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

6 - The Role of Metastasis Suppressor Genes in Metastasis

from GENES

Summary

In the 1970s and 1980s, clever scientific insight and innovation rapidly advanced our understanding of the molecular mechanisms of cancer biology. The discoveries of oncogenes and tumor suppressors, and the elucidation of their functions, greatly aided in studies aimed at a molecular understanding of the etiology of primary tumors. Despite this, cancer biologists had little understanding of the molecular aspects of metastasis. Considering the devastating consequences, scientists were anxious for a breakthrough. The first clue would come from the study of tumor suppressors.

Tumor suppressor genes were identified when it was discovered that their loss of function was critical to tumorigenesis. Prior to their discovery, researchers were of the mindset that the oncogenic phenotype was always dominant. In other words, a mutation need happen on only a single allele for a normal cell to be transformed into a tumor cell. However, not all disease incidence data seemed to fit neatly into this hypothesis. By studying retinoblastoma case histories, a “two-hit” hypothesis emerged, predicting that for at least some cancers, two mutations must occur (one on each allele) to successfully transform a cell [1]. Indeed, the retinoblastoma gene, or Rb, would become known as the first described tumor suppressor. We now know that the “two hits” need not come in the form of distinct somatic mutations but may be the result of any combination of germinal and/or somatic mutations, mitotic recombinations, gene conversions, and functional inactivation of genes owing to promoter hypermethylation.

References
Knudson, AG. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 68: 820–3.
Steeg, PS, Bevilacqua, G, Pozzatti, R, Liotta, , Sobel, ME (1988) Altered expression of NM23, a gene associated with low tumor metastatic potential, during adenovirus 2 Ela inhibition of experimental metastasis. Cancer Res. 48: 6550–4.
Steeg, PS, Bevilacqua, G, Kopper, L et al. (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst. 80: 200–4.
Leone, A, Flatow, U, King, CR et al. (1991) Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell. 65: 25–35.
Leone, A, Flatow, U, VanHoutte, K, Steeg, PS (1993) Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene. 8: 2325–33.
McNeill, CA, Brown, RL (1980) Genetic manipulation by means of microcell-mediated transfer of normal human chromosomes into recipient mouse cells. Proc Natl Acad Sci USA. 77: 5394–8.
Welch, DR (1997) Technical considerations for studying cancer metastasis in vivo. Clin Exp Metastasis. 15: 272–306.
Steeg, PS (2003) Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 3: 55–63.
Steeg, PS, Bevilacqua, G, Kopper, L et al. (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst. 80: 200–4.
Steeg, P (2003) Metastasis suppressors alter the signal transduction of cancer cells. Nature Cancer Rev. 3: 55–63.
Rinker-Schaeffer, CW, O'Keefe, JP, Welch, DR, Theodorescu, D (2006) Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clin Cancer Res. 12: 3882–9.
Parhar, RS, Shi, Y, Zou, M, Farid, NR, Ernst, P, al-Sedairy, ST (1995) Effects of cytokine-mediated modulation of nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. Int J Cancer. 60: 204–10.
Lee, HY, Lee, H (1999) Inhibitory activity of nm23-H1 on invasion and colonization of human prostate carcinoma cells is not mediated by its NDP kinase activity. Cancer Lett. 145: 93–9.
Tagashira, H, Hamazaki, K, Tanaka, N, Gao, C, Namba, M (1998) Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform. Int J Mol Med. 2: 65–8.
Bhujwalla, ZM, Aboagye, EO, Gillies, RJ, Chacko, VP, Mendola, CE, Backer, JM (1999) Nm23-transfected MDA-MB-435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: a 31P nuclear magnetic resonance study in vivo and in vitro. Magn Reson Med. 41: 897–903.
Miyazaki, H, Fukuda, M, Ishijima, Y et al. (1999) Overexpression of Nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clin Cancer Res. 5: 4301–7.
Boissan, M, Wendum, D, Arnaud-Dabernat, S, et al. (2005) Increased lung metastasis in transgenic NM23-Null/SV40 mice with hepatocellular carcinoma. J Natl Cancer Inst. 97: 836–45.
Lacombe, ML, Milon, L, Munier, A, Mehus, JG, Lambeth, (2000) The human Nm23/nucleoside diphosphate kinases. J Bioenerg Biomembr. 32: 247–58.
McDermott, WG, Boissan, M, Lacombe, ML, Steeg, PS, Horak, CE (2008) Nm23-H1 homologs suppress tumor cell motility and anchorage independent growth. Clin Exp Metastasis. 25: 131–8.
Hartsough, MT, Morrison, DK, Salerno, M et al. (2002) Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem. 277: 32389–99.
Aguirre-Ghiso, JA, Estrada, Y, Liu, D, Ossowski, L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res. 63: 1684–95.
Aguirre-Ghiso, JA, Ossowski, L, Rosenbaum, SK (2004) Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res. 64: 7336–45.
Ranganathan, AC, Adam, AP, Aguirre-Ghiso, JA (2006) Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy. Cell Cycle. 5: 1799–807.
Steeg, PS, Horak, CE, Miller, KD (2008) Clinical-translational approaches to the Nm23-H1 metastasis suppressor. Clin Cancer Res. 14: 5006–12.
Horak, CE, Lee, JH, Elkahloun, AG et al. (2007) Nm23-H1 suppresses tumor cell motility by down-regulating the lysophosphatidic acid receptor EDG2. Cancer Res. 67: 7238–46.
Horak, CE, Mendoza, A, Vega-Valle, E et al. (2007) Nm23-H1 suppresses metastasis by inhibiting expression of the lysophosphatidic acid receptor EDG2. Cancer Res. 15;67(24):11751–9.
Ouatas, T, Halverson, D, Steeg, PS (2003) Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds. Clin Cancer Res. 9: 3763–72.
Ohtaki, T, Shintani, Y, Honda, S et al. (2001) Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 411: 613–7.
Kotani, M, Detheux, M, Vandenbogaerde, A et al. (2001) The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 276: 34631–6.
Castellano, JM, Roa, J, Luque, RM et al. (2008) KiSS-1/kisspeptins and the metabolic control of reproduction: Physiologic roles and putative physiopathological implications. Peptides. 30(1): 139–45.
Nash, KT, Phadke, PA, Navenot, JM et al. (2007) Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. J Natl Cancer Inst. 99: 309–21.
Ichikawa, T, Ichikawa, Y, Isaacs, JT (1991) Genetic factors and metastatic potential of prostatic cancer. Cancer Surv. 11: 35–42.
Takahashi, M, Sugiura, T, Abe, M, Ishii, K, Shirasuna, K (2007) Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int J Cancer. 121: 1919–29.
Bandyopadhyay, S, Zhan, R, Chaudhuri, A et al. (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med. 12: 933–8.
Prince, S, Carreira, S, Vance, KW, Abrahams, A, Goding, CR. (2004) Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor. Cancer Res. 64: 1669–74.
Tsai, YC, Mendoza, A, Mariano, JM et al. (2007) The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nat Med. 13: 1504–9.
Sridhar, SC, Miranti, CK (2006) Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases. Oncogene. 25: 2367–78.
Chekmareva, MA, Hollowell, CM, Smith, RC, Davis, EM, LeBeau, MM, Rinker-Schaeffer, CW (1997) Localization of prostate cancer metastasis-suppressor activity on human chromosome 17. Prostate. 33: 271–80.
Vander Griend, DJ, Kocherginsky, M, Hickson, JA, Stadler, WM, Lin, A, Rinker-Schaeffer, CW (2005) Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res. 65: 10984–91.
Yamada, SD, Hickson, JA, Hrobowski, Y et al. (2002) Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Cancer Res. 62: 6717–23.
Hickson, JA, Huo, D, Vander Griend, DJ, Lin, A, Rinker-Schaeffer, CW, Yamada, SD (2006) The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer Res. 66: 2264–70.
Chang, L, Karin, M (2001) Mammalian MAP kinase signalling cascades. Nature. 410: 37–40.
Whitmarsh, AJ, Davis, RJ (2007) Role of mitogen-activated protein kinase kinase 4 in cancer. Oncogene. 26: 3172–84.
Teng, DH, Perry, WL, Hogan, JK et al. (1997) Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res. 57: 4177–82.
Su, GH, Song, JJ, Repasky, EA, Schutte, M, Kern, SE (2002) Mutation rate of MAP2K4/MKK4 in breast carcinoma. Human Mutation. 19: 81.
Su, GH, Hilgers, W, Shekher, MC et al. (1998) Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 58: 2339–42.
Xin, W, Yun, KJ, Ricci, F et al. (2004) MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course. Clin Cancer Res. 10: 8516–20.
Cunningham, SC, Kamangar, F, Kim, MP et al. (2006) MKK4 status predicts survival after resection of gastric adenocarcinoma. Arch Surg. 141: 1095–9; discussion 1100.
Stark, AM, Tongers, K, Maass, N, Mehdorn, HM, Held-Feindt, J (2005) Reduced metastasis-suppressor gene mRNA-expression in breast cancer brain metastases. J Cancer Res Clin Oncol. 131: 191–8.
Kim, HL, Vander Griend, DJ, Yang, X et al. (2001) Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res. 61: 2833–7.
Kennedy, NJ, Davis, RJ (2003) Role of JNK in tumor development. Cell Cycle. 2: 199–201.
Wang, L, Pan, Y, Dai, JL (2004) Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors. Oncogene. 7: 7.
Cunningham, SC, Gallmeier, E, Hucl, T et al. (2006) Targeted deletion of MKK4 in cancer cells: a detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss. Cancer Res. 66: 5560–4.
Lotan, TL, Lyon, M, Huo, D et al. (2007) Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. J Pathol. 212: 386–94.
Lotan, T, Hickson, J, Souris, J et al. (2008) JNKK1/MKK4 mediated inhibition of SKOV3ip.1 ovarian cancer metastasis involves growth arrest and p21 upregulation. Cancer Res. 1;68(7):2166–75.
Seraj, MJ, Samant, RS, Verderame, MF, Welch, DR (2000) Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res. 60: 2764–9.
Shevde, , Samant, RS, Goldberg, SF et al. (2002) Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1. Exp Cell Res. 273: 229–39.
Seraj, MJ, Harding, MA, Gildea, JJ, Welch, DR, Theodorescu, D (2000) The relationship of BRMS1 and RhoGDI2 gene expression to metastatic potential in lineage related human bladder cancer cell lines. Clin Exp Metastasis. 18: 519–25.
Saunders, MM, Seraj, MJ, Li, Z et al. Breast cancer metastatic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication. Cancer Res 2001) 61: 1765–7.
Hedley, BD, Vaidya, KS, Phadke, P et al. (2008) BRMS1 suppresses breast cancer metastasis in multiple experimental models of metastasis by reducing solitary cell survival and inhibiting growth initiation. Clin Exp Metastasis. 25(7):727–40.
DeWald, DB, Torabinejad, J, Samant, RS et al. (2005) Metastasis suppression by breast cancer metastasis suppressor 1 involves reduction of phosphoinositide signaling in MDA-MB-435 breast carcinoma cells. Cancer Res. 65: 713–7.
Zhang, S, Lin, QD, Di, W (2006) Suppression of human ovarian carcinoma metastasis by the metastasis-suppressor gene, BRMS1. Int J Gynecol Cancer. 16: 522–31.
Vaidya, KS, Harihar, S, Phadke, PA et al. (2008) Breast cancer metastasis suppressor-1 differentially modulates growth factor signaling. J Biol Chem. 283: 28354–60.
Hurst, DR, Xie, Y, Vaidya, KS et al. (2008) Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells. J Biol Chem. 283: 7438–44.
Gildea, JJ, Seraj, MJ, Oxford, G et al. (2002) RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res. 62: 6418–23.
Titus, B, Frierson, HF., Conaway, M et al. (2005) Endothelin axis is a target of the lung metastasis suppressor gene RhoGDI2. Cancer Res. 65: 7320–7.
Chiappori, AA, Haura, E, Rodriguez, FA et al. (2008) Phase I/II study of atrasentan, an endothelin A receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer. Clin Cancer Res. 14: 1464–9.
Hagan, S, Al-Mulla, F, Mallon, E et al. (2005) Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Clin Cancer Res. 11: 7392–7.
Fu, Z, Smith, PC, Zhang, L et al. (2003) Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst. 95: 878–89.
Keller, ET (2004) Metastasis suppressor genes: a role for raf kinase inhibitor protein (RKIP). Anticancer Drugs. 15: 663–9.
Chatterjee, D, Bai, Y, Wang, Z et al. (2004) RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J Biol Chem. 279: 17515–23.
Zlobec, I, Baker, K, Minoo, P, Jass, JR, Terracciano, L, Lugli, A (2008) Node-negative colorectal cancer at high risk of distant metastasis identified by combined analysis of lymph node status, vascular invasion, and Raf-1 kinase inhibitor protein expression. Clin Cancer Res. 14: 143–8.
Granovsky, AE, Rosner, MR (2008) Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor. Cell Res. 18: 452–7.
Iizumi, M, Bandyopadhyay, S, Watabe, K. Interaction of Duffy antigen receptor for chemokines and Kai1: a critical step in metastasis suppression. Cancer Res. 67: 1411–14.
Eves, EM, Shapiro, P, Naik, K, Klein, UR, Trakul, N, Rosner, MR (2006) Raf kinase inhibitory protein regulates aurora B kinase and the spindle checkpoint. Mol Cell 23: 561–74.
Fu, Z, Smith, PC, Zhang, L, Rubin, MA, Dunn, RL, Yao, Z, Keller, ET (2003) Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J Natl Cancer Inst 95: 878–89.
Schuierer, MM, Bataille, F, Hagan, S, Kolch, W, Bosserhoff, AK (2004) Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. Cancer Res 64: 5186–92.
Rodrigues, S, Wever, O, Bruyneel, E, Rooney, RJ, Gespach, C (2007) Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis. Oncogene 26: 5615–25.
Stupack, DG, Teitz, T, Potter, MD, Mikolon, D, Houghton, PJ, Kidd, VJ, Lahti, JM, Cheresh, DA (2006) Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439: 95–99.
Fujita, H, Okada, F, Hamada, J, Hosokawa, M, Moriuchi, T, Koya, RC, Kuzumaki, N (2001) Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect. Int J Cancer 93: 773–80.
Kippenberger, S, Loitsch, S, Thaci, D, Muller, J, Guschel, M, Kaufmann, R, Bernd, A (2006) Restoration of E-cadherin sensitizes human melanoma cells for apoptosis. Melanoma Res 16: 393–403.
Michl, P, Barth, C, Buchholz, M, Lerch, MM, Rolke, M, Holzmann, KH, Menke, A, Fensterer, H, Giehl, K, Lohr, M, et al. (2003) Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res 63: 6265–71.
Gao, AC, Lou, W, Dong, JT, Isaacs, JT (1997) CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p13. Cancer Res 57: 846–9.
Gao, AC, Lou, W, Sleeman, JP, Isaacs, JT (1998) Metastasis suppression by the standard CD44 isoform does not require the binding of prostate cancer cells to hyaluronate. Cancer Res 58: 2350–2.
Sato, S, Miyauchi, M, Kato, M, Kitajima, S, Kitagawa, S, Hiraoka, M, Kudo, Y, Ogawa, I, Takata, T (2004) Upregulated CD44v9 expression inhibits the invasion of oral squamous cell carcinoma cells. Pathobiology 71: 171–5.
Sato, S, Miyauchi, M, Ogawa, I, Kudo, Y, Kitagawa, S, Hiraoka, M, Takata, T (2003) Inhibition of CD44v9 upregulates the invasion ability of oral squamous cell carcinoma cells. Oral Oncol 39: 27–30.