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 specific 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 suffer 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 specific 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 findings 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 indifferent 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

Mr Balance and Mr Shattock, are studying the nature of the seed. They are like scientific 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 Paget’s “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 definitive proof of Paget’s 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