Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Metastasis

Dissemination and growth of cancer cells in metastatic sites

Nature Reviews Cancer volume 2, pages 563–572 (2002)Cite this article

Key Points

  • Metastasis consists of a series of sequential steps, all of which must be successfully completed. These include shedding of cells from a primary tumour into the circulation, survival of the cells in the circulation, arrest in a new organ, extravasation into the surrounding tissue, initiation and maintenance of growth, and vascularization of the metastatic tumour.

  • Some types of tumour show an organ-specific pattern of metastasis. Both 'seed' (the cancer cell) and 'soil' (factors in the organ environment) contribute to this organ specificity.

  • Mechanical factors influence the initial fate of cancer cells after they have left a primary tumour. Blood-flow patterns from the primary tumour determine which organ the cells travel to first. There, the relative sizes of cancer cells and capillaries lead to the efficient arrest of most circulating cancer cells in the first capillary bed that they encounter.

  • After cells have arrested in an organ, their ability to grow is dictated by molecular interactions of the cells with the environment in the organ.

  • Metastasis is an inefficient process. In vivo videomicroscopy and cell-fate analysis have led to the conclusion that early steps in metastasis are completed very efficiently. By contrast, later steps in the process are inefficient. Metastatic inefficiency is due primarily to the regulation of cancer-cell growth in secondary sites.

  • Metastases can occur many years after primary cancer treatment. Tumour dormancy might be due to pre-angiogenic micrometastases that subsequently acquire the ability to become vascularized, or solitary cells that persist for an extended period of time without division in a secondary site. These cells would be resistant to current cancer therapies that target actively dividing cells.

  • Because growth of metastases is a primary determinant of metastatic outcome, the growth phase of the metastatic process is a promising therapeutic target. Treatments that target the specific 'seed–soil' compatibility that results in organ-specific metastatic growth would be especially useful.

Abstract

Metastases, rather than primary tumours, are responsible for most cancer deaths. To prevent these deaths, improved ways to treat metastatic disease are needed. Blood flow and other mechanical factors influence the delivery of cancer cells to specific organs, whereas molecular interactions between the cancer cells and the new organ influence the probability that the cells will grow there. Inhibition of the growth of metastases in secondary sites offers a promising approach for cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The metastatic process.
Figure 2: Vascular flow patterns and corresponding movement of cancer cells arising in different organs.
Figure 3: Cancer and normal cells arrest in the circulation.
Figure 4: Chemokines can influence organ-specific metastatic growth of cancer cells.
Figure 5: Activation of RAS signalling pathways can protect small metastases and promote their early growth.

Similar content being viewed by others

References

  1. Folkman, J. The role of angiogenesis in tumor growth. Semin. Cancer Biol. 3, 65–71 (1992).

    CAS  PubMed  Google Scholar 

  2. Woodhouse, E. C., Chuaqui, R. F. & Liotta, L. A. General mechanisms of metastasis. Cancer 80, 1529–1537 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Fidler, I. J. Critical determinants of cancer metastasis: rationale for therapy. Cancer Chemother. Pharmacol. 43, S3–S10 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Wyckoff, J. B., Jones, J. G., Condeelis, J. S. & Segall, J. E. A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res. 60, 2504–2511 (2000).This study used in vivo confocal microscopy to study details of the intravasation step of the metastatic process, and showed that metastatic tumours complete this step more efficiently than do non-metastatic tumours.

    CAS  PubMed  Google Scholar 

  6. Fidler, I. J. Orthotopic implantation of human colon carcinomas into nude mice provides a valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev. 10, 229–243 (1991).

    Article  CAS  PubMed  Google Scholar 

  7. Welch, D. R. Technical considerations for studying cancer metastasis in vivo. Clin. Exp. Metastasis 15, 272–306 (1997).A thorough compilation of technical and experimental design factors that should be considered when studying metastasis in experimental animals.

    Article  CAS  PubMed  Google Scholar 

  8. Chambers, A. F. & Tuck, A. B. Ras-responsive genes and tumor metastasis. Crit. Rev. Oncog. 4, 95–114 (1993).

    CAS  PubMed  Google Scholar 

  9. Kohn, E. C. & Liotta, L. A. Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res. 55, 1856–1862 (1995).

    CAS  PubMed  Google Scholar 

  10. Roberts, D. D. Regulation of tumor growth and metastasis by thrombospondin. FASEB J. 10, 1183–1191 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Chambers, A. F. & Matrisian, L. M. Changing views of the role of matrix metalloproteinases in metastasis. J. Natl Cancer Inst. 89, 1260–1270 (1997).In vivo video microscopy studies summarized in this review led to a changing paradigm for the role of matrix metalloproteinases (MMPs) in the metastatic process, and indicated that MMPs have a broader role and affect more steps in the metastatic process than was previously believed.

    Article  CAS  PubMed  Google Scholar 

  12. Freije, J. M., MacDonald, N. J. & Steeg, P. S. Nm23 and tumour metastasis: basic and translational advances. Biochem. Soc. Symp. 63, 261–271 (1998).

    CAS  PubMed  Google Scholar 

  13. Eccles, S. A. The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J. Mammary Gland Biol. Neoplasia 6, 393–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Skubitz, A. P. Adhesion molecules. Cancer Treat. Res. 107, 305–329 (2002).

    CAS  PubMed  Google Scholar 

  15. Chambers, A. F., MacDonald, I. C., Schmidt, E. E., Morris, V. L. & Groom, A. C. Preclinical assessment of anti-cancer therapeutic strategies using in vivo videomicroscopy. Cancer Metastasis Rev. 17, 263–269 (1998/99).

  16. Koop, S. et al. Overexpression of metalloproteinase inhibitor in B16F10 cells does not affect extravasation but reduces tumor growth. Cancer Res. 54, 4791–4797 (1994).

    CAS  PubMed  Google Scholar 

  17. Wylie, S. et al. The matrix metalloproteinase inhibitor batimastat inhibits angiogenesis in liver metastases of B16F1 melanoma cells. Clin. Exp. Metastasis 17, 111–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Chambers, A. F., MacDonald, I. C., Schmidt, E. E., Morris, V. L. & Groom, A. C. Clinical targets for anti-metastasis therapy. Adv. Cancer Res. 79, 91–121 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 99–101 (1889).An often-cited article, which initiated the current discussions on 'seed' and 'soil'. Reference 20 is a re-publication of this article, which might be more accessible to some readers, and is introduced by a commentary by Poste and Paruch (see reference 21).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Poste, G. & Paruch, L. Stephen Paget, M. D., F. R. C. S. (1855–1926): a retrospective. Cancer Metastasis Rev. 8, 93–97 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Ewing, J. in Neoplastic Diseases. A Treatise on Tumors 77–89 (W. B. Saunders Co., Philadelphia & London, 1928).The chapter on metastasis in this oncology text is often mentioned in the context of the 'seed' and 'soil' discussion, but the whole chapter is well worth reading for its clinical and pathological observations, which reflect the state of thinking at the time that this text was written.

    Google Scholar 

  23. Weiss, L. & Harlos, J. P. The validity of negative necropsy reports for metastases in solid organs. J. Pathol. 148, 203–206 (1986).

    Article  CAS  PubMed  Google Scholar 

  24. Weiss, L. et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J. Pathol. 150,195–203 (1986).

    Article  CAS  PubMed  Google Scholar 

  25. Weiss, L. et al. Metastatic patterns of renal carcinoma: an analysis of 687 necropsies. J. Cancer Res. Clin. Oncol. 114, 605–612 (1988).

    Article  CAS  PubMed  Google Scholar 

  26. Weiss, L. Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clin. Exp. Metastasis 10, 191–199 (1992).A detailed analysis of published data on metastatic patterns from autopsy studies, which provides evidence for two important points in the 'seed' and 'soil' debate: much organ-specific metastasis can be accounted for by mechanical blood-flow patterns between primary tumours and secondary sites, but some primary-tumour–secondary-site pairs show evidence of organ-specific enhancement or suppression of specific tumour types.

    Article  CAS  PubMed  Google Scholar 

  27. Hart, I. R. 'Seed and soil' revisited: mechanisms of site-specific metastasis. Cancer Metastasis Rev. 1, 5–16 (1982).

    Article  CAS  PubMed  Google Scholar 

  28. Zetter, B. R. The cellular basis of site-specific tumor metastasis. N. Engl. J. Med. 322, 605–612 (1990).

    Article  CAS  PubMed  Google Scholar 

  29. Fidler, I. J. Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surg. Oncol. Clin. N.Am. 10, 257–269 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. 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).The first study to quantify the metastatic efficiency of individual, sequential steps in the metastatic process. Early stages in haematogenous metastasis are completed quite efficiently, whereas the growth phases of metastasis are very inefficient, indicating that regulation of growth in a secondary site is a key regulator of overall metastatic ability. Similar conclusions were reached, for a different cell line and target organ, in reference 31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cameron, M. D. et al. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res. 60, 2541–2546 (2000).

    CAS  PubMed  Google Scholar 

  32. Varghese, H. J. et al. Activated Ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases. Cancer Res. 62, 887–891 (2002).

    CAS  PubMed  Google Scholar 

  33. Potter, R. F. & Groom, A. C. Capillary diameter and geometry in cardiac and skeletal muscle studied by means of corrosion casts. Microvasc. Res. 25, 68–84 (1983).

    Article  CAS  PubMed  Google Scholar 

  34. Panes, J. & Granger, D. N. Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinal disease. Gastroenterology 114, 1066–1090 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Morris, V. L. et al. Effects of the disintegrin eristostatin on individual steps of hematogenous metastasis. Exp. Cell Res. 219, 571–578 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Hangan, D. et al. Integrin VLA-2 (α2β1) function in postextravasation movement of human rhabdomyosarcoma RD cells in the liver. Cancer Res. 56, 3142–3149 (1996).

    CAS  PubMed  Google Scholar 

  37. Orr, F. W. & Wang, H. H. Tumor cell interactions with the microvasculature: a rate-limiting step in metastasis. Surg. Oncol. Clin. N. Am. 10, 357–381 (2001).Documents that the activation state of the endothelium can influence whether cancer cells arrest by adhesive interactions in pre-capillary vessels or by size restriction in smaller capillaries.

    Article  CAS  PubMed  Google Scholar 

  38. Radinsky, R. Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment. Cancer Metastasis Rev. 14, 323–338 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Fidler, I. J. Modulation of the organ microenvironment for treatment of cancer metastasis. J. Natl Cancer Inst. 87, 1588–1592 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Radinsky, R. Molecular mechanisms for organ-specific colon carcinoma metastasis. Eur. J. Cancer 31A, 1091–1095 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Radinsky, R. & Ellis, L. M. Molecular determinants in the biology of liver metastasis. Surg. Oncol. Clin. N. Am. 5, 215–229 (1996).Studies reviewed in references 38–41 show clearly that molecular interactions between cancer cells and secondary organs can contribute to organ-specific metastasis, and provide molecular evidence for the nature of these interactions.

    Article  CAS  PubMed  Google Scholar 

  42. Mundy, G. R. Mechanisms of bone metastasis. Cancer 80,1546–1556 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Yoneda, T., Williams, P. J., Hiraga, T., Niewolna, M. & Nishimura, R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J. Bone Miner. Res. 16, 1486–1495 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Kuo,T. H. et al. Liver colonization competence governs colon cancer metastasis. Proc. Natl Acad. Sci. USA 92, 12085–12099 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nakajima, M., Morikawa, K., Fabra, A., Bucana, C. D. & Fidler, I. J. Influence of organ environment on extracellular matrix degradative activity and metastasis of human colon carcinoma cells. J. Natl Cancer Inst. 82,1890–1898 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Gohji, K. et al. Organ-site dependence for the production of urokinase-type plasminogen activator and metastasis by human renal cell carcinoma cells. Am. J. Pathol. 151, 1655–1661 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Dalton, W. S. The tumor microenvironment as a determinant of drug response and resistance. Drug Resist. Updat. 2, 285–288 (1999).References 45–48 show that gene expression and cancer-cell behaviour can be markedly altered by the environment that cancer cells encounter in specific secondary sites.

    Article  CAS  PubMed  Google Scholar 

  49. Yu, J. L., Rak, J. W., Coomber, B. L., Hicklin, D. J. & Kerbel, R. S. Effect of p53 status on tumor response to antiangiogenic therapy. Science 295, 1526–1528 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Hendrix, M. J. et al. Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res. 62, 665–668 (2002).

    CAS  PubMed  Google Scholar 

  51. Rinker-Schaeffer, C. W., Welch, D. R. & Sokoloff, M. Defining the biologic role of genes that regulate prostate cancer metastasis. Curr. Opin. Urol. 10, 397–401 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Welch, D. R., Steeg, P. S. & Rinker-Schaeffer, C. W. Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis. Breast Cancer Res. 2, 408–416 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Campbell, J. J. & Butcher, E. C. Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr. Opin. Immunol. 12, 336–341 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Homey, B., Muller, A. & Zlotnik, A. Chemokines: agents for the immunotherapy of cancer? Nat. Rev. Immunol. 2, 175–184 (2002).|PubMed|

    Article  CAS  PubMed  Google Scholar 

  58. Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).A conceptually important study that identifies molecular interactions that might contribute to organ-specific metastasis. This study is discussed in references 59–61.

    Article  PubMed  Google Scholar 

  59. Liotta, L. A. An attractive force in metastasis. Nature 410, 24–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Moore, M. A. The role of chemoattraction in cancer metastases. Bioessays 23, 674–676 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Murphy, P. M. Chemokines and the molecular basis of cancer metastasis. N. Engl. J. Med. 345, 833–835 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Popik, W., Hessselgesser, J. E. & Pitha, P. M. Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway. J. Virol. 72, 6406–6413 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tarin, D. Molecular genetics of metastasis. Ciba Found. Symp. 141,149–169 (1988).

    CAS  PubMed  Google Scholar 

  64. Greenberg, A. H., Egan, S. E. & Wright, J. A. Oncogenes and metastatic progression. Invasion Metastasis 9, 360–378 (1989).

    CAS  PubMed  Google Scholar 

  65. McKenna, W. G. et al. The role of the H-ras oncogene in radiation resistance and metastasis. Int. J. Radiat. Oncol. Biol. Phys. 18, 849–859 (1990).

    Article  CAS  PubMed  Google Scholar 

  66. Matrisian, L. M. et al. The role of the matrix metalloproteinase stromelysin in the progression of squamous cell carcinomas. Am. J. Med. Sci. 302, 157–162 (1991).

    Article  CAS  PubMed  Google Scholar 

  67. Chambers, A. F. Mechanisms of oncogene-mediated alterations in metastatic ability. Biochem. Cell. Biol. 70, 817–821 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Rak, J. et al. Oncogenes as inducers of tumor angiogenesis. Cancer Metastasis Rev. 14, 263–277 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Joneson, T. & Bar-Sagi, D. Ras effectors and their role in mitogenesis and oncogenesis. J. Mol. Med. 75, 587–593 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Katz, M. E. & McCormick, F. Signal transduction from multiple Ras effectors. Curr. Opin. Genet. Dev. 7, 75–79 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J. & Der, C. J. Increasing complexity of Ras signaling. Oncogene 17, 1395–1413 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Webb, C. P. et al. Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene 17, 2019–2025 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Webb, C. P., Van Aelst, L., Wigler, M. H. & Vande Woude, G. F. Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc. Natl Acad. Sci. USA 95, 8773–8778 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Akhurst, R. J. & Derynck, R. TGF-β signaling in cancer: a double-edged sword. Trends Cell Biol. 11, S44–S51 (2001).

    CAS  PubMed  Google Scholar 

  75. Malaney, S. & Daly, R. J. The Ras signaling pathway in mammary tumorigenesis and metastasis. J. Mammary Gland Biol. Neoplasia 6, 101–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Pruitt, K. & Der, C. J. Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett. 171, 1–10 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Bos, J. L. Ras oncogenes in human cancer: a review. Cancer Res. 49, 4682–4689 (1989).

    CAS  PubMed  Google Scholar 

  78. Clark, G. J. & Der, C. J. Aberrant function of the Ras signal transduction pathway in human breast cancer. Breast Cancer Res. Treat. 35, 133–144 (1995).

    Article  CAS  PubMed  Google Scholar 

  79. Koop, S. et al. Independence of metastatic ability and extravasation: metastatic Ras-transformed and control fibroblasts extravasate equally well. Proc. Natl Acad. Sci. USA 93, 11080–11084 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Weiss, L. Metastatic inefficiency. Adv. Cancer Res. 54, 159–211 (1990).

    Article  CAS  PubMed  Google Scholar 

  81. Sugarbaker, P. H. Metastatic inefficiency: the scientific basis for resection of liver metastases from colorectal cancer. J. Surg. Oncol. Suppl. 3, 158–160 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  83. Naumov, G. M. et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 62, 2162–2168 (2002).This study documents that solitary dormant cancer cells might persist for long periods of time in secondary sites, neither dividing nor undergoing apoptosis. These cells could contribute to tumour dormancy, and would not be susceptible to therapies that target actively dividing cancer cells.

    CAS  PubMed  Google Scholar 

  84. Meltzer, A. Dormancy and breast cancer. J. Surg. Oncol. 43, 181–188 (1990).

    Article  CAS  PubMed  Google Scholar 

  85. Karrison, T. G., Ferguson, D. J. & Meier, P. Dormancy of mammary carcinoma after mastectomy. J. Natl Cancer Inst. 91, 80–85 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Naumov, G. N., MacDonald, I. C., Chambers, A. F. & Groom, A. C. Solitary cancer cells as a possible source of tumour dormancy? Semin. Cancer Biol. 11, 271–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Demicheli, R. Tumour dormancy: findings and hypotheses from clinical research on breast cancer. Semin. Cancer Biol. 11, 297–306 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Demicheli, R., Terenziani, M. & Bonadonna, G. Estimate of tumor growth time for breast cancer local recurrences: rapid growth after wake-up? Breast Cancer Res. Treat. 51, 133–137 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Holmgren, L., O'Reilly, M. S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1,149–153 (1995).This study documents that pre-angiogenic micrometastases can exist in a 'dormant' state, in which active proliferation is balanced by apoptosis owing to a failure to attract new blood vessels, resulting in no net growth, and indicates that this form of tumour dormancy could be broken by the acquisition of angiogenic ability.

    Article  CAS  PubMed  Google Scholar 

  91. Hahnfeldt, P., Panigrahy, D., Folkman, J. & Hlatky, L. Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res. 59, 4770–4775 (1999).

    CAS  PubMed  Google Scholar 

  92. Morris, V. L. et al. Mammary carcinoma cell lines of high and low metastatic potential differ not in extravasation but in subsequent migration and growth. Clin. Exp. Metastasis 12, 357–367 (1994).

    Article  CAS  PubMed  Google Scholar 

  93. Naumov, G. N. et al. Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. J. Cell Sci. 112, 1835–1842 (1999).This study describes the utility of a heritable transfected fluorescent marker, GFP (green fluorescent protein), in monitoring and quantifying individual steps in the metastatic process.

    Article  CAS  PubMed  Google Scholar 

  94. Pegram, M. D., Konecny, G. & Slamon, D. J. The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of Herceptin (trastuzumab) therapy for breast cancer. Cancer Treat. Res. 103, 57–75 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Slichenmyer, W. J. & Fry, D. W. Anticancer therapy targeting the erbB family of receptor tyrosine kinases. Semin. Oncol. 28, 67–79 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Griffin, J. The biology of signal transduction inhibition: basic science to novel therapies. Semin. Oncol. 28, 3–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Adjei, A. A. Blocking oncogenic Ras signaling for cancer therapy. J. Natl Cancer Inst. 93, 1062–1074 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Diel, I. J., Solomayer, E. F. & Bastert, G. Bisphosphonates and the prevention of metastasis: first evidences from preclinical and clinical studies. Cancer 88, 3080–3088 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Theriault, R. L. & Hortobagyi, G. N. The evolving role of bisphosphonates. Semin. Oncol. 28, 284–290 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to those authors whose work we could not cite directly due to space constraints. The authors acknowledge the contributions of current and former laboratory members to the work discussed in this review. We thank especially G. Naumov and H. Varghese for their creativity and expertise in helping to develop the figures. The authors' research summarized here is supported by the Canadian Institutes of Health Research, the US Department of Defense Breast Cancer Research Program and the Lloyd Carr–Harris Foundation.

Author information

Authors and Affiliations

  1. London Regional Cancer Centre, London, N6A 4L6, Ontario, Canada

    Ann F. Chambers

  2. Department of Oncology, University of Western Ontario, London, N6A 4L6, Ontario, Canada

    Ann F. Chambers & Ian C. MacDonald

  3. Department of Medical Biophysics, University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Ann F. Chambers, Alan C. Groom & Ian C. MacDonald

Authors
  1. Ann F. Chambers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan C. Groom
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian C. MacDonald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ann F. Chambers.

Related links

Related links

DATABASES

Cancer.gov

bone cancer

brain cancer

breast cancer

colorectal cancer

liver cancer

lung cancer

melanoma

prostate cancer

stomach cancer

testicular cancer

LocusLink

actin

BRMS1

CCL21

CCL27

CCR7

CCR10

CXCR4

epidermal growth-factor receptor

HRAS

IL-1α

IL-6

insulin-like growth-factor 1

MAPK

MMPs

parathyroid hormone-related protein

RAS

TGF-α

TGF-β

TIMP1

Medscape DrugInfo

Glivec

Herceptin

FURTHER INFORMATION

Ann Chambers' lab

PBS Nova show 'Cancer Warrior'

Glossary

ANGIOGENESIS

The formation of new blood vessels that are needed for growth of primary tumours and metastases that are beyond a minimal size.

ORTHOTOPIC INJECTION

Injection of cancer cells into the 'correct' anatomical site for primary tumour growth — for example, mammary fat pad for breast cancer cells.

HAEMATOGENOUS METASTASIS

Metastasis via the bloodstream.

ISCHAEMIA

A reduction in local tissue oxygen levels due to inadequate blood supply.

VASCULAR MIMICRY

The formation of blood-flow channels that lack an endothelium, which might be formed by tumour cells in some tumours.

TRASTUZUMAB

(Herceptin). A humanized monoclonal antibody against the ERBB2 receptor that is used to treat breast cancers that are shown to be positive for this receptor.

IMATINIB

(Glivec). A small-molecule therapy that targets the Abelson leukaemia (ABL) kinase. It is used to treat patients with chronic myelogenous leukaemia.

FARNESYLTRANSFERASE INHIBITORS

Therapeutic agents that target a specific post-translational modification — farnesylation — which allows the RAS protein to attach to the inner cell membrane and which is necessary for RAS-mediated signalling.

BISPHOSPHONATES

A class of compounds that inhibit the bone-resorptive activity of osteoclasts, and are used to treat osteoporosis. They might also be useful in the treatment and prevention of metastases growing in the bone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chambers, A., Groom, A. & MacDonald, I. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2, 563–572 (2002). https://doi.org/10.1038/nrc865

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc865

This article is cited by

Search

Advanced search

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