In 1889, Stephen Paget proposed the “seed and soil” hypothesis for the growth of cancer metastases. Paget was struck by the preferential localization of breast cancer metastases in bone and liver, and suggested that the spread of metastatic cancers depended upon the environment of the receiving tissue as well as on the properties of the incoming metastatic cells (Paget 1889). For a long time, Paget’s hypothesis was ignored by cancer biologists, who focused instead on the mutations and epimutations that convert normal cells to cancer cells, and on the selective advantage of cells that escape normal growth controls, avoid apoptosis, promote the growth of their own blood supply, etc. Recently, however, as oncologists have recognized that the development of cancer is a Darwinian process of mutation and selection, they have begun to pay more attention to the ecological interactions that affect the fitness of cancer cells (Merlo et al. 2006). These interactions include not only the interactions between tumor cells and the normal cells, extracellular matrix, and extracellular fluids that surround them, but also the relationships between different cell lineages within a tumor, and between primary tumors and their metastases. A new article by Scott Morgan and Chris Parker has reviewed the evidence for cooperation between primary tumors and their metastatic colonies (Morgan and Parker 2011). Renal cell carcinoma is the one well-documented case for such cooperation. Several studies have shown that nephrectomy results in systemic benefits and improved survival of patients with metastatic renal cell carcinoma. The mechanism of these beneficial effects isn’t clear; the primary tumors may secrete cytokines or other substances that promote the growth of metastases, or they may attract and sequester cytotoxic T cells that then become free to attack the metastases. Whatever the mechanism, primary renal cell cancers appear to enhance the fitness of their metastatic offshoots. These observations have direct clinical relevance. Oncologists have been reluctant to propose surgery or other radical local therapy for patients with metastatic cancers because they believed that removal of primary tumors would be unlikely to help these patients. Now, however, nephrectomy is the standard of care for some patients with metastatic renal cell carcinoma. There is anecdotal evidence for similar cooperative interactions between other kinds of primary tumors and their metastases; removing these other primary tumors may also benefit patients. Of course, ecological interactions are complex; tumors in different parts of the body, or cell lineages within a single tumor, may compete (for space, or for nutrients and growth factors) as well as cooperate (Merlo et al. 2006). If competitive interactions dominate, removal of primary tumors or destruction of cell lineages by chemotherapy may increase the fitness of the remaining cells and so may have detrimental consequences. Understanding the ecology of metastatic cancers and using this understanding to improve patient care will require careful clinical investigation. Morgan and Parker’s provocative paper has called attention to the importance of cancer ecology and to the necessity for these clinical studies.

Merlo, L. M., et al. 2006. Cancer as an evolutionary and ecological process. Nat Rev Cancer 6(12):924-35.

Morgan, S. C., and C. C. Parker. 2011. Local treatment of metastatic cancer-killing the seed or disturbing the soil? Nat Rev Clin Oncol 8(8):504-6.

Paget, S. 1889. The distribution of secondary growths in cancer of the breast. Lancet 133(3421, March 23):571–73.