From the Archives

The seed and soil hypothesis revisited

Isaiah J Fidler, George Poste
Lancet Oncol 2008; 9: 808 Cancer Metastasis Research Center, MD Anderson Cancer Center, Houston, TX, USA (Prof I J Fidler PhD); and The Biodesign Institute, Arizona State University, Tempe, AZ, USA (Prof G Poste PhD) Correspondence to: Prof Isaiah J Fidler, Cancer Metastasis Research Center, MD Anderson Cancer Center, Houston, TX 77030, USA idler@mdanderson.org

The pathogenesis of metastasis consists of a series of sequential, interrelated steps. The outcome of the process is dependent on both the intrinsic properties of tumour cells and the response of the host.1 The current concept that metastasis occurs when tumour cells interact with a specic organ microenvironment is not new. In 1889, the English surgeon, Stephen Paget, published his report, Distribution of secondary growths in cancer of the breast, to answer the question, What is it that decides what organs shall suer in a case of disseminated cancer?.2 He scrutinised the autopsy records of 735 women with fatal breast cancer and was struck by the discrepancy between the relative blood supply and the frequency of metastasis in some organs. He commented especially on the high incidence of metastasis in the liver, ovary, and specic bones, and the low incidence in the spleen. He also noted that this disproportion was less pronounced with melanoma than with breast or uterine cancer. These ndings contradicted the prevailing theory proposed by Virchow3 that metastasis can be explained merely by the lodgement of tumour-cell emboli in the vasculature. Paget concluded that remote organs cannot be altogether passive or indierent regarding embolism and provided the everlasting seed and soil principle, stating: When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil. He concluded his report with the endearing statement, All reasoning from statistics is liable to many errors. But the analogy from other diseases seems to support what these records have suggested, the dependence of the seed upon the soil. The best work in the pathology of cancer is now done by those who, like
Key ndings of the 1889 paper by Paget The pattern of metastasis is not random One remote organ is more prone to be the seat of secondary growth than another In breast cancer, the incidence of metastasis to the ovaries is higher than to the spleen and kidneys combined Bone metastasis cannot be explained by the theory of embolism alone There is a high incidence of bone metastasis from thyroid cancer, and some bones have more metastases than others

Mr Balance and Mr Shattock, are studying the nature of the seed. They are like scientic botanists, and he who turns over the records of cases of cancer is only the ploughman, but his observations of the properties of the soil may also be helpful. In 1929, James Ewing challenged Pagets seed and soil theory and proposed that metastatic dissemination occurs by purely mechanical factors that are determined by the anatomical structure of the vascular system.4 This viewpoint prevailed for many decades. In the 1970s, the selective nature of metastasis was documented along with the biological heterogeneity of neoplasms.5 Our studies, in which we grafted fragments of kidney, ovary, and lung tissue into the subcutis or muscle of syngeneic mice, followed by the intravenous injection of melanoma cells, provided the denitive proof of Pagets hypothesis by showing that although tumour cells reached the vasculature of all organs, metastases developed in the orthotopic and grafted lungs and ovaries, but not in the kidneys.6 There are few scientists whose work will withstand 120 years of scrutiny or not succumb to the depressing trend of modern publications to ignore papers published more than 5 years ago. Pagets seminal paper was virtually unknown outside the metastasis community and was not accorded serious consideration during his lifetime. He has been completely vindicated. The seed and soil hypothesis is now widely accepted and cited. The seed has been renamed to progenitor cell, initiating cell, cancer stem cell, or metastatic cell, and the soil to host factors, stroma, or the organ microenvironment. Regardless of the terminology, no one now disputes that the outcome of metastasis is dependent on the cross-talk between tumour cells and receptive tissues.
Conicts of interest The authors declared no conicts of interest. References 1 Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980; 283: 13946. 2 Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889; 133: 57173. 3 Virchow R. Cellularpathologie, 4th edn. Berlin: Hirschwald, 1858. 4 Ewing J. Neoplastic diseases. 6th edn. Philadelphia, PA: WB Saunders, 1928. 5 Fidler IJ, Kripke ML. Metastasis results from pre-existing variant cells within a malignant tumor. Science 1977; 197: 89395. 6 Hart I, Fidler IJ. Role of organ selectivity in the determination of metastatic spread of the B16 melanoma. Cancer Res 1980; 40: 228187.

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www.thelancet.com/oncology Vol 9 August 2008