Genetic determinants of cancer metastasis

Key Points

  • The term metastasis encompasses specific biological traits that together enable the spread of aggressive tumour cells.

  • Different tumour types metastasize to distinct secondary organs, reflecting the influence of: the malignant cell of origin, aggressiveness of the primary tumour, the direction of circulation, and the capacity to co-opt supporting components of the microenvironment.

  • Underlying each of these factors are genetic determinants that are largely distinct from those that mediate malignant transformation.

  • Mediators of metastasis can be classified as metastasis initiation, metastasis progression and metastasis virulence genes, on the basis of the tumour stage, location in the body where they act, and their biological function.

  • By combining genome-wide technologies, functional experimentation in model systems and clinical validation, it is becoming possible to identify genetic alterations that are relevant to human metastatic disease.

  • These integrative approaches have uncovered genetic, epigenetic, somatic and inherited alterations, and serve as precedents for future metastasis gene discovery, prognosis and therapy.


Metastasis can be viewed as an evolutionary process, culminating in the prevalence of rare tumour cells that overcame stringent physiological barriers as they separated from their original environment and developmental fate. This phenomenon brings into focus long-standing questions about the stage at which cancer cells acquire metastatic abilities, the relationship of metastatic cells to their tumour of origin, the basis for metastatic tissue tropism, the nature of metastasis predisposition factors and, importantly, the identity of genes that mediate these processes. With knowledge cemented in decades of research into tumour-initiating events, current experimental and conceptual models are beginning to address the genetic basis for cancer colonization of distant organs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Classes of genes participating in the metastasis process.
Figure 2: A model for the integration of four metastasis theories.


  1. 1

    Weigelt, B., Peterse, J. L. & van 't Veer, L. J. Breast cancer metastasis: markers and models. Nature Rev. Cancer 5, 591–602 (2005).

    CAS  Article  Google Scholar 

  2. 2

    van de Wouw, A. J., Jansen, R. L., Speel, E. J. & Hillen, H. F. The unknown biology of the unknown primary tumour: a literature review. Ann. Oncol. 14, 191–6 (2003).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Weiss, L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev. 19, 193–383 (2000).

    Article  Google Scholar 

  4. 4

    Norton, L. & Massagué, J. Is cancer a disease of self-seeding? Nature Med. 12, 875–878 (2006).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Christofori, G. New signals from the invasive front. Nature 441, 444–450 (2006).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature Rev. Cancer 3, 453–458 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Gupta, G. P. & Massagué, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Mundy, G. R. Metastasis to bone: causes, consequences and therapeutic opportunities. Nature Rev. Cancer 2, 584–593 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nature Med. 12, 895–904 (2006).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Capasso, L. L. Antiquity of cancer. Int. J. Cancer 113, 2–13 (2005).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).

    CAS  PubMed  Google Scholar 

  13. 13

    Ewing, J. Neoplastic Diseases edn 6 (Saunders, Philadelphia, 1928).

    Google Scholar 

  14. 14

    Fisher, B. & Fisher, E. R. The interrelationship of hematogenous and lymphatic tumor cell dissemination. Surg. Gynecol. Obstet. 122, 791–798 (1966).

    CAS  PubMed  Google Scholar 

  15. 15

    Crespi, B. & Summers, K. Evolutionary biology of cancer. Trends Ecol. Evol. 20, 545–552 (2005).

    Article  PubMed  Google Scholar 

  16. 16

    Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    CAS  Article  Google Scholar 

  17. 17

    Fidler, I. J. Selection of successive tumour lines for metastasis. Nature New Biol. 242, 148–149 (1973).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Fidler, I. J. & Kripke, M. L. Metastasis results from preexisting variant cells within a malignant tumor. Science 197, 893–895 (1977).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    CAS  Article  Google Scholar 

  20. 20

    Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789–799 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Bernards, R. & Weinberg, R. A. A progression puzzle. Nature 418, 823 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumors. Nature Genet. 33, 49–54 (2003).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

    CAS  Article  Google Scholar 

  26. 26

    van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  Article  Google Scholar 

  28. 28

    Kerbel, R. S., Waghorne, C., Korczak, B., Lagarde, A. & Breitman, M. L. Clonal dominance of primary tumours by metastatic cells: genetic analysis and biological implications. Cancer Surv. 7, 597–629 (1988).

    CAS  PubMed  Google Scholar 

  29. 29

    Steeg, P. S. Metastasis suppressors alter the signal transduction of cancer cells. Nature Rev. Cancer 3, 55–63 (2003).

    CAS  Article  Google Scholar 

  30. 30

    Schmidt-Kittler, O. et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc. Natl Acad. Sci. USA 100, 7737–7742 (2003). A cytogenetic analysis of single tumour cells from the bone marrow of breast cancer patients, leading to the suggestion that metastatic cells disseminate early and evolve independently of their primary tumour.

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Schardt, J. A. et al. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8, 227–239 (2005).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Huber, M. A., Kraut, N. & Beug, H. Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr. Opin. Cell Biol. 17, 548–558 (2005).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Stupack, D. G. et al. Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439, 95–99 (2006).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Gupta, G. P. et al. Mediators of vascular remodelling co-opted for metastatic extravasation. Nature 446, 765–770 (2007).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005). References 36 and 37 integrate in vivo selection with clinical validation to identify mediators of lung-specific metastasis, linking aggressive primary tumorigenesis to organ-specific colonization.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Minn, A. J. et al. Lung metastasis genes couple breast tumor size and metastatic spread. Proc. Natl Acad. Sci. USA 104, 6740–6745 (2007).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Richards, F. M. et al. Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum. Mol. Genet. 8, 607–610 (1999). This report links the inactivation of a developmentally regulated cell-adhesion gene with predisposition to cancer progression.

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nature Rev. Cancer 4, 118–132 (2004).

    CAS  Article  Google Scholar 

  41. 41

    Kapitanovic, S. et al. nm23-H1 expression and loss of heterozygosity in colon adenocarcinoma. J. Clin. Pathol. 57, 1312–1318 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Kim, M. et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell 125, 1269–1281 (2006). An integrative approach that uses a mouse model to filter human aCGH data and characterize chromosomal aberrations that are associated with melanoma metastasis.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Thompson, E. W. & Newgreen, D. F. Carcinoma invasion and metastasis: a role for epithelial–mesenchymal transition? Cancer Res. 65, 5991–5995 (2005).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Tarin, D. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 65, 5996–6000 (2005).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Kaelin, W. G. The von Hippel–Lindau tumor suppressor protein: roles in cancer and oxygen sensing. Cold Spring Harb. Symp. Quant. Biol. 70, 159–166 (2005).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Staller, P. et al. Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003). An example of how somatic mutations that are acquired during tumour progression can affect the expression of a metastasis-specific gene.

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001). This paper describes how non-immunological tumour cells can express the chemokine receptor CXCR4 and respond to a chemokine source to settle in certain organs.

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nature Rev. Genet. 7, 21–33 (2006).

    CAS  Article  Google Scholar 

  50. 50

    Baylin, S. B. & Ohm, J. E. Epigenetic gene silencing in cancer — a mechanism for early oncogenic pathway addiction? Nature Rev. Cancer 6, 107–116 (2006).

    CAS  Article  Google Scholar 

  51. 51

    Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002). This paper reports the deregulation of stem-cell epigenetic regulators during metastatic progression.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Kim, J. H. et al. Transcriptional regulation of a metastasis suppressor gene by Tip60 and b-catenin complexes. Nature 434, 921–926 (2005). A study that links the progenitor WNT/β-catenin pathway to the transcriptional repression of a metastasis suppressor gene.

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Bandyopadhyay, S. et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nature Med. 12, 933–938 (2006).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Frank, S. A. Genetic predisposition to cancer — insights from population genetics. Nature Rev. Genet. 5, 764–772 (2004).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Pharoah, P. D. et al. Polygenic susceptibility to breast cancer and implications for prevention. Nature Genet. 31, 33–36 (2002).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Carey, L. A. et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295, 2492–2502 (2006).

    CAS  Article  Google Scholar 

  58. 58

    Lifsted, T. et al. Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int. J. Cancer 77, 640–644 (1998).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Park, Y. G. et al. Comparative sequence analysis in eight inbred strains of the metastasis modifier QTL candidate gene Brms1. Mamm. Genome 13, 289–292 (2002).

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Park, Y. G. et al. SIPA1 is a candidate for underlying the metastasis efficiency modifier locus MTES1. Nature Genet. 37, 1055–1062 (2005). The first experimental identification of a polymorphism that affects metastatic potential in mice.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Crawford, N. P. et al. Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer. Breast Cancer Res. 8, R16 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nature Cell Biol. 8, 1369–1375 (2006).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Gupta, P. B. et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nature Genet. 37, 1047–1054 (2005).

    CAS  Article  PubMed  Google Scholar 

  64. 64

    Yu, Y. et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein SIX-1 as key metastatic regulators. Nature Med. 10, 175–181 (2004).

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004). A gene-expression analysis that identified a role for a transcriptional regulator of embryo development during mouse mammary tumour intravasation.

    CAS  Article  PubMed  Google Scholar 

  66. 66

    de Visser, K. E., Eichten, A. & Coussens, L. M. Paradoxical roles of the immune system during cancer development. Nature Rev. Cancer 6, 24–37 (2006).

    CAS  Article  Google Scholar 

  67. 67

    Karin, M. Nuclear factor-kB in cancer development and progression. Nature 441, 431–436 (2006).

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Park, B. K. et al. NF-kB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nature Med. 13, 62–69 (2007).

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Luo, J. L. et al. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 18 March 2007 (doi:10.1038/nature05656).

    CAS  Article  PubMed  Google Scholar 

  70. 70

    Kang, Y. et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl Acad. Sci. USA 102, 13909–13914 (2005).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Olsson, A. K., Dimberg, A., Kreuger, J. & Claesson-Welsh, L. VEGF receptor signalling — in control of vascular function. Nature Rev. Mol. Cell Biol. 7, 359–371 (2006).

    CAS  Article  Google Scholar 

  72. 72

    Weis, S., Cui, J., Barnes, L. & Cheresh, D. Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J. Cell Biol. 167, 223–229 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Bierie, B. & Moses, H. L. Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer. Nature Rev. Cancer 6, 506–520 (2006).

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Siegel, P. M. & Massagué, J. Cytostatic and apoptotic actions of TGFβ in homeostasis and cancer. Nature Rev. Cancer 3, 807–821 (2003).

    CAS  Article  Google Scholar 

  76. 76

    Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    CAS  Article  Google Scholar 

  78. 78

    Debnath, J. & Brugge, J. S. Modelling glandular epithelial cancers in three-dimensional cultures. Nature Rev. Cancer 5, 675–688 (2005).

    CAS  Article  Google Scholar 

  79. 79

    Van Dyke, T. & Jacks, T. Cancer modeling in the modern era: progress and challenges. Cell 108, 135–144 (2002).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Gingrich, J. R. et al. Metastatic prostate cancer in a transgenic mouse. Cancer Res. 56, 4096–4102 (1996).

    CAS  PubMed  Google Scholar 

  82. 82

    Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005).

    CAS  Article  Google Scholar 

  83. 83

    Kim, C. F. et al. Mouse models of human non-small-cell lung cancer: raising the bar. Cold Spring Harb. Symp. Quant. Biol. 70, 241–250 (2005).

    CAS  Article  PubMed  Google Scholar 

  84. 84

    Nathoo, N., Toms, S. A. & Barnett, G. H. Metastases to the brain: current management perspectives. Expert Rev. Neurother. 4, 633–640 (2004).

    Article  PubMed  Google Scholar 

  85. 85

    Douma, S. et al. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 430, 1034–1039 (2004).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    Brumby, A. M. & Richardson, H. E. Using Drosophila melanogaster to map human cancer pathways. Nature Rev. Cancer 5, 626–639 (2005).

    CAS  Article  Google Scholar 

  87. 87

    Woodhouse, E. C. et al. Drosophila screening model for metastasis: Semaphorin 5c is required for l(2)gl cancer phenotype. Proc. Natl Acad. Sci. USA 100, 11463–11468 (2003).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227–1231 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Dupuy, A. J., Akagi, K., Largaespada, D. A., Copeland, N. G. & Jenkins, N. A. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436, 221–226 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Collier, L. S., Carlson, C. M., Ravimohan, S., Dupuy, A. J. & Largaespada, D. A. Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436, 272–276 (2005).

    CAS  Article  Google Scholar 

  91. 91

    Dickins, R. A. et al. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nature Genet. 37, 1289–1295 (2005).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Ellsworth, R. E. et al. Allelic imbalance in primary breast carcinomas and metastatic tumors of the axillary lymph nodes. Mol. Cancer Res. 3, 71–77 (2005).

    CAS  Article  PubMed  Google Scholar 

  93. 93

    Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Laird, P. W. The power and the promise of DNA methylation markers. Nature Rev. Cancer 3, 253–266 (2003).

    CAS  Article  Google Scholar 

  95. 95

    Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    CAS  Article  Google Scholar 

  96. 96

    Varambally, S. et al. Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression. Cancer Cell 8, 393–406 (2005).

    CAS  Article  PubMed  Google Scholar 

  97. 97

    Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Wang, Y. et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365, 671–679 (2005).

    CAS  Article  PubMed  Google Scholar 

  99. 99

    Fan, C. et al. Concordance among gene-expression-based predictors for breast cancer. N. Engl. J. Med. 355, 560–569 (2006). An analysis of five prominent breast cancer gene signatures that shows that, despite little overlap in gene identity, these signatures can classify similar subsets of patient who are at risk for metastatic relapse.

    CAS  Article  Google Scholar 

  100. 100

    Massagué, J. Sorting out breast-cancer gene signatures. N. Engl. J. Med. 356, 294–297 (2007).

    Article  PubMed  Google Scholar 

  101. 101

    Chang, H. Y. et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc. Natl Acad. Sci. USA 102, 3738–3743 (2005).

    CAS  Article  Google Scholar 

  102. 102

    Liu, R. et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356, 217–226 (2007).

    CAS  Article  PubMed  Google Scholar 

  103. 103

    Rhodes, D. R. & Chinnaiyan, A. M. Integrative analysis of the cancer transcriptome. Nature Genet. 37, S31–S37 (2005).

    CAS  Article  Google Scholar 

  104. 104

    Luzzi, K. J. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 153, 865–873 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Fidler, I. J. & Nicolson, G. L. Fate of recirculating B16 melanoma metastatic variant cells in parabiotic syngeneic recipients. J. Natl Cancer Inst. 58, 1867–1872 (1977).

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Khanna, C. & Hunter, K. Modeling metastasis in vivo. Carcinogenesis 26, 513–523 (2005).

    CAS  Article  Google Scholar 

  107. 107

    Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000). The first study to combine genomic profiling and in vivo selection for the identification of metastasis genes.

    CAS  Article  PubMed  Google Scholar 

  108. 108

    Khanna, C. et al. The membrane–cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nature Med. 10, 182–186 (2004).

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Minn, A. J. et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J. Clin. Invest. 115, 44–55 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Pinkel, D. & Albertson, D. G. Comparative genomic hybridization. Annu. Rev. Genomics Hum. Genet. 6, 331–354 (2005).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Adler, A. S. et al. Genetic regulators of large-scale transcriptional signatures in cancer. Nature Genet. 38, 421–430 (2006).

    CAS  Article  Google Scholar 

  112. 112

    Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).

    CAS  Article  Google Scholar 

  113. 113

    Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Sweet-Cordero, A. et al. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nature Genet. 37, 48–55 (2005).

    CAS  Article  Google Scholar 

  115. 115

    Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003).

    CAS  Article  PubMed  Google Scholar 

  116. 116

    Tarin, D., Vass, A. C., Kettlewell, M. G. & Price, J. E. Absence of metastatic sequelae during long-term treatment of malignant ascites by peritoneo-venous shunting. A clinico-pathological report. Invasion Metastasis 4, 1–12 (1984).

    CAS  PubMed  Google Scholar 

  117. 117

    Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513–520 (2005).

    CAS  Article  PubMed  Google Scholar 

  118. 118

    Nierodzik, M. L. & Karpatkin, S. Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell 10, 355–362 (2006).

    CAS  Article  PubMed  Google Scholar 

  119. 119

    Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    CAS  Article  PubMed  Google Scholar 

  120. 120

    Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).

    CAS  Article  Google Scholar 

  121. 121

    Chang, H. Y. et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2, e7 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Chi, J. T. et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med. 3, e47 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Bild, A. H. et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439, 353–357 (2006).

    CAS  Article  Google Scholar 

Download references


We apologize for omitting primary references and the work of those we could not cite owing to space limitations. We would like to thank A. Incassati, A. Chiang, P. Bos, D. Padua, G. Gupta and S.Tavazoie for insightful discussions. J.M. was funded by the National Institutes of Health, USA, grant P01-94060, and by a grant of the Keck Foundation, USA. D.X.N. is a Berlex postdoctoral fellow of the Damon Runyon Cancer Research Foundation, USA. J.M. is an Investigator of the Howard Hughes Medical Institute, USA.

Author information



Corresponding author

Correspondence to Joan Massagué.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


The Massagué laboratory at HHMI

The Massagué laboratory at SKI


Primary tumour

Cancer that arises from the malignant conversion of cells from an initial organ site.

Histological grade

Morphologically identifiable steps of tumour progression that are used to classify disease stage.

Organ tropism

A predilection of a primary tumour to spread to specific secondary organs.


The pathological growth of new blood vessels to support tumour growth.


Entry of tumour cells into the bloodstream.


Exit of tumour cells out of capillary beds into the parenchyma of an organ.


The main functional portion of an organ.


Clumped tumour cells that typically lodge in blood vessels.

Haematogenous dissemination

The spread of cancer cells through the bloodstream.


Skin cancer that is initiated by the transformation of melanocytes.

Metastasis suppressor gene

A gene in which loss of function specifically enhances metastasis without affecting primary tumour growth.

Mesenteric circulation

Blood flow from the intestines.

Peritoneal cavity

The space within the abdomen that contains the intestines, the stomach and the liver.

Palliative shunt

Diversion of malignant fluid to alleviate symptoms that arise from its accumulation in the body cavity.


A detectable accumulation of free fluid in the peritoneal cavity.

Metastasis initiation genes

A gene that is engaged in the invasion and intravasation of metastatic cells.

Metastasis progression gene

A gene that has dual functions in mediating primary tumorigenesis and metastatic colonization.

Metastasis virulence gene

A gene that is exclusively involved in distant organ colonization.

Focal contacts

Dynamic cell-adhesion structures.


A group of small signalling proteins (cytokines) that are usually secreted by immune cells.

Neural crest cell

Highly motile cells that originate from the ectoderm during development.


Paediatric malignancy that arises from skeletal muscle cells.

Stromal activation

Stimulation and mobilization of host cells in the microenvironment that surrounds a tumour.


The differentiation and activation of osteoclasts that mediates bone resorption.


Implantation of human tumour cells into an immunocompromized animal.

Orthotopic site

Transplant of tumour cells into the anatomical location of an animal that best recapitulates the original source of primary tumorigenesis.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nguyen, D., Massagué, J. Genetic determinants of cancer metastasis. Nat Rev Genet 8, 341–352 (2007).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing