“What is it that decides what organs shall suffer a case of disseminated cancer?” This question intrigued Stephen Paget, assistant surgeon to the West London hospital and the Metropolitan hospital, whose self-effacing paper of 1889 records his careful analyses of case histories that led to the visionary 'soil and seed' hypothesis of metastasis.

“When a plant goes to seed, its seeds are carried in all directions,” he wrote. “But they can only live and grow if they fall on congenial soil.” This idea was at odds with one prevalent theory of the time, which stated that cancer cells, having been spread through the body in the blood or lymph, could lodge in a tissue and persuade the surrounding cells to grow similarly. However, Paget followed the school of thought that all cancer cells could continually develop wherever they settled, but grew only in certain organs that were somehow predisposed to a secondary cancer.

Paget reasoned that if the organs where secondary tumours arose were 'passive' in the process, then these cancers would be distributed randomly. By analysing 735 case histories of fatal breast cancer, he found that metastases formed in the liver far more often than in any other organ — even those such as the spleen that could be considered to have the same exposure to the cancer cells because of similar blood flows.

This was enough to persuade Paget that sites of secondary growths are not a matter of chance, and that some organs provide a more fertile environment than others for the growth of certain metastases. “The best work in the pathology of cancer is now done by those who ... are studying the nature of the seed,” he noted. “They are like scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observation of the properties of the soil may also be useful.”

This proved to be the case and, although it languished in the shadows for many years, the seed and soil hypothesis was revived fully in 1980 by Ian Hart and IsaiahFidler. By this time, clinical observations had established that certain organs were, indeed, more susceptible to metastasis, even after specific properties of the tumour cells and other host factors had been accounted for.

So, Hart and Fidler examined whether the locations of metastases exist merely because tumour cells tend to come to rest in particular organs — for instance, because the blood capillaries are more narrow — or because the distributed cells can only grow at particular sites, in accordance with the Paget hypothesis. Using mice, they grafted kidney, ovary and lung tissue under the skin or into the muscle, and showed that the transplanted tissues established their own blood supply. They then injected the mice with melanoma cells. Metastases developed in the grafted lung and ovary tissue but not in the renal tissue, thereby showing a distinct preference.

Notably, radioactive labelling of the injected cells showed that they were equally likely to be trapped in the kidney tissue as in either of the other transplants. So, just landing in a tissue is not sufficient for cancer cells to develop a secondary tumour; rather, some property of the tissue itself must sustain the new growth. The idea that cancer cells require some 'nourishment' from their environment to develop still motivates research today, with the focus now being on unravelling the molecular mechanisms that bring seed and soil together to promote metastases.