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.

  • Timeline
  • Published:

The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited

Nature Reviews Cancer volume 3, pages 453–458 (2003)Cite this article

Abstract

Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?

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
Figure 2: The main steps in the formation of a metastasis.
Figure 3: Sequential steps in the pathogenesis of cancer metastasis.
Figure 4: Metastatic heterogeneity.

References

  1. Weiss, L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev. 19, 193–400 (2000).

    Article  Google Scholar 

  2. Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 1, 571–573 (1889).

    Article  Google Scholar 

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

    Google Scholar 

  4. Hart, I. R. & Fidler, I. J. Role of organ selectivity in the determination of metastatic patterns of the B16 melanoma. Cancer Res. 40, 2281–2287 (1980).

    CAS  PubMed  Google Scholar 

  5. Sugarbaker, E. V. Cancer metastasis: a product of tumour-host interactions. Curr. Probl. Cancer 3, 1–59 (1979).

    Article  CAS  Google Scholar 

  6. Poste, G. & Fidler, I. J. The pathogenesis of cancer metastasis. Nature 283, 139–146 (1979).

    Article  Google Scholar 

  7. Fidler, I. J. The organ microenvironment and cancer metastasis. Differentiation 70, 498–505 (2002).

    Article  Google Scholar 

  8. Coman, D. R., de Long, R. P. & McCutcheon, M. Studies on the mechanism of metastasis: the distribution of tumours in various organs in relation to the distribution of arterial emboli. Cancer Res. 11, 648–654 (1951).

    CAS  PubMed  Google Scholar 

  9. Lucke, B. et al. Differential growth of metastatic tumours in liver and lung: experiments with rabbit V2 carcinoma. Cancer Res. 12, 734–738 (1952).

    CAS  PubMed  Google Scholar 

  10. Zeidman, I., McCutcheon, M. & Coman, D. R. Factors affecting the number of tumour metastases, experiments with a transplantable mouse tumour. Cancer Res. 10, 357–364 (1950).

    CAS  PubMed  Google Scholar 

  11. Zeidman, I. & Buss, J. M. Transpulmonary passage of tumour cell emboli. Cancer Res. 12, 731–737 (1952).

    CAS  PubMed  Google Scholar 

  12. Fisher, E. R. & Fisher B. Recent observations on concepts of metastasis. Arch. Pathol. 83, 321–324 (1967).

    CAS  PubMed  Google Scholar 

  13. Zeidman, I. Metastasis: a review of recent advances. Cancer Res. 17, 157–164 (1957).

    CAS  PubMed  Google Scholar 

  14. Fisher, B. & Fisher, E. R. The organ distribution of disseminated 51Cr-labeled tumour cells. Cancer Res. 27, 412–419 (1967).

    CAS  PubMed  Google Scholar 

  15. Fidler, I. J. Metastasis: quantitative analysis of distribution and fate of tumour emboli labeled with 125I-5-iodo-2′-deoxyuridine. J. Natl Cancer Inst. 45, 773–782 (1970).

    CAS  PubMed  Google Scholar 

  16. Weiss, L. Metastatic inefficiency: causes and consequences. Cancer Metastasis Rev. 3, 1–24 (1986).

    Google Scholar 

  17. Fidler, I. J. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 50, 6130–6138 (1990).

    CAS  PubMed  Google Scholar 

  18. Heppner, G. Tumour heterogeneity. Cancer Res. 44, 2259–2265 (1984).

    CAS  PubMed  Google Scholar 

  19. Nicolson, G. L. Generation of phenotypic diversity and progression in metastatic tumour cells. Cancer Metastasis Rev. 3, 25–42 (1984).

    Article  CAS  Google Scholar 

  20. Foulds, L. The experimental study of tumour progression. Cancer Res. 14, 327–339 (1954).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Luria, S. E. & Delbruck, M. Mutations of bacteria from virus sensitive to virus resistance. Genetics 28, 491–511 (1943).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Cifone, M. A. & Fidler, I. J. Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc. Natl Acad. Sci. USA 78, 6949–6952 (1981).

    Article  CAS  Google Scholar 

  24. Hart, I. R. & Easty, D. Tumour cell progression and differentiation in metastasis. Semin. Cancer Biol. 2, 87–97 (1991).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  26. Poste, G. Experimental systems for analysis of the malignant phenotype. Cancer Metastasis Rev. 1, 141–200 (1982).

    Article  CAS  Google Scholar 

  27. Nicolson, G. L. Cancer metastasis: tumour cell and host organ properties important in metastasis to specific secondary sites. Biochem. Biophys. Acta 948, 175–224 (1988).

    CAS  PubMed  Google Scholar 

  28. Fidler, I. J. & Kripke, M. L. Metastasis results from pre-existing variant cells within a malignant tumour. Science 197, 893–895 (1977).

    Article  CAS  Google Scholar 

  29. Fidler, I. J. et al. Demonstration of multiple phenotype diversity in a murine melanoma of recent origin. J. Natl Cancer Inst. 67, 947–956 (1981).

    CAS  PubMed  Google Scholar 

  30. Kerbel, R. S., Man, M. S. & Dexter, D. A model of human cancer metastasis: extensive spontaneous and artificial metastasis of a human pigmented melanoma and derived variant sublines in nude mice. J. Natl Cancer Inst. 72, 93–108 (1984).

    Article  CAS  Google Scholar 

  31. Talmadge, J. E., Wolman, S. R. & Fidler, I. J. Evidence for the clonal origin of spontaneous metastasis. Science 217, 361–363 (1982).

    Article  CAS  Google Scholar 

  32. Fidler, I. J. & Talmadge, J. E. Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumour cell. Cancer Res. 46, 5167–5171 (1986).

    CAS  PubMed  Google Scholar 

  33. Tarin, D. et al. Clinicopathological observations on metastasis in man studied in patients treated with peritoneovenous shunts. BMJ 288, 749–751 (1984).

    Article  CAS  Google Scholar 

  34. Tarin, D. et al. Mechanisms of human tumour metastasis studied in patients with peritoneovenous shunts. Cancer Res. 44, 3584–3592 (1984).

    CAS  PubMed  Google Scholar 

  35. Schackert, G. & Fidler, I. J. Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or the meninges of syngeneic animals. Cancer Res. 48, 3478–3484 (1988).

    CAS  PubMed  Google Scholar 

  36. Simone, N. L. et al. Laser capture microdissection: opening the microscopic frontier to molecular analysis. Trends Genet. 14, 272–276 (1998).

    Article  CAS  Google Scholar 

  37. Pasqualini, R. & Ruoslahti, E. Organ targeting in vivo using phage display peptide libraries. Nature 380, 364–366 (1996).

    Article  CAS  Google Scholar 

  38. Uehara, H. et al. Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases.. J. Natl Cancer Inst. 95, 458–470 (2003).

    Article  CAS  Google Scholar 

  39. Folkman, J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial award lecture. Cancer Res. 46, 467–743 (1986).

    CAS  PubMed  Google Scholar 

  40. Liotta, L. A. Tumour invasion and metastasis — role of the extracellular matrix: Rhoads memorial award lecture. Cancer Res. 46, 1–7 (1986).

    Article  CAS  Google Scholar 

  41. Fisher, B. & Fisher, E. R. The interrelationship of hematogenous and lymphatic tumour cell dissemination. Surg. Gynecol. Obstet. 122, 791–797 (1966).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. the Department of Cancer Biology, The University of Texas, M. D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Isaiah J. Fidler

Authors
  1. Isaiah J. Fidler
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

cancer.gov

breast cancer

colon cancer

melanoma

ovarian cancer

renal-cell carcinoma

FURTHER INFORMATION

National Cancer Institute's questions and answers about metastatic cancer

Glossary

ASCITES

The intraperitoneal accumulation of transudate (watery fluid).

CINEPHOTOMICROGRAPHY

The process of recording (making movies of) the movements of objects that are viewed through a microsope.

CROTON OIL

Oil that is produced from the seed of the tree Croton tiglium. It is an irritant that is used as a tumour promoter.

PERITONEOVENOUS SHUNTS

Drainage of ascitic fluids into the jugular vein through a tube.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fidler, I. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453–458 (2003). https://doi.org/10.1038/nrc1098

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1098

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