Mechanisms of Metastasis: Seed and Soil

  • Adriano Piris
  • Martin C. Mihm
Part of the Cancer Treatment and Research book series (CTAR, volume 135)

Stephen Paget published in 1889 in The Lancet a paper by the title of “The distribution of secondary growths in cancer of the breast” inspired by the work of Fuchs “Das Sarkom des Uvealtractus” in 1882 published in Graefe’s Archiv Fur Ophthalmologie. Although Fuchs has written previously about the metastatic embolus and its relationship to the recipient tissue, it is Paget who spread the concept of the “seed and soil” that continues to be regarded as a major contribution to the area of cancer metastasis.The “seeds” refer to certain tumor cells with metastatic capability, and the “soil” is any organ or tissue providing a proper environment for growth of the seeds (1). Paget suggested that the spread of metastatic cells was organ specific and not merely anatomic.


Sentinel Lymph Node Cancer Stem Cell Focal Adhesion Kinase Cancer Metastasis Positive Sentinel Lymph Node 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1:571–3, 1889.CrossRefGoogle Scholar
  2. 2.
    Ewing J. Neoplastic Diseases. 6th edition. WB Saunders, Philadelphia. 1928.Google Scholar
  3. 3.
    Sugarbaker EV. Cancer metastasis: a product of tumor host interactions. Curr Probl Cancer 3:1–59, 1979.PubMedCrossRefGoogle Scholar
  4. 4.
    Hart IR, Fidler IJ. Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 40:2281–87, 1980.PubMedGoogle Scholar
  5. 5.
    Fidler IJ. Modulation of the organ environment for the treatment of cancer metastasis (editorial). J Natl Cancer Inst 84:1588–92, 1995.CrossRefGoogle Scholar
  6. 6.
    Schakert G, Fidler IJ. Site-specific metastasis of mouse melanomas and a fibrosarcoma in the brain or the meninges of syngeneic animals. Cancer Res 48:3478–3484, 1988b.Google Scholar
  7. 7.
    Fidler IJ. Critical determinants of metastasis. Semin Cancer Biol 12:89–96, 2002.PubMedCrossRefGoogle Scholar
  8. 8.
    Fidler IJ. Critical factors in the biology of human cancer metastasis: Twenty-Eighth GHA Clowes Memorial Lecture. Cancer Res 50:6130–6138, 1990.PubMedGoogle Scholar
  9. 9.
    Talmadge JE, Fidler IJ. Cancer metastasis is selective or random depending on the parent tumor population. Nature 297:593–4, 1982.PubMedCrossRefGoogle Scholar
  10. 10.
    Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64:327–336, 1991.PubMedCrossRefGoogle Scholar
  11. 11.
    Bernards R, Weinberg RA. A progression puzzle. Nature. 2002 Aug 22;418(6900):823.PubMedCrossRefGoogle Scholar
  12. 12.
    Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006 Jul 6;355(1):51–65.PubMedCrossRefGoogle Scholar
  13. 13.
    Axelson H, Fredlund E, Ovenberger M, Landberg G, Pahlman S. Hypoxia-induced dedifferentiation of tumor cells–a mechanism behind heterogeneity and aggressiveness of solid tumors. Semin Cell Dev Biol. 2005 Aug-Oct;16(4–5):554–63. Epub 2005 Apr 26. Review.Google Scholar
  14. 14.
    Wang H, Fu W, Im JH, Zhou Z, Santoro SA, Iyer V, DiPersio CM, Yu QC, Quaranta V, Al-Mehdi A, Muschel RJ. Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J Cell Biol. 2004 Mar 15;164(6):935–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Byers HR, Etoh T, Vink J, Franklin N, Gattoni-Celli S, Mihm MC Jr. Actin organization and cell migration of melanoma cells relate to differential expression of integrins and actin-associated proteins. J Dermatol. 1992 Nov;19(11):847–52.PubMedGoogle Scholar
  16. 16.
    Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, and Christofori G. (2006). Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9, 261–272.PubMedCrossRefGoogle Scholar
  17. 17.
    Wai PY, Guo L, Gao C, Mi Z, Guo H, Kuo PC. Osteopontin inhibits macrophage nitric oxide synthesis to enhance tumor proliferation. Surgery. 2006 Aug;140(2):132–40.PubMedCrossRefGoogle Scholar
  18. 18.
    Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997;3:730–737.PubMedCrossRefGoogle Scholar
  19. 19.
    Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004 Nov 18;432(7015):324–31. Review.PubMedCrossRefGoogle Scholar
  20. 20.
    Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006 Nov 17;127(4):679–95. Review.PubMedCrossRefGoogle Scholar
  21. 21.
    Overall CM, Kleifeld O. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006 Mar;6(3):227–39. Review.Google Scholar
  22. 22.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005 May 6;121(3):335–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Ruiter D, Bogenrieder T, Elder D, Herlyn M. Melanoma-stroma interactions: structural and functional aspects. Lancet Oncol. 2002 Jan;3(1):35–43. Review.PubMedCrossRefGoogle Scholar
  24. 24.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996 Aug 9;86(3):353–64. Review.PubMedCrossRefGoogle Scholar
  25. 25.
    Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005 Sep;18(9):1232–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Nash GF, Turner LF, Scully MF, and Kakkar AK. (2002). Platelets and cancer. Lancet Oncol. 3, 425–430.PubMedCrossRefGoogle Scholar
  27. 27.
    Ruiter DJ, van Krieken JH, van Muijen GN, de Waal RM. Tumour metastasis: is tissue an issue? Lancet Oncol. 2001 Feb;2(2):109–12. Review.Google Scholar
  28. 28.
    Morales J, Homey B, Vicari AP, Hudak S, Oldham E, Hedrick J, Orozco R, Copeland NG, Jenkins NA, McEvoy LM, Zlotnik A. CTAK, a skin associated chemokine that preferentially attracts skin homing memory T cells. Proc Natl Acad Sci USA 96:14470–75, 1999.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang H, Fu W, Im JH, Zhou Z, Santoro SA, Iyer V, DiPersio CM, Yu QC, Quaranta V, Al-Mehdi A, Muschel RJ. Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J Cell Biol. 2004 Mar 15;164(6):935–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001 Mar 1;410(6824):50–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Al-Mehdi, AD, Tozawa K, Fisher AD, Shientag L, Lee A, and Muschel RJ. (2000). Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat. Med. 6, 100–102.PubMedCrossRefGoogle Scholar
  32. 32.
    Kahnna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, and Helman LJ. (2004). The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat. Med. 10, 182–186.CrossRefGoogle Scholar
  33. 33.
    Criscuoli ML, Nguyen M, and Eliceiri BP. (2005). Tumor metastasis but not tumor growth is dependent on Src-mediated vascular permeability. Blood 105, 1508–1514.PubMedCrossRefGoogle Scholar
  34. 34.
    Tarin D, Price JE, Kettlewell MGW, Souter RG, Vass ACR, Crossley B. Clinicopathological observations on metastasis in man studied in patients treated with peritoneovenous shunts, Br Med J 288:749–751, 1984a.CrossRefGoogle Scholar
  35. 35.
    Tarin D, Price JE, Kettlewell MGW, Souter RG, Vass ACR, Crossley B. Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res 44:3584–3592, 1984b.PubMedGoogle Scholar
  36. 36.
    Kaplan RN, Rafii S, Lyden D. Preparing the “soil”: the premetastatic niche. Cancer Res. 2006 Dec 1;66(23):11089–93. Review.PubMedCrossRefGoogle Scholar
  37. 37.
    Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol. 2006 Sep;6(9):659–70. Review.Google Scholar
  38. 38.
    Cochran AJ, Morton DL, Stern S, Lana AM, Essner R, Wen DR. Sentinel lymph nodes show profound downregulation of antigen-presenting cells of the paracortex: implications for tumor biology and treatment. Mod Pathol. 2001 Jun;14(6):604–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Adriano Piris
    • 1
  • Martin C. Mihm
    • 1
  1. 1.Department of DermatopathologyMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations