Weiss L. Concepts of metastasis. Cancer Metastasis Rev. 2000;19:219–234
  31. Fidler IJ. Selection of successive tumor lines for metastasis. Nature New Biol. 1973;242:148–149
  32. Holmgren L. Antiangiogenesis restricted tumor dormancy. Cancer Metastasis Rev. 1996;15:241–245
  33. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, et al. Multistep nature of metastatic inefficiency—dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 1998;153:865–873
  34. Yoshida BA, Dubauskas Z, Chekmareva MA, Zaucha MM, Christiano TR, Christiano AP, et al. Identification and characterization of candidate prostate cancer metastasis-suppressor genes encoded on human chromosome 17. Cancer Res. 1999;59:5483–5487
  35. Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 2002;62:2162–2168
  36. Holmgren L, O'Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1995;1:149–153
  37. Wong CW, Lee A, Shientag L, Yu J, Dong Y, Kao G, et al. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 2001;61:333–338
  38. Cameron MD, Schmidt EE, Kerkvliet N, Nadkarni KV, Morris VL, Groom AC, et al. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res. 2000;60:2541–2546
  39. Chishima T, Yang M, Miyagi Y, Li L, Tan Y, Baranov E, et al. Governing step of metastasis visualized in vitro. Proc. Natl Acad. Sci. 1997;94:11573–11576
  40. Hoffman RM. Visualization of GFP-expressing tumors and metastasis in vivo. Biotechniques. 2001;30:1016–1020
  41. Harms JF, Budgeon LR, Christensen ND, Welch DR. Maintaining green fluorescent protein tissue fluorescence through bone decalcification and long-term storage. Biotechniques. 2002;33:1197–1200
  42. Harms JF, Welch DR. MDA-MB-435 human breast carcinoma metastasis to bone. Clin. Exptl Metastasis. 2003; in press
  43. Welch DR, Rinker-Schaeffer CW. What defines a useful marker of metastasis in human cancer?. J. Natl Cancer Inst. 1999;91:1351–1353
  44. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat. Genet. 2003;33:49–54
  45. Nishizaki T, Devries S, Chew K, Goodson WH, Ljung BM, Thor A, et al. Genetic alterations in primary breast cancers and their metastases—direct comparison using modified comparative genomic hybridization. Genes Chromosomes Cancer. 1997;19:267–272
  46. Nakao K, Shibusawa M, Ishihara A, Yoshizawa H, Tsunoda A, Kusano M, et al. Genetic changes in colorectal carcinoma tumors with liver metastases analyzed by comparative genomic hybridization and DNA ploidy. Cancer. 2001;91:721–726
  47. Redon R, Muller D, Caulee K, Wanherdrick K, Abecassis J, Du Manoir S. A simple specific pattern of chromosomal aberrations at early stages of head and neck squamous cell carcinomas: PIK3CA but not p63 gene as a likely target of 3q26-qter gains. Cancer Res. 2001;61:4122–4129
  48. Wu WG, Tang XM, Hu W, Lotan R, Hong WK, Mao L. Identification and validation of metastasis-associated proteins in head and neck cancer cell lines by two-dimensional electrophoresis and mass spectrometry. Clin. Exptl Metastasis. 2002;19:319–326
  49. Nakayama T, Taback B, Turner R, Morton DL, Hoon DSB. Molecular clonality of in-transit melanoma metastasis. Am. J. Pathol. 2001;158:1371–1378
  50. Massi D, Sardi I, Urso C, Franchi A, Borgognoni L, Salvador A, et al. Microsatellite analysis in cutaneous malignant melanoma. Melanoma Res. 2002;12:577–584
  51. Shih JY, Yang SC, Hong TM, Yuan A, Chen JJ, Yu CJ, et al. Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J. Natl Cancer Inst. 2001;93:1392–1400
  52. Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, et al. Molecular genetic analysis of malignant melanomas for aberrations of the Wnt signaling pathway genes CTNNB1, APC, ICAT and BTRC. Int. J. Cancer. 2002;100:549–556
  53. Goldberg SF, Miele ME, Hatta N, Takata M, Paquette-Straub CA, Freedman LP, et al. Melanoma metastasis suppression by chromosome 6: Evidence for a pathway regulated by CRSP3 and TXNIP. Cancer Res. 2003;63
  54. Gopalkrishnan RV, Kang DC, Fisher PB. Molecular markers and determinants of prostate cancer metastasis. J. Cell Physiol. 2001;189:245–256
  55. Welch DR, Wei LL. Genetic and epigenetic regulation of human breast cancer progression and metastasis. Endocrine-related Cancer. 1998;5:155–197
  56. Yoshida BA, Sokoloff M, Welch DR, Rinker-Schaeffer CW. Metastasis-suppressor genes: a review and perspective on an emerging field. J. Natl Cancer Inst. 2000;92:1717–1730
  57. Rinker-Schaeffer CW, Welch DR, Sokoloff M. Defining the biologic role of genes that regulate prostate cancer metastasis. Curr. Opin. Urol. 2001;10:397–401
  58. Luu HH, Zagaja GP, Dubauskas Z, Chen SL, Smith RC, Watabe K, et al. Identification of a novel metastasis-suppressor region on human chromosome 12. Cancer Res. 1998;58:3561–3565
  59. Kauffman EC, Robinson VL, Stadler WM, Sokoloff MH, Rinker-Schaeffer CW. Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J. Urol. 2003;169:1122–1133
  60. Chekmareva MA, Hollowell CMP, Smith RC, Davis EM, LeBeau MM, Rinker-Schaeffer CW. Localization of prostate cancer metastasis-suppressor activity on human chromosome 17. Prostate. 1997;33:271–280
  61. Fidler IJ, Radinsky R. Genetic control of cancer metastasis. J. Natl Cancer Inst. 1990;82:166–168
  62. Welch DR. Technical considerations for studying cancer metastasis in vivo. Clin. Exptl Metastasis. 1997;15:272–306
  63. Welch DR, Goldberg SF. Molecular mechanisms controlling human melanoma progression and metastasis. Pathobiology. 1997;65:311–330
  64. Welch DR, Chen P, Miele ME, McGary CT, Bower JM, Weissman BE, et al. Microcell-mediated transfer of chromosome 6 into metastatic human C8161 melanoma cells suppresses metastasis but does not inhibit tumorigenicity. Oncogene. 1994;9:255–262
  65. Miele ME, de la Rosa A, Lee JH, Hicks DJ, Dennis JU, Steeg PS, et al. Suppression of human melanoma metastasis following introduction of chromosome 6 is independent of NME1 (Nm23). Clin. Exptl Metastasis. 1997;15:259–265
  66. You J, Miele ME, Dong C, Welch DR. Suppression of human melanoma metastasis by introduction of chromosome 6 may be partially due to inhibition of motility, but not to inhibition of invasion. Biochem. Biophys. Res. Comm. 1995;208:476–484
  67. Goldberg SF, Harms JF, Quon K, Welch DR. Metastasis-suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clin. Exptl Metastasis. 1999;17:601–607
  68. Lee J-H, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J. Natl Cancer Inst. 1996;88:1731–1737
  69. Miele ME, Lee J-H, Robertson G, Coleman A, McGary CT, Fisher PB, et al. Metastasis is suppressed in human melanoma cell line MelJuSo following introduction of chromosomes 1 or 6 but tumorigenicity and local invasiveness are unaffected. Proc. Am. Assoc. Cancer Res. 1996;37:527
  70. Phillips KK, Welch DR, Miele ME, Lee J-H, Wei LL, Weissman BE. Suppression of MDA-MB-435 breast carcinoma cell metastasis following the introduction of human chromosome 11. Cancer Res. 1996;56:1222–1226
  71. Steeg PS, Bevilacqua G, Kopper L, Thorqeirsson UP, Talmadge JE, Liotta LA, et al. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl Cancer Inst. 1988;80:200–204
  72. Salerno M, Ouatas T, Palmieri D, Steeg PS. Inhibition of signal transduction by the nm23 metastasis suppressor: Possible mechanisms. Clin. Exptl Metastasis. 2003;20:3–10
  73. Lombardi D, Lacombe ML, Paggi MG. nm23: Unraveling its biological function in cell differentiation. J. Cell Physiol. 2000;182:144–149
  74. Otsuki Y, Tanaka M, Yoshii S, Kawazoe N, Nakaya K, Sugimura H. Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc. Natl Acad. Sci. 2001;98:4385–4390
  75. Postel EH, Berberich SJ, Flint SJ, Ferrone CA. Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science. 1993;261:478–480
  76. Wagner PD, Steeg PS, Vu ND. Two-component kinase-like activity of nm23 correlates with its motility-suppressing activity. Proc. Natl Acad. Sci. 1997;94:9000–9005
  77. Hartsough MT, Morrison DK, Salerno M, Palmieri D, Ouatas T, Mair M, et al. Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of ras via a histidine protein kinase pathway. J. Biol. Chem. 2002;277:32389–32399
  78. Steeg PS, Palmieri D, Ouatas T, Salerno M. Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer. Cancer Lett. 2003;190:1–12
  79. Hartsough MT, Clare SE, Mair M, Elkahloun AG, Sgroi D, Osborne CK, et al. Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition. Cancer Res. 2001;61:2320–2327
  80. Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J. Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell. 2003;112:659–672
  81. chikawa T, Ichikawa Y, Dong J, Hawkins AL, Griffin CA, Isaacs WB, et al. Localization of metastasis suppressor gene(s) for prostatic cancer to the short arm of human chromosome 11. Cancer Res. 1992;52:3486–3490
  82. Dong JT, Lamb PW, Rinker-Schaeffer CW, Vukanovic J, Ichikawa T, Isaacs JT, et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 1995;268:884–886
  83. Quinn CC, Gray GE, Hockfield S. A family of proteins implicated in axon guidance and outgrowth. J. Neurobiol. 1999;41:158–164
  84. Dong JT, Suzuki H, Pin SS, Bova GS, Schalken JA, Isaacs WB, et al. Down-regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelic loss. Cancer Res. 1996;56:4387–4390
  85. Yang XH, Welch DR, Phillips KK, Weissman BE, Wei LL. KAI1, a putative marker for metastatic potential in human breast cancer. Cancer Lett. 1997;119:149–155
  86. Phillips KK, White AE, Hicks DJ, Welch DR, Barrett JC, Wei LL, et al. Correlation between reduction of metastasis in the MDA-MB-435 model system and increased expression of the Kai-1 protein. Molec. Carcinog. 1998;21:111–120
  87. Takaoka A, Hinoda Y, Sato S, Itoh F, Adachi M, Hareyama M, et al. Reduced invasive and metastatic potentials of KAI1-transfected melanoma cells. Jpn. J. Cancer Res. 1998;89:397–404
  88. Takaoka A, Hinoda Y, Satoh S, Adachi Y, Itoh F, Adachi M, et al. Suppression of invasive properties of colon cancer cells by a metastasis suppressor KAI1 gene. Oncogene. 1998;16:1443–1453
  89. Duriez C, Falette N, Cortes U, Moyret-Lalle C, Puisieux A. Absence of p53-dependent induction of the metastatic suppressor KAI1 gene after DNA damage. Oncogene. 2000;19:2461–2464
  90. Mashimo T, Watabe M, Hirota S, Hosobe S, Miura K, Tegtmeyer PJ, et al. The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by p53. Proc. Natl Acad. Sci. 1998;95:11307–11311
  91. Sekita N, Suzuki H, Ichikawa T, Kito H, Akakura K, Igarashi T, et al. Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines. Jpn. J. Cancer Res. 2001;92:947–951
  92. Odintsova E, Sugiura T, Berditchevski F. Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1. Curr. Biol. 2000;10:1009–1012
  93. Delaguillaumie A, Lagaudriere-Gesbert C, Popoff MR, Conjeaud H. Rho GTPases link cytoskeletal rearrangements and activation processes induced via the tetraspanin CD82 in T lymphocytes. J. Cell Sci. 2002;115:433–443
  94. Lynch HT, Casey MJ, Lynch J, White TEK, Godwin AK. Genetics and ovarian carcinoma. Sem. Oncol. 1998;25:265–280
  95. Lee J-H, Welch DR. Identification of highly expressed genes in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int. J. Cancer. 1997;71:1035–1044
  96. Lee J-H, Welch DR. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 1997;57:2384–2387
  97. Goldberg SF, Miele ME, Paquette CA, Welch DR. Identifying metastasis suppressor genes in human melanoma. Anticancer Res. 2001;
  98. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J. Biol. Chem. 2001;276:34631–34636
  99. Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, et al. AXOR12: a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J. Biol. Chem. 2001;276:28969–28975
  100. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al. Metastasis suppressor gene KiSS1 encodes peptide ligand of a G-protein-coupled receptor. Nature (London). 2001;411:613–617
  101. Ringel MD, Hardy E, Bernet VJ, Burch HB, Schuppert F, Burman KD, et al. Metastin receptor Is overexpressed in papillary thyroid cancer and activates MAP Kinase in thyroid cancer cells. J. Clin. Endocrin. Metab. 2002;87:2399
  102. Stafford LJ, Xia CZ, Ma WB, Cai Y, Liu MY. Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer Res. 2002;62:5399–5404
  103. Yan CH, Wang H, Boyd DD. KiSS-1 represses 92kDa type IV collagenase expression by down- regulating NFκB binding to the promoter as a consequence of IκB α-induced block of p65/p50 nuclear translocation. J. Biol. Chem. 2001;276:1164–1172
  104. Janneau JL, Maldonado-Estrada J, Tachdjian G, Miran I, Motte N, Saulnier P, et al. Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells. J. Clin. Endocrin. Metab. 2002;87:5336–5339
  105. Shirasaki F, Takata M, Hatta N, Takehara K. Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res. 2001;61:7422–7425
  106. Chen KS, DeLuca HF. Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim. Biophys. Acta. 1994;1219:26–32
  107. Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Ann. Rev. Immunol. 1997;15:351–369
  108. Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, et al. Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J. Biol. Chem. 1999;274:21645–21650
  109. Yamanaka H, Maehira F, Oshiro M, Asato T, Yanagawa Y, Takei H, et al. A possible interaction of thioredoxin with VDUP1 in HeLa cells detected in a yeast two-hybrid system. Biochem. Biophys. Res. Comm. 2000;271:796–800
  110. Saitoh T, Tanaka S, Koike T. Rapid induction and Ca(2+) influx-mediated suppression of vitamin D3 up- regulated protein 1 (VDUP1) mRNA in cerebellar granule neurons undergoing apoptosis. J. Neurochem. 2001;78:1267–1276
  111. Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J. Immunol. 2000;164:6287–6295
  112. Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA, Marks PA, et al. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc. Natl Acad. Sci. 2002;99:11700–11705
  113. Naar AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R. Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature (London). 1999;398:828–832
  114. Taatjes DJ, Naar AM, Andel F, Nogales E, Tjian R. Structure, function, and activator-induced conformations of the CRSP coactivator. Science. 2002;295:1058–1062
  115. Ryu S, Zhou S, Ladurner AG, Tjian R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature (London). 1999;397:446–450
  116. Jiang YF, Goldberg ID, Shi YE. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene. 2002;21:2245–2252
  117. Chang C, Werb Z. The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol. 2001;11:S37–S43
  118. Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, et al. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int. J. Cancer. 2002;97:425–431
  119. Ylisirnio S, Hoyhtya M, Makitaro R, Paaakko P, Risteli J, Kinnula VL, et al. Elevated serum levels of type I collagen degradation marker ICTP and tissue inhibitor of metalloproteinase (TIMP) 1 are associated with poor prognosis in lung cancer. Clin. Cancer Res. 2001;7:1633–1637
  120. Pellegrini P, Contasta I, Berghella AM, Gargano E, Mammarella C, Adorno D. Simultaneous measurement of soluble carcinoembryonic antigen and the tissue inhibitor of metalloproteinase TIMP1 serum levels for use as markers of pre-invasive to invasive colorectal cancer. Cancer Immunol. Immunother. 2000;49:388–394
  121. Ylisirnio S, Hoyhtya M, Turpeenniemi-Hujanen T. Serum matrix metalloproteinases -2, -9 and tissue inhibitors of metalloproteinases -1, -2 in lung cancer—TIMP-1 as a prognostic marker. Anticancer Res. 2000;20:1311–1316
  122. Blavier L, Henriet P, Imren S, DeClerck YA. Tissue inhibitors of matrix metalloproteinases in cancer. Ann. NY Acad. Sci. 1999;878:108–119
  123. Mareel M, Boterberg T, Noe V, van Hoorde L, Vermeulen S, Bruyneel E, et al. E-cadherin/catenin/cytoskeleton complex: a regulator of cancer invasion. J. Cell Physiol. 1997;173:271–274
  124. Vermeulen SJ, Bruyneel EA, Bracke ME, De Bruyne GK, Vennekens KM, Vleminckx KL, et al. Transition from the noninvasive to the invasive phenotype and loss of α-catenin in human colon cancer cells. Cancer Res. 1995;55:4722–4728
  125. Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J. Cell Biol. 1991;113:173–185
  126. Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature (London). 1998;392:190–193
  127. Christofori G, Semb H. The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem. Sci. 1999;24:73–76
  128. Beavon IRG. The E-cadherin–catenin complex in tumour metastasis: structure, function and regulation. Eur. J. Cancer. 2000;36:1607–1620
  129. Nakayama S, Sasaki A, Mese H, Alcalde RE, Tsuji T, Matsumura T. The E-cadherin gene is silenced by CpG methylation in human oral squamous cell carcinomas. Int. J. Cancer. 2001;93:667–673
  130. Jiang WG. E-cadherin and its associated protein catenins, cancer invasion and metastasis. Br. J. Surg. 1996;83:437–446
  131. Shiozaki H, Oka H, Inoue M, Tamura S, Monden M. E-cadherin mediated adhesion system in cancer cells. Cancer. 1996;77:1605–1613
  132. Nam JS, Ino Y, Sakamoto M, Hirohashi S. Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. Clin. Cancer Res. 2002;8:2430–2436
  133. Berx G, Cleton-Jansen AM, Strumane K, De Leeuw WJF, Nollet F, Van Roy F, et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene. 1996;13:1919–1925
  134. Cavallaro U, Christofori G. Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim. Biophys. Acta Rev. Cancer. 2001;1552:39–45
  135. Kashima T, Nakamura K, Kawaguchi J, Takanashi M, Ishida T, Aburatani H, et al. Overexpression of cadherins suppresses pulmonary metastasis of osteosarcoma in vivo. Int. J. Cancer. 2003;104:147–154
  136. Nieman MT, Prudoff RS, Johnson KR, Wheelock MJ. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J. Cell Biol. 1999;147:631–643
  137. Tran NL, Nagle RB, Cress AE, Heimark RL. N-Cadherin expression in human prostate carcinoma cell lines, an epithelial-mesenchymal transformation mediating adhesion with stromal cells. Am. J. Pathol. 1999;155:787–798
  138. Pishvaian MJ, Feltes CM, Thompson P, Bussemakers MJ, Schalken JA, Byers SW. Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res. 1999;59:947–952
  139. Li G, Satyamoorthy K, Herlyn M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res. 2001;61:3819–3825
  140. Hazan RB, Phillips GR, Qiao RF, Norton L, Aaronson SA. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J. Cell Biol. 2000;148:779–790
  141. Teng DHF, Perry WL, Hogan JK, Baumgard M, Bell R, Berry S, et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 1997;57:4177–4182
  142. Yoshida BA, Dubauskas Z, Chekmareva MA, Christiano TR, Stadler WM, Rinker-Schaeffer CW. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. 1999;59:5483–5487
  143. Kim HL, Van der Griend DJ, Yang X, Benson DA, Dubauskas Z, Yoshida BA, et al. Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res. 2001;61:2833–2837
  144. Yamada SD, Hickson JA, Hrobowski Y, VanderGriend DJ, Benson D, Montag A, et al. Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Cancer Res. 2002;62:6717–6723
  145. Seraj MJ, Samant RS, Verderame MF, Welch DR. Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res. 2000;60:2764–2769
  146. Shevde LA, Samant RS, Goldberg SF, Sikaneta T, Alessandrini A, Donahue HJ, et al. Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1. Exp. Cell Res. 2002;273:229–239
  147. Samant RS, Debies MT, Shevde LA, Verderame MF, Welch DR. Identification and characterization of murine ortholog (Brms1) of breast cancer metastasis suppressor 1 (BRMS1). Int. J. Cancer. 2002;97:15–20
  148. Samant RS, Seraj MJ, Saunders MM, Sakamaki T, Shevde LA, Harms JF, et al. Analysis of mechanisms underlying BRMS1 suppression of metastasis. Clin. Exptl Metastasis. 2001;18:683–693
  149. Saunders MM, Seraj MJ, Li ZY, Zhou ZY, Winter CR, Welch DR, et al. Breast cancer metastatic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication. Cancer Res. 2001;61:1765–1767
  150. Li Z, Zhou Z, Saunders MM, Casey G, Welch DR, Donahue HJ. Connexin and osteopontin expression correlate with breast cancer metastatic potential. Proc. Am. Assoc. Cancer Res. 2001;42
  151. Seraj MJ, Harding MA, Gildea JJ, Welch DR, Theodorescu D. The relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines. Clin. Exptl Metastasis. 2001;18:519–525
  152. Hunter KW, Broman KW, LeVoyer T, Lukes L, Cozma D, Debies MT, et al. Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1. Cancer Res. 2001;61:8866–8872
  153. LeVoyer T, Lifsted T, Williams M, Hunter K. era of hope—Department of Defense Breast Cancer Research Program. era of hope—Department of Defense Breast Cancer Research Program. Vol. 2. 2000; p. 625
  154. Park YG, Lukes L, Yang H, Debies MT, Samant RS, Welch DR, et al. Comparative sequence analysis in eight inbred strains of the metastasis modifier QTL candidate gene Brms1. Mamm. Genome. 2002;13:289–292
  155. Lin X, Tombler E, Nelson PJ, Ross M, Gelman IH. A novel src- and ras-suppressed protein kinase C substrate associated with cytoskeletal architecture. J. Biol. Chem. 1996;271:28430–28438
  156. Gelman IH. The role of SSeCKS/gravin/AKAP12 scaffolding proteins in the spaciotemporal control of signaling pathways in oncogenesis and development. Front. Biosci. 2002;7:d1782–d1797
  157. Nauert JB, Klauck TM, Langeberg LK, Scott JD. Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr. Biol. 1997;7:52–62
  158. Nelson PJ, Gelman IH. Cell-cycle regulated expression and serine phosphorylation of the myristylated protein kinase C substrate, SSeCKS: correlation with culture confluency, cell cycle phase and serum response. Mol. Cell. Biochem. 1997;175:233–241
  159. Lin X, Nelson P, Gelman IH. SSeCKS, a major protein kinase C substrate with tumor suppressor activity, regulates G(1)→S progression by controlling the expression and cellular compartmentalization of cyclin D. Molec. Cell. Biol. 2000;20:7259–7272
  160. Xia W, Unger P, Miller L, Nelson J, Gelman IH. The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer Res. 2001;61:5644–5651
  161. Boettner B, VanAelst L. The role of Rho GTPases in disease development. Gene. 2002;286:155–174
  162. Gildea JJ, Seraj MJ, Oxford G, Harding MA, Hampton GM, Moskaluk CA, et al. RhoGD12 is an invasion and metastasis suppressor gene in human cancer. Cancer Res. 2002;62:6418–6423
  163. van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, et al. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms. Lab. Invest. 1997;77:85–92
  164. Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res. 1998;58:4439–4444
  165. Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 2000;60:749–755
  166. Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, et al. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 2003;63
  167. Agarwala KL, Kokame K, Kato H, Miyata T. Phosphorylation of RTP, an ER stress-responsive cytoplasmic protein. Biochem. Biophys. Res. Comm. 2000;272:641–647
  168. Motwani M, Sirotnak FM, She Y, Commes T, Schwartz GK. Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells. Cancer Res. 2002;62:3950–3955
  169. Castellani V, Rougon G. Control of semaphorin signaling. Curr. Opin. Neurobiol. 2002;12:532–541
  170. Dickson BJ. Molecular mechanisms of axon guidance. Science. 2002;298:1959–1964
  171. Goshima Y, Ito T, Sasaki Y, Nakamura F. Semaphorins as signals for cell repulsion and invasion. J. Clin. Invest. 2002;109:993–998
  172. Comoglio PM, Trusolino L. Invasive growth: from development to metastasis. J. Clin. Invest. 2002;109:857–862
  173. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature (London). 1997;387:921–924
  174. Fujita H, Okada F, Hamada J, Hosokawa M, Moriuchi T, Koya RC, et al. Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect. Int. J. Cancer. 2001;93:773–780
  175. Tanaka M, Müllauer L, Ogiso Y, Fujita H, Moriya S, Furuuchi K, et al. Gelsolin: a candidate for suppressor of human bladder cancer. Cancer Res. 1995;55:3228–3232
  176. Sagawa N, Fujita H, Banno Y, Nozawa Y, Katoh H, Kuzumaki N. Gelsolin suppresses tumorigenicity through inhibiting PKC activation in a human lung cancer cell line, PC10. Br. J. Cancer. 2003;88:606–612
  177. Zou Z, Anisowicz A, Hendrix MJC, Thor A, Neveu M, Sheng S, et al. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science. 1994;263:526–529
  178. Reddy KB, McGowen R, Schuger L, Visscher D, Sheng SJ. Maspin expression inversely correlates with breast tumor progression in MMTV/TGF-alpha transgenic mouse model. Oncogene. 2001;20:6538–6543
  179. Jiang N, Meng YH, Zhang SL, Mensah-Osman E, Sheng SJ. Maspin sensitizes breast carcinoma cells to induced apoptosis. Oncogene. 2002;21:4089–4098
  180. Zhang M, Volpert O, Shi YH, Bouck N. Maspin is an angiogenesis inhibitor. Nature Med. 2000;6:196–199
  181. Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, et al. Role for DNA methylation in the control of cell type-specific maspin expression. Nat. Genet. 2002;31:175–179
  182. Costello JF, Vertino PM. Methylation matters: a new spin on maspin. Nat. Genet. 2002;31:123–124
  183. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, et al. p53 regulates the expression of the tumor suppressor gene maspin. J. Biol. Chem. 2000;275:6051–6054
  184. Kirschmann DA, Lininger RA, Gardner LMG, Seftor EA, Odero VA, Ainsztein AM, et al. Down-regulation of HP1Hs1 expression is associated with the metastatic phenotype in breast cancer. Cancer Res. 2000;60:3359–3363
  185. Gao AC, Lou W, Dong JT, Isaacs JT. CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. Cancer Res. 1997;57:846–849
  186. Yu DH, Qu CK, Henegariu O, Lu X, Feng GS. Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J. Biol. Chem. 1998;273:21125–21131
  187. Chekmareva MA, Kadkhodaian MM, Hollowell CMP, Kim H, Yoshida BA, Luu HH, et al. Chromosome 17-mediated dormancy of AT6.1 prostate cancer micrometastases. Cancer Res. 1998;58:4963–4969
  188. Steeg PS, Ouatas T, Halverson D, Palmieri D, Salerno M. Metastasis suppressor genes: Basic biology and potential clinical use. Clin. Breast Cancer. 2003; in press
  189. Zimmer SG, Graff JR. The emerging role for the mRNA cap-binding protein, EIF-4E, in metastatic progression. In:  Welch DR editors. Cancer Metastasis: Biology and Treatment. Dordrecht: Kluwer Academic Publishers; 2002;p. 257–278
  190. Graff JR, Zimmer SG. Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. Clin. Exptl Metastasis. 2003;20:265–273
  191. Plass C, Soloway PD. DNA methylation imprinting and cancer. Eur. J. Hum. Genet. 2002;10:6–16
  192. Plass C. Cancer epigenomics. Hum. Molec. Genet. 2002;11:2479–2488
  193. Imhof A, Becker PB. Modifications of the histone N-terminal domains, evidence for an epigenetic code?. Mol. Biotechnol. 2001;17:1–13
  194. Karpf AR, Jones DA. Reactivating the expression of methylation silenced genes in human cancer. Oncogene. 2002;21:5496–5503
  195. Kelly WK, O'Connor OA, Marks PA. Histone deacetylase inhibitors: from target to clinical trials. Expert Opin. Investig. Drugs. 2002;11:1695–1713
  196. Elledge RM, Lee WH. Life and death by p53. BioEssays. 1995;17:923–930
  197. Mabjeesh NJ, Post DE, Willard MT, Kaur B, VanMeir EG, Simons JW, et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 2002;62:2478–2482
  198. Ouatas T, Halverson D, Steeg PS. Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor expression in metastatic human breast carcinoma cells via glucocorticoid receptor-dependent, transcriptional and post-transcriptional mechanisms: new uses for old compounds, Clin. Cancer Res. 2003; in press
  199. Desprez PY, Lin CQ, Thomasset N, Sympson CJ, Bissell MJ, Campisi J. Novel pathway for mammary epithelial cell invasion induced by the helix-loop-helix protein Id-1. Mol. Cell. Biol. 1998;18:4577–4588
  200. Singh J, Murata K, Itahana Y, Desprez PY. Constitutive expression of the Id-1 promoter in human metastatic breast cancer cells is linked with the loss of NF-1/Rb/HDAC-1 transcription repressor complex. Oncogene. 2002;21:1812–1822
  201. Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines, cDNA cloning, expression, and protein analyses. J. Biol. Chem. 1994;269:22958–22963
  202. Nicolson GL, Nawa A, Toh Y, Taniguchi S, Nishimori K, Moustafa A. Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. Clin. Exptl Metastasis. 2003;20:19–24

PII: S0304-3835(03)00304-5

doi: 10.1016/S0304-3835(03)00304-5

Cancer Letters
Volume 198, Issue 1 , Pages 1-20 , 30 July 2003