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Chapter
  • Print publication year: 2011
  • Online publication date: June 2012

5 - Metastasis-Promoting Genes

from GENES
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Summary

Accurately defining whether a tumor is benign or malignant is critical in determining the most appropriate course of therapy and, consequently, clinical outcome. Benign tumors, which are characterized by hyperproliferating cells, can, in most cases, be effectively treated by surgical removal if the tumor is located in an accessible and nonessential site in the body. However, when a tumor becomes malignant – acquiring dysplasia, dedifferentiation, and metastatic properties – treatment becomes extremely difficult because of profound genetic and epigenetic changes in the tumor that counteract host defense mechanisms, as well as exogenously delivered therapeutics [1]. Additionally, effective delivery to metastatic lesions can be difficult and inefficient. This chapter focuses on the genes and their products that have been identified and shown to be involved in regulating metastasis.

Metastasis is a dynamic process in which a transformed tumor cell migrates from its initial site of origin and colonizes at new locations in the body. In the biological cascade of metastasis, distinct steps have been delineated [2, 3]:

(1) Tumor cells become less adherent to the surrounding stroma and are shed from the primary tumor.

(2) Tumor cells acquire motility, degrade the surrounding extracellular matrix, and invade into it.

(3) The tumor cells enter into the circulation and survive (these processes are characteristic of the “intravasation” component of metastasis).

(4) Tumor cells emerge from the circulation and attach and enter new tissue (these processes are characteristic of the “extravasation” component of metastasis).

(5) Tumor cells proliferate and generate new secondary colonies of cells that are dependent on formation of a new blood supply – the process of angiogenesis. To perform each specific task, specific proteins (gene products) are necessary.

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Cancer Metastasis
  • Online ISBN: 9780511976117
  • Book DOI: https://doi.org/10.1017/CBO9780511976117
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References
Hanahan, D, Weinberg, RA (2000) The hallmarks of cancer. Cell. 100: 57–70.
Chambers, AF, Groom, AC, MacDonald, IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2: 563–72.
Fidler, IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3: 453–8.
Kang, DC, LaFrance, R, Su, ZZ, Fisher, PB (1998) Reciprocal subtraction differential RNA display: an efficient and rapid procedure for isolating differentially expressed gene sequences. Proc Natl Acad Sci USA. 95: 13788–93.
Su, ZZ, Goldstein, NI, Jiang, H et al. (1999) PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis. Proc Natl Acad Sci U S A 96: 15115–20.
Gschwind, A, Fischer, OM, Ullrich, A (2004) The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 4: 361–70.
Hynes, NE, Lane, HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 5: 341–54.
Shaulian, E, Karin, M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol. 4: E131–6.
Ozanne, BW, Spence, HJ, McGarry, LC, Hennigan, RF (2007) Transcription factors control invasion: AP-1 the first among equals. Oncogene. 26: 1–10.
Blume-Jensen, P, Hunter, T (2001) Oncogenic kinase signalling. Nature. 411: 355–65.
Stommel, JM, Kimmelman, AC, Ying, H, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 318: 287–90.
Downward, J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 3: 11–22.
Campbell, SL, Khosravi-Far, R, Rossman, KL, Clark, GJ, Der, CJ (1998) Increasing complexity of Ras signaling. Oncogene. 17: 1395–413.
Takai, Y, Sasaki, T, Matozaki, T (2001) Small GTP-binding proteins. Physiol Rev. 81: 153–208.
Yeatman, TJ (2004) A renaissance for SRC. Nat Rev Cancer. 4: 470–80.
Roche, S, Fumagalli, S, Courtneidge, SA (1995) Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. Science. 269: 1567–9.
Jones, RJ, Avizienyte, E, Wyke, AW, Owens, DW, Brunton, VG, Frame, MC (2002) Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. Br J Cancer. 87: 1128–35.
Brown, MT, Cooper, JA (1996) Regulation, substrates and functions of Src. Biochim Biophys Acta. 1287: 121–49.
Masaki, T, Okada, M, Tokuda, M et al. (1999) Reduced C-terminal Src kinase (Csk) activities in hepatocellular carcinoma. Hepatology. 29: 379–84.
Bjorge, JD, Pang, A, Fujita, DJ (2000) Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. J Biol Chem. 275: 41439–46.
Schaller, MD, Hildebrand, JD, Shannon, JD, Fox, JW, Vines, RR, Parsons, JT (1994). Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol. 14: 1680–8.
Thomas, JW, Ellis, B, Boerner, RJ, Knight, WB, White, GC, Schaller, MD (1998) SH2- and SH3-mediated interactions between focal adhesion kinase and Src. J Biol Chem. 273: 577–83.
Sastry, SK, Burridge, K (2000) Focal adhesions: a nexus for intracellular signaling and cytoskeletal dynamics. Exp Cell Res. 261: 25–36.
Jamora, C, Fuchs, E (2002) Intercellular adhesion, signalling and the cytoskeleton. Nat Cell Biol. 4: E101–8.
Zamir, E, Geiger, B (2001) Molecular complexity and dynamics of cell-matrix adhesions. J Cell Sci. 114: 3583–90.
Heasman, SJ, Ridley, AJ (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 9: 690–701.
Hauck, CR, Hsia, DA, Schlaepfer, DD (2002) The focal adhesion kinase – a regulator of cell migration and invasion. IUBMB Life. 53: 115–9.
Owens, LV, Xu, L, Craven, RJ et al. (1995) Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res. 55: 2752–5.
Chang, JH, Gill, S, Settleman, J, Parsons, SJ (1995) c-Src regulates the simultaneous rearrangement of actin cytoskeleton, p190RhoGAP, and p120RasGAP following epidermal growth factor stimulation. J Cell Biol. 130: 355–68.
Fincham, VJ, Frame, MC (1998) The catalytic activity of Src is dispensable for translocation to focal adhesions but controls the turnover of these structures during cell motility. EMBO J. 17: 81–92.
Yap, AS, Brieher, WM, Gumbiner, BM (1997) Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell Dev Biol. 13: 119–46.
Cavallaro, U, Christofori, G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 4: 118–32.
Schreiber, SC, Giehl, K, Kastilan, C et al. (2008) Polysialylated NCAM represses E-cadherin-mediated cell-cell adhesion in pancreatic tumor cells. Gastroenterology. 134: 1555–66.
Kang, Y, Massague, J (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 118: 277–9.
Thiery, JP (2002). Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2: 442–54.
Trusolino, L, Comoglio, PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer. 2: 289–300.
Boccaccio, C, Comoglio, PM (2006) Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer. 6: 637–45.
Gottardi, CJ, Wong, E, Gumbiner, BM (2001) E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol. 153: 1049–60.
Fujita, Y, Krause, G, Scheffner, M, et al. (2002) Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol. 4: 222–31.
Hsia, DA, Mitra, SK, Hauck, CR et al. (2003) Differential regulation of cell motility and invasion by FAK. J Cell Biol. 160: 753–67.
Ridley, AJ (2001) Rho GTPases and cell migration. J Cell Sci. 114: 2713–22.
Sahai, E, Marshall, CJ (2002) RHO-GTPases and cancer. Nat Rev Cancer. 2: 133–42.
Clark, EA, Golub, TR, Lander, ES, Hynes, RO (2000) Genomic analysis of metastasis reveals an essential role for RhoC. Nature. 406: 532–5.
Liotta, , Kohn, EC (2001) The microenvironment of the tumour-host interface. Nature. 411: 375–9.
Kim, M, Gans, JD, Nogueira, C, et al. (2006) Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell. 125: 1269–81.
Boukerche, H, Su, ZZ, Prevot, C, Sarkar, D, Fisher, PB (2008) mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. Proc Natl Acad Sci USA. 105: 15914–9.
Egeblad, M, Werb, Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2: 161–74.
Friedl, P, Wolf, K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 3: 362–74.
Brooks, PC, Stromblad, S, Sanders, LC et al. (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell. 85: 683–93.
Zucker, S, Drews, M, Conner, C et al. (1998) Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J Biol Chem. 273: 1216–22.
Hood, JD, Cheresh, DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer. 2: 91–100.
Croucher, DR, Saunders, DN, Lobov, S, Ranson, M (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer. 8: 535–45.
Duffy, MJ (2004) The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des. 10: 39–49.
Foekens, JA, Peters, HA, Look, MP et al. (2000) The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res. 60: 636–43.
Karin, M (2006) Nuclear factor-kappaB in cancer development and progression. Nature. 441: 431–6.
Gupta, GP, Massague, J (2006) Cancer metastasis: building a framework. Cell. 127: 679–95.
Stupack, DG, Teitz, T, Potter, MD et al. (2006) Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature. 439: 95–9.
Brodeur, GM (2003) Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 3: 203–16.
Weis, SM, Cheresh, DA (2005) Pathophysiological consequences of VEGF-induced vascular permeability. Nature. 437: 497–504.
Khanna, C, Wan, X, Bose, S et al. (2004) The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 10: 182–6.
Orimo, A, Gupta, PB, Sgroi, DC et al. (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121: 335–48.
Visser, KE, Eichten, A, Coussens, LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 6: 24–37.
Dannenberg, AJ, Subbaramaiah, K (2003) Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell. 4: 431–6.
Condeelis, J, Pollard, JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 124: 263–6.
Nguyen, DX, Massague, J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet. 8: 341–52.
Brown, DM, Ruoslahti, E (2004) Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell. 5: 365–74.
Su, ZZ, Kang, DC, Chen, Y et al. (2002) Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene. 21: 3592–602.
Sarkar, D, Park, ES, Emdad, L, Lee, SG, Su, ZZ, Fisher, PB (2008) Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res. 68: 1478–84.
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.
Bellahcene, A, Castronovo, V, Ogbureke, KU, Fisher, LW, Fedarko, NS (2008) Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer. 8: 212–26.
Wai, PY, Kuo, PC (2008) Osteopontin: regulation in tumor metastasis. Cancer Metastasis Rev. 27: 103–18.
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