Molecular Genetics of Metastasis

Georg F Weber, University of Cincinnati, Cincinnati, Ohio, USA

Published online: April 2010

DOI: 10.1002/9780470015902.a0022447

Metastasis is the spread of cancer cells throughout the body. Although it is frequently the cause of death from malignant growths, it is the most poorly understood aspect of carcinogenesis. The underlying process of cancer cell dissemination is controlled by genetic programs in the tumour cells and in the host. The tumour cell-intrinsic genetic programs of metastasis confer invasiveness and anchorage-independence. The responsible genes are typically deregulated by aberrant expression or splicing. Organ preference of metastasis depends on more complex tumour–host interactions. Metastasis suppressor genes, when expressed, can negatively regulate tumour spread. The molecular genetics of metastasis has led to the development of diagnostic tests, based on gene expression profiles that help predict metastatic potential. Further, it has opened prospects for the targeting of key culprit genes in antimetastasis therapy.

Key Concepts:

  • Cancer invasiveness constitutes the breaking of tumour cells through tissue barriers and represents the earliest manifestation of metastasis.
  • The genetic basis of metastasis formation is the aberrant expression or splicing of stress response genes.
  • The biologic activity of metastasis-mediating gene products is extensively regulated by posttranscriptional mechanisms.
  • Cancer metastasis is guided by two intrinsic characteristics of cancer cells, invasiveness and anchorage-independent survival.
  • Cancer cell invasiveness is mediated by secreted proteases, homing receptors, cytokine ligands and associated signalling molecules.
  • The acquisition of invasiveness by tumour cells is accompanied by a characteristic, reversible remodelling, called the epithelial-mesenchymal transition.
  • Cancers shed their tumour cells into the blood or lymph stream from the earliest stages of growth on; most cells die in the circulation.
  • Fully transformed cells can survive without anchorage for extended periods of time.
  • Genetic programs of metastasis encode consistent patterns of organ preference by individual malignancies.
  • Like other functions within cancer cells, the ability to metastasise is under positive and negative genetic control.

Keywords: metastasis; invasion; anoikis; homing receptor; cytokine; protease

Figure 1. Systemic tumour metastasis. The tumour suppressor P53 is defective in about half of all human cancers. Osteosarcomas develop spontaneously in mice with loss-of-function mutations in the trp53 gene, which encodes P53. These tumours metastasise to the liver (top) and the lungs (bottom). Metastasis formation in this context depends on the gene for the homing receptor CD44. In the absence of the cd44 gene, osteosarcoma metastasis is almost completely suppressed. The figure shows hematoxylin-/eosin-stained tissue sections. Reproduced from Weber et al. (2002).
Figure 2. Organ preferences in metastasis. Tumours of a particular organ origin tend to display consistent organ preference for metastasis. The figure shows common target organs and examples of the most important tumours that metastasise to them. The anatomical picture is reproduced under a license from Zygote Media Group.
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 References
    Bos PD, Zhang XH, Nadal C et al. (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459: 1005–1009.
    Butler TP and Gullino PM (1975) Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Research 35: 512–516.
    Connor KM, Hempel N, Nelson KK et al. (2007) Manganese superoxide dismutase enhances the invasive and migratory activity of tumor cells. Cancer Research 67: 10260–10267.
    Frisch SM and Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. Cell Biology 124: 619–626.
    Glaves D, Huben RP and Weiss L (1988) Haematogenous dissemination of cells from human renal adenocarcinomas. British Journal of Cancer 57: 32–35.
    Glinsky GV and Glinsky VV (1996) Apoptosis and metastasis: a superior resistance of metastatic cancer cells to programmed cell death. Cancer Letters 101: 43–51.
    Gregory PA, Bracken CP, Bert AG and Goodall GJ (2008) MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle 7: 3112–3118.
    He B, Mirza M and Weber GF (2006) An osteopontin splice variant induces anchorage independence in human breast cancer cells. Oncogene 25: 2192–2202.
    Hiratsuka S, Watanabe A, Sakurai Y et al. (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nature Cell Biology 10: 1349–1355.
    Horak CE, Lee JH, Marshall JC, Shreeve SM and Steeg PS (2008) The role of metastasis suppressor genes in metastatic dormancy. APMIS 116: 586–601.
    Kaplan RN, Rafii S and Lyden D (2006) Preparing the “soil”: the premetastatic niche. Cancer Research 66: 11089–11093.
    Kaplan RN, Riba RD and Zacharoulis S (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438: 820–827.
    Korpal M and Kang Y (2008) The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biology 5: 115–119.
    Mani SA, Guo W and Liao MJ (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133: 704–715.
    McAllister SS, Gifford AM, Greiner AL et al. (2008) Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133: 994–1005.
    Meredith JE Jr, Fazeli B and Schwartz MA (1993) The extracellular matrix as a cell survival factor. Molecular Biology of Cell 4: 953–961.
    Nelson KK, Ranganathan AC, Mansouri J et al. (2003) Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clinical Cancer Research 9: 424–432.
    Ramaswamy S, Ross KN, Lander ES and Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nature Genetics 33: 49–54.
    Rinker-Schaeffer CW, O'Keefe JP, Welch DR and Theodorescu D (2006) Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clinical Cancer Research 12: 3882–3889.
    Streeter PR, Berg EL, Rouse BT et al. (1988) A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 331: 41–46.
    Takaoka A, Adachi M, Okuda H et al. (1997) Anti-cell death activity promotes pulmonary metastasis of melanoma cells. Oncogene 14: 2971–2977.
    book Weber GF (2007) Molecular Mechanisms of Cancer. Dordrecht: Springer.
    Weber GF (2008) Molecular mechanisms of metastasis. Cancer Letters 270: 181–190.
    Weber GF and Ashkar S (2000) Stress response genes: the genes that make cancer metastasize. Journal of Molecular Medicine 78: 404–408.
    Weber GF, Bronson R, Ilagan J et al. (2002) Absence of CD44 prevents sarcoma metastasis. Cancer Research 62: 2281–2286.
    Wong CW, Lee A, Shientag L et al. (2001) Apoptosis: an early event in metastatic inefficiency. Cancer Research 61: 333–338.
    Zhang G, He B and Weber GF (2003) Growth factor signaling induces metastasis genes in transformed cells. A molecular connection between Akt kinase and osteopontin in breast cancer. Molecular and Cellular Biology 23: 6507–6519.
 Further Reading
    Eccles SA and Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369: 1742–1757.
    Geiger TR and Peeper DS (2009) Metastasis mechanisms. Biochimica et Biophysica Acta 1796: 293–308.
    Hedley BD and Chambers AF (2009) Tumor dormancy and metastasis. Advances in Cancer Research 102: 67–101.
    Nguyen DX, Bos PD and Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nature Reviews. Cancer 9: 274–284.
    Saad Z, Bramwell VH, Wilson SM et al. (1998) Expression of genes that contribute to proliferative and metastatic ability in breast cancer resected during various menstrual phases. Lancet 351: 1170–1173.

Related Sub-Topics:

Cell Biology of Cancer | Cell Cycle | Cancer Genetics | Techniques and Tools in Clinical Genetics | Gene Expression Profiling of Genetic Disease
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Article Title: Molecular Genetics of Metastasis
 
How to Cite close
Weber, Georg F(Apr 2010) Molecular Genetics of Metastasis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022447]