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Metastasis suppressors alter the signal transduction of cancer cells - Nature Reviews Cancer

  • ️Steeg, Patricia S.
  • ️Wed Jan 01 2003
  • Fidler, I. Critical determinants of metastasis. Semin. Cancer Biol. 12, 89–96 (2002).

    PubMed  Google Scholar 

  • Pozzatti, R. et al. Primary rat embryo cells transformed by one or two oncogenes show different metastatic potentials. Science 232, 223–227 (1986).

    CAS  PubMed  Google Scholar 

  • Wylie, A. et al. Rodent fibroblast tumors expressing human myc and ras genes: growth, metastasis and endogenous oncogene expression. Br. J. Cancer 56, 251–259 (1987).

    Google Scholar 

  • Chambers, A., Groom, A. & MacDonald, I. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).

    CAS  Google Scholar 

  • Chambers, A. et al. Critical steps in hematogenous metastsis: an overview. Surg. Oncol. Clin. N. Am. 10, 243–255 (2001).

    CAS  PubMed  Google Scholar 

  • Chambers, A., Naumov, G., Vantyghem, S. & Tuck, A. Molecular biology of breast cancer metastasis: clinical implications of experimental studies on metastatic inefficiency. Breast Cancer Res. 2, 400–407 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshida, B., Sokoloff, M., Welch, D. & Rinker-Schaeffer, C. Metastasis-suppressor genes: a review and perspective on an emerging field. J. Natl Cancer Inst. 92, 1717–1730 (2000).

    CAS  PubMed  Google Scholar 

  • OkabeKado, J. et al. Inhibitory actions of nm23 proteins on induction of erythroid differentiation of human leukemia cells. Biochim. Biophys. Acta 1267, 101–106 (1995).

    Google Scholar 

  • Shinohara, T. et al. Transduction of KAI1/CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice. Int. J. Cancer 94, 16–23 (2001).

    CAS  PubMed  Google Scholar 

  • Heimann, R., Ferguson, D. & Hellman, S. The relationship between nm23, angiogenesis, and the metastatic proclivity of node-negative breast cancer. Cancer Res. 58, 2766–2771 (1998).

    CAS  PubMed  Google Scholar 

  • Schindl, M., Birner, P., Breitnecker, G. & Oberhuber, G. Downregulation of KAI1 metastasis suppressor protein is associated with a dismal prognosis in epithelial ovarian cancer. Gyn. Oncol. 83, 244–248 (2001).

    CAS  Google Scholar 

  • Steeg, P. S. et al. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl Cancer Inst. 80, 200–204 (1988).

    CAS  PubMed  Google Scholar 

  • Dearolf, C., Tripoulas, N., Biggs, J. & Shearn, A. Molecular consequences of awdb3, a cell autonomous lethal mutation of Drosophila induced by hybrid dysgenesis. Dev. Biol. 129, 169–178 (1988).

    CAS  PubMed  Google Scholar 

  • Dearolf, C., Hersperger, E. & Shearn, A. Developmental consequences of awdb3, a cell autonomous lethal mutation of Drosophila induced by hybrid dysgenesis. Dev. Biol. 129, 159–168 (1988).

    CAS  PubMed  Google Scholar 

  • Kantor, J. D., McCormick, B., Steeg, P. S. & Zetter, B. R. Inhibition of cell motility after nm23 transfection of human and murine tumor cells. Cancer Res. 53, 1971–1973 (1993).

    CAS  PubMed  Google Scholar 

  • Leone, A., Flatow, U., VanHoutte, K. & Steeg, P. S. 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, 2325–2333 (1993).

    CAS  PubMed  Google Scholar 

  • Howlett, A. R., Petersen, O. W., Steeg, P. S. & Bissell, M. J. A novel function for Nm23: overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest. J. Natl Cancer Inst. 86, 1838–1844 (1994).

    CAS  PubMed  Google Scholar 

  • Freije, J. M. P., Blay, P., MacDonald, N. J., Manrow, R. E. & Steeg, P. S. Site-directed mutation of Nm23-H1. Mutations lacking motility suppressive capacity upon transfection are deficient in histidine-dependent protein phosphotransferase pathways in vitro. J. Biol. Chem. 272, 5525–5532 (1997).

    CAS  PubMed  Google Scholar 

  • Wagner, P. D., Steeg, P. S. & Vu, N. -D. Two-component kinase like activity of Nm23 correlates with its motility suppressing activity. Proc. Natl Acad. Sci. USA 94, 9000–9005 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hartsough, M. et al. Nm23-H1 metastasis suppressor phosphorylation of Kinase suppressor of ras (KSR), via a histidine protein kinase pathway. J. Biol. Chem. 277, 32389–32399 (2002). Identifies KSR as a substrate of the NM23 histidine kinase, and ties NM23 expression to the ERK–MAPK pathway.

    CAS  PubMed  Google Scholar 

  • Morrison, D. KSR: a MAPK scaffold of the ras pathway? J. Cell Sci. 114, 1609–1612 (2001).

    CAS  PubMed  Google Scholar 

  • Cacace, A. et al. Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen activated protein kinase binding and KSR overexpression. Mol. Cell. Biol. 19, 229–240 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Volle, D. et al. Phosphorylation of the kinase suppressor of ras by associated kinases. Biochemistry 38, 5130–5137 (1999).

    CAS  PubMed  Google Scholar 

  • Adeyinka, A. et al. Activated mitogen-activated protein kinase expression during human breast tumorigenesis and breast cancer progression. Clin. Cancer Res. 8, 1747–1753 (2002).

    CAS  PubMed  Google Scholar 

  • Albanell, J. et al. Activated extracellular signal-related kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. Cancer Res. 61, 6500–6510 (2001).

    CAS  PubMed  Google Scholar 

  • Webb, C., VanAelst, L., Wigler, M. & VandeWoude, G. Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc. Natl Acad. Sci. USA 95, 8773–8778 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ward, Y. et al. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific exchange factor pathways. Mol. Cell. Biol. 21, 5958–5969 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Spector, M. et al. Activation of mitogen-activated protein kinases is required for alpha (1)-adrenergic agonist-induced cell scattering in transfected HepG2 cells. Exp. Cell Res. 258, 109–120 (2000).

    CAS  PubMed  Google Scholar 

  • Simon, C. et al. PD 098059, an inhibitor of ERK1 activation, attenuates the in vivo invasiveness of head and neck squamous cell carcinoma. Br. J. Cancer 80, 1412–1419 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yao, J. et al. Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-β1 in human breast cancer cells. Oncogene 20, 8066–8074 (2001).

    CAS  PubMed  Google Scholar 

  • Ellenrieder, V. et al. Transforming growth factor-β1 treatment leads to an epithelial–mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-related kinase 2 activation. Cancer Res. 61, 4222–4228 (2001).

    CAS  PubMed  Google Scholar 

  • Kim, H. 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. 61, 2833–2837 (2001).

    CAS  PubMed  Google Scholar 

  • Yamada, S. et al. Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Cancer Res. 62, 6717–6723 (2002).

    CAS  PubMed  Google Scholar 

  • Robinson, V., Hickson, J., Griend, D. V., Dubauskas, Z. & Rinker–Schaeffer, C. MKK4 and metastasis suppression: a marriage of signal transduction and metastasis research. Clin. Exp. Metast. (in the press).

  • Yang, X. et al. Overexpression of KAI1 supprresses in vitro invasiveness and in vivo metastasis in breast cancer cells. Cancer Res. 61, 5284–5288 (2001).

    CAS  PubMed  Google Scholar 

  • Bienstock, R. & Barrett, J. KAI1, a prostate metastasis suppressor: prediction of solvated structure and interactions with binding partners, integrins, caherins and cell-surface receptor proteins. Mol. Carcinog. 32, 139–153 (2001).

    CAS  PubMed  Google Scholar 

  • Odintsova, E., Sugiura, T. & Berditchevski, F. Attenuation of EGF receptor signaling by a metastasis supressor, the tetraspanin CD82/KAI-1. Curr. Biol. 10, 1009–1012 (2000). Mechanistic analysis of KAI1 suppressor inhibition of epidermal growth factor receptor signalling.

    CAS  PubMed  Google Scholar 

  • Bienstock, R. & Barrett, J. Kai1, a prostate metastais suppressor: prediction of solvated structure and interactions with binding partners, integrins, cadherins, and cell-surface receptor proteins. Mol. Carcinog. 32, 139–153 (2001).

    CAS  PubMed  Google Scholar 

  • Kondapaka, S., Fridman, R. & Reddy, K. Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9 (MMP-9) in human breast cancer cells. Int. J. Cancer 70, 722–726 (1997).

    CAS  PubMed  Google Scholar 

  • Turner, T., Chen, P., Goodly, L. & Wells, A. EGF receptor signaling enhances in vivo invasiveness of DU-145 human prostate carcinoma cells. Clin. Exp. Metast. 14, 409–418 (1996).

    CAS  Google Scholar 

  • Kaufmann, A., Lichtner, R., Schirrmacher, V. & Khazaie, K. Induction of apoptosis by EGF receptor in rat mammary adenocarcinoma cells coincides with enhanced spontaneous tumour metastasis. Oncogene 13, 2349–2358 (1996).

    CAS  PubMed  Google Scholar 

  • Lichtner, R. et al. Ligand-mediated activation of ectopic EGF receptor promotes matrix protein adhesion and lung colonization of rat mammary adenocarcinoma cells. Oncogene 10, 1823–1832 (1995).

    CAS  PubMed  Google Scholar 

  • Mendelsohn, J. & Baselga, J. The EGF receptor family as targets for cancer therapy. Oncogene 19, 6550–6565 (2000).

    CAS  PubMed  Google Scholar 

  • Giannelli, G. et al. Role of the α3β1 and α6β4 integrins in tumor invasion. Clin. Exp. Metast. 19, 217–233 (2002).

    CAS  Google Scholar 

  • Cooper, C., Chay, C. & Pienta, K. The role of αvβ3 in prostate cancer progression. Neoplasia 4, 191–194 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ziober, B., Silverman, S. & Kramer, R. Adhesive mechanisms regulating invasion and metastasis in oral cancer. Crit. Rev. Oral Biol. Med. 12, 499–510 (2001).

    CAS  PubMed  Google Scholar 

  • Hunter, K. et al. Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis supressor gene Brms1. Cancer Res. 61, 8866–8872 (2001).

    CAS  PubMed  Google Scholar 

  • Samant, R. et al. Analysis of mechanisms underlying BRMS1 suppression of metastasis. Clin. Exp. Metast. 18, 683–693 (2001).

    Google Scholar 

  • Saunders, M. et al. Breast cancer metastastic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication. Cancer Res. 61, 1765–1767 (2001). First demonstration that a metastasis suppressor can affect intercellular communication.

    CAS  PubMed  Google Scholar 

  • Lee, J. & Welch, D. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, Kiss-1. Cancer Res. 57, 2384–2387 (1997).

    CAS  PubMed  Google Scholar 

  • Kotani, M. et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GRP54. J. Biol. Chem. 276, 34631–34636 (2001).

    CAS  PubMed  Google Scholar 

  • Muir, A. et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide Kiss-1. J. Biol. Chem. 276, 28969–28975 (2001).

    CAS  PubMed  Google Scholar 

  • Ohtaki, T. et al. Metastasis suppressor Kiss-1 encodes a peptide ligand of a G-protein-coupled receptor. Nature 411, 613–617 (2001). Demonstration that a KiSS1 -encoded secreted peptide mediates its metastasis-suppressive effect.

    CAS  PubMed  Google Scholar 

  • Shih, J. -Y. et al. Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J. Natl Cancer Inst. 93, 1392–1400 (2001).

    CAS  PubMed  Google Scholar 

  • Steeg, P. Collapsin response mediator protein-1: a lung cancer invasion suppressor with nerve. J. Natl Cancer Inst. 93, 1364–1365 (2001).

    CAS  PubMed  Google Scholar 

  • Gildea, J. et al. RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res. 62, 6418–6423 (2002). Identification and functional demonstration of RHOGDI2 as a metastasis-suppressor gene. Demonstration of the use of microarray technology to identify potential metastasis-suppressor genes.

    CAS  PubMed  Google Scholar 

  • Jaffe, A. & Hall, A. Rho GTPases in transformation and metastasis. Adv. Cancer Res. 65, 57–79 (2002).

    Google Scholar 

  • Schmitz, A., Govek, E., Bottner, B. & VanAelst, L. RhoGTPases: signaling, migration and invasion. Exp. Cell Res. 261, 1–12 (2000).

    CAS  PubMed  Google Scholar 

  • Evers, E. et al. Rho family proteins in cell adhesion and cell migration. Eur. J. Cancer 36, 1269–1274 (2000).

    CAS  PubMed  Google Scholar 

  • Aozarena, I., Matallanas, D. & Crespo, P. Maintenance of Cdc42 GDP-bound state by Rho-GDI inhibits MAP kinase activation by the exchange factor Ras-GRF. J. Biol. Chem. 276, 21878–21884 (2001).

    Google Scholar 

  • Su, L., Knoblauch, R. & Garabedian, M. Rho GTPases as modulators of the estrogen receptor transcriptional response. J. Biol. Chem. 276, 3231–3237 (2001).

    CAS  PubMed  Google Scholar 

  • Welch, D. et al. Microcell-mediated transfer of chromosome 6 into metastatic human C8161 melanoma cells suppresses metastasis but does not inhibit tumorigenitiy. Oncogene 9, 255–262 (1994).

    CAS  PubMed  Google Scholar 

  • Miele, M. E. et al. Suppression of human melanoma metastasis following introduction of chromosome 6 is independent of NME1 (nm23). Clin. Exp. Metastasis 15, 259–265 (1997).

    CAS  PubMed  Google Scholar 

  • Lee, J. et al. Kiss-1, a novel human malignant melanoma metastasis-suppressor gene. J. Natl Cancer Inst. 88, 1731–1737 (1996). The identification and functional demonstration of the KiSS1 metastasis-suppressor gene.

    CAS  PubMed  Google Scholar 

  • Ryu, S., Zhou, S., Ladurner, A. & Tijan, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999).

    CAS  PubMed  Google Scholar 

  • Junn, E. et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J. Immunol. 164, 6287–6295 (2000).

    CAS  PubMed  Google Scholar 

  • Miyazaki, T. et al. Mutation and expression of the metastasis suppressor gene KAI1 in esophageal squamous cell carcinoma. Cancer 89, 955–962 (2000).

    CAS  PubMed  Google Scholar 

  • Cropp, C. et al. NME1 protein expression and loss of heterozygosity mutations in primary human breast tumors. J. Natl Cancer Inst. 86, 1167–1169 (1994).

    CAS  PubMed  Google Scholar 

  • Shinohara, T. et al. Nuclear factor-κB-dependent expression of metastasis suppressor Kai1/CD82 gene in lung cancer cell lines expressing mutant p53. Cancer Res. 61, 673–678 (2001).

    CAS  PubMed  Google Scholar 

  • Mashimo, T. et al. The expression of the KAI-1 gene, a tumor metastasis suppressor, is directly activated by p53. Proc. Natl Acad. Sci USA 95, 11307–11311 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akita, H. et al. Induction of KAI-1 expression in metastatic cancer cells by phorbol esters. Cancer Lett. 153, 79–83 (2000).

    CAS  PubMed  Google Scholar 

  • Sekita, N. et al. Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines. Jpn. J. Cancer Res. 92, 947–951 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hartsough, M. et al. Elevation of breast carcinoma nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition. Cancer Res. 61, 2320–2327 (2001). Proposes the identification of drugs to elevate metastasis-suppressor expression. DNA methylation inhibition elevated NM23 expression and blocked in vitro motility.

    CAS  PubMed  Google Scholar 

  • Ouatas, T., Clare, S., Hartsough, M., DeLaRosa, A. & Steeg, P. A cassette of mammary-specific transcription factor binding sites contributes to nm23-H1 promoter activity in human breast carcinoma cell lines. Clin. Exp. Metastasis 19, 35–42 (2002).

    CAS  PubMed  Google Scholar 

  • Liu, F., Qi, H. -L. & Chen, H. -L. Effects of all-trans retinoic acid and epidermal growth factor on the expression of nm23-H1 in human hepatocarcinoma cells. J. Cancer Res. Clin. Oncol. 126, 85–90 (2000).

    CAS  PubMed  Google Scholar 

  • Jiang, W., Hiscox, S., Bryce, R., Horrobin, D. & Mansel, R. The effects of n-6 polyunsaturated fatty acids on the expression of nm-23 in human cancer cells. Br. J. Cancer 77, 731–738 (1988).

    Google Scholar 

  • Greenlee, R., Hill-Harmon, M., Murray, T. & Thun, M. Cancer Statistics, 2001. CA Cancer J. Clin. 51, 15–36 (2001).

    CAS  PubMed  Google Scholar 

  • Chekmareva, M. et al. Chromosome 17-mediated dormancy of AT6. 1 prostate cancer micrmetastases. Cancer Res. 58, 4963–4969 (1998).

    CAS  PubMed  Google Scholar 

  • Goldberg, S., Harms, J., Quon, K. & Welch, D. Metastasis suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clin. Exp. Metastasis 58, 4963–4969 (1999). References 78 and 79 demonstrate the important concept that metastasis suppressors inhibit metastatic colonization — the final outgrowth of tumour cells at a distant site.

    Google Scholar 

  • Shevde, L. et al. Suppression of human melanoma metastasis by the metastasis suppressor gene, BRMS1. Exp. Cell Res. 273, 229–239 (2002).

    CAS  PubMed  Google Scholar 

  • Johnson, J. et al. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br. J. Cancer 84, 1424–1431 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rizzo, M. & Romero, G. Pharmacological importance of phospholipase D and phosphtidic acid in the regulation of the mitogen-activated protein kinase cascade. Pharmacol. Therapeut. 94, 35–50 (2002).

    CAS  Google Scholar 

  • Yart, A., Chap, H. & Raynal, P. Phosphoinositide 3-kinases in lysophosphatidic acid signaling: regulation and cross-talk with the Ras/mitogen-activated protein kinase pathway. Biochem. Biophys. Acta 1582, 107–111 (2002).

    CAS  PubMed  Google Scholar 

  • Chen, J., Baskerville, C., Han, Q., Pan, Z. & Huang, S. αv integrin, p38 mitogen-activated protein kinase, and urokinase plasminogen activator are functionally linked in invasive breast cancer cells. J. Biol. Chem. 276, 47901–47905 (2001).

    CAS  PubMed  Google Scholar 

  • Elder, D., Halton, D., Playle, L. & Paraskeva, C. The MEK/ERK pathway mediated COX-2-selective NSAID-induced apoptosis and induced COX-2 protein expression in colorectal carcinoma cells. Int. J. Cancer 99, 323–327 (2002).

    CAS  PubMed  Google Scholar 

  • Magne, N. et al. Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD 1839 ('Iressa'). Br. J. Cancer 86, 1518–1523 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sarker, M., Ruiz-Ruiz, C., Robledo, G. & Lopez-Rivas, A. Stimulation of the mitogen-activated protein kinase pathway antagonizes TRAIL-induced apoptosis downstream of BID cleavage in human breast cancer MCF-7 cells. Oncogene 21, 4323–4327 (2002).

    CAS  PubMed  Google Scholar 

  • MacKeigan, J. et al. Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen-activated protein kinase kinase inhibition. Clin. Cancer Res. 8, 2091–2099 (2002).

    CAS  PubMed  Google Scholar 

  • Orlowski, R., Small, G. & Shi, Y. Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-meidated apoptosis. J. Biol. Chem. 277, 27864–27871 (2002).

    CAS  PubMed  Google Scholar 

  • Sledge, G. Vascular endothelial growth factor in breast cancer: biologic and therapeutic aspects. Semin. Oncol. 29, 104–110 (2002).

    CAS  PubMed  Google Scholar 

  • Folkman, J. Seminars in medicine of the Beth Israel Hospital, Boston: clinical applications of research on angiogenesis. N. Engl. J. Med. 333, 1757–1763 (1995).

    CAS  PubMed  Google Scholar 

  • Wong, C. et al. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 61, 333–338 (2001).

    CAS  PubMed  Google Scholar 

  • Ladeda, V., Adam, A., Puricello, L. & Joffe, E. Apoptotic cell death in mammary adenocarcinoma cells is prevented by soluble factors present in the target organ of metastasis. Breast Cancer Res. Treat. 69, 39–51 (2001).

    CAS  PubMed  Google Scholar 

  • Zavadil, J. et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc. Natl Acad. Sci. USA 98, 6686–6691 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kiefer, J. & Farach-Carson, M. Type I collagen-mediated proliferation of PC3 prostate carcinoma cell line: implications for enhanced growth in the bone microenvironment. Matrix Biol. 20, 429–437 (2001).

    CAS  PubMed  Google Scholar 

  • Zvibel, I., Brill, S., Halpern, Z. & Papa, M. Hepatocyte extracellular matrix modulates expression of growth factors and growth factor receptors in human colon cancer cells. Exp. Cell Res. 245, 123–131 (1998).

    CAS  PubMed  Google Scholar 

  • Elion, E. MAP Kinase Modules in Signaling 119–129 (Academic Press, San Diego, 2002).

    Google Scholar 

  • Wang, W. et al. Sequential activation of the MEK-extracellular signal regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol. Cell. Biol. 22, 3389–3403 (2002).

    PubMed  PubMed Central  Google Scholar 

  • Shields, J., Mehta, H., Pruitt, K. & Der, C. Opposing roles of the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase cascades in Ras–mediated downregulation or tropomyosin. Mol. Cell. Biol. 22, 2304–2317 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leone, A. et al. Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65, 25–35 (1991). The first functional demonstration of a metastasis-suppressor gene.

    CAS  PubMed  Google Scholar 

  • Baba, H. et al. Two isotypes of murine nm23/nucleoside diphosphate kinase, nm23-M1 and nm23-M2, are involved in metastatic suppression of a murine melanoma line. Cancer Res. 55, 1977–1981 (1995).

    CAS  PubMed  Google Scholar 

  • Parhar, R. S. et al. Effects of cytokine mediated modulation of Nm23 expression on the invasion and metastatic behavior of B16F10 melanoma cells. Int. J. Cancer 60, 204–210 (1995).

    CAS  PubMed  Google Scholar 

  • Fukuda, M. et al. Metastatic potential of rat mammary adenocarcinoma cells associated with decreased expression of nucleoside diphosphate kinase/nm23: reduction by transfection of NDP kinase a isoform, an nm23-H2 gene homolog. Int. J. Cancer 65, 531–537 (1996).

    CAS  PubMed  Google Scholar 

  • Bhujwalla, Z. et al. 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. Magnetic Res. Med. 41, 897–903 (1999).

    CAS  Google Scholar 

  • Russell, R. et al. Relationship of nm23 to proteolytic factors, proliferation and motility in breast cancer tissues and cell lines. Br. J. Cancer 78, 710–717 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tagashira, H., Hamazaki, K., Tanaka, N., Gao, C. & Namba, M. Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2 rat nucleoside diphosphate kinase a isoform. Int. J. Mol. Med. 2, 65–68 (1998).

    CAS  PubMed  Google Scholar 

  • Miyazaki, H. et al. 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, 4301–4307 (1999).

    CAS  PubMed  Google Scholar 

  • Yoshida, B. et al. Mitogen-activated protein kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. 59, 5483–5487 (1999). The identification and functional demonstration of MKK4 as a metastasis-suppressor gene. This paper links metastasis suppressors to the p38 and JNK arms of the MAPK pathway.

    CAS  PubMed  Google Scholar 

  • Dong, J. et al. Kai1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 268, 884–886 (1995). The identification and functional demonstration of the KAI1 metastasis-suppressor gene.

    CAS  PubMed  Google Scholar 

  • Seraj, M., Samant, R., Verderame, M. & Welch, D. Functional evidence for a novel human breast carcinoma metastasis suppressor, BRMS1, encoded at chromosome 11q13. Cancer Res. 60, 2764–2769 (2000). The identification and functional demonstration of the BRMS1 metastasis-suppressor gene.

    CAS  PubMed  Google Scholar 

  • Goldberg, S. et al. Melanoma metastasis suppression by chromosome 6: evidence for a pathway regulated by CRSP3 and TXNIP. Cancer Res. (in the press).