MILESTONES MILESTONE 1 Observations from a ploughman “What is it that decides what organs shall suffer be considered to have the same exposure to the in accordance with the Paget hypothesis. Using a case of disseminated cancer?” This question cancer cells because of similar blood flows. mice, they grafted kidney, ovary and lung tissue intrigued Stephen Paget, assistant surgeon to This was enough to persuade Paget that under the skin or into the muscle, and showed the West London hospital and the Metropolitan sites of secondary growths are not a matter that the transplanted tissues established their hospital, whose self-effacing paper of 1889 of chance, and that some organs provide a own blood supply. They then injected the mice records his careful analyses of case histories that more fertile environment than others for with melanoma cells. Metastases developed led to the visionary ‘soil and seed’ hypothesis of the growth of certain metastases. “The best in the grafted lung and ovary tissue but not in metastasis. work in the pathology of cancer is now done the renal tissue, thereby showing a distinct “When a plant goes to seed, its seeds are by those who … are studying the nature of preference. carried in all directions,” he wrote. “But they the seed,” he noted. “They are like scientific Notably, radioactive labelling of the injected can only live and grow if they fall on con- botanists; and he who turns over the records cells showed that they were equally likely to be genial soil.” This idea was at odds with one of cases of cancer is only a ploughman, but trapped in the kidney tissue as in either of the prevalent theory of the time, which stated his observation of the properties of the soil other transplants. So, just landing in a tissue that cancer cells, having been spread through may also be useful.” is not sufficient for cancer cells to develop a the body in the blood or lymph, could lodge This proved to be the case and, although secondary tumour; rather, some property of the in a tissue and persuade the surrounding it languished in the shadows for many years, tissue itself must sustain the new growth. The cells to grow similarly. However, Paget fol- the seed and soil hypothesis was revived fully idea that cancer cells require some ‘nourish- lowed the school of thought that all cancer in 1980 by Ian Hart and Isaiah Fidler. By this ment’ from their environment to develop still cells could continually develop wherever they time, clinical observations had established that motivates research today, with the focus now settled, but grew only in certain organs that certain organs were, indeed, more susceptible being on unravelling the molecular mechanisms were somehow predisposed to a secondary to metastasis, even after specific properties of that bring seed and soil together to promote cancer. the tumour cells and other host factors had been metastases. Paget reasoned that if the organs where accounted for. Helen Dell, Nature, Locum Associate secondary tumours arose were ‘passive’ in the So, Hart and Fidler examined whether the News and Views Editor process, then these cancers would be distributed locations of metastases exist merely because References and links randomly. By analysing 735 case histories of fatal tumour cells tend to come to rest in particular ORIGINAL RESEARCH PAPERS Paget, S. The distribution of breast cancer, he found that metastases formed organs — for instance, because the blood capil- secondary growths in cancer of the breast. Lancet 1, 571–573 (1889) | Hart, I. R. & Fidler, I. J. Role of organ selectivity in the in the liver far more often than in any other laries are more narrow — or because the dis- determination of metastatic patterns of B16 melanoma. Cancer organ — even those such as the spleen that could tributed cells can only grow at particular sites, Res. 40, 2281–2287 (1980) NATURE MILESTONES | CANCER APRIL 2006 | S7 © 2006 Nature Publishing Group MILESTONES MILESTONE 2 which he had also discovered and named. By following the fate of cells with different chromosomes, he surmised that individual Lack of principles chromosomes were qualitatively dis- similar and transmitted different inheritance The genetic basis of cancer is a cornerstone of factors. He then suggested that aberrant modern cancer research that began to unravel mitoses led to the unequal distribution over a century ago. of chromosomes, which, in most cases, In 1890, David von Hansemann described would be detrimental. Yet, on occasion, a “par- © Neil Smith in detail the mitotic figures of 13 different ticular, incorrect combination of chromosomes” carcinoma samples. In every case, he found would generate a malignant cell endowed with With astonishing prescience, Boveri applied examples of aberrant mitotic figures. These the ability of “schrankenloser Vermehrung” his model further to explain the emergence of included multipolar mitoses and anaphase (unlimited growth), which would pass the defect different tumour types within one tissue, and figures that showed asymmetric distribution on to its progeny. The foundations for viewing anticipated the clonal origin of tumours, the of ‘chromatin loops’ (or chromosomes). He cancer as a genetic disease were laid. allelic loss of recessive chromosome elements, postulated that these aberrant cell divisions Boveri applied his concept to explain dis- the heritability of cancer susceptibilities, the sim- were responsible for the decreased or increased parate phenomena linked to cancer, and made ilarity of the steps that initiate tumorigenesis and chromatin content found in cancer cells. a number of bold and bafflingly accurate pre- those responsible for cancer progression, and the At the beginning of the twentieth century, the dictions. Today, we can see that he foretold the sensitivity of cancer cells to radiotherapy. All of zoologist Theodor Boveri pursued this — largely existence of cell-cycle checkpoints (“hemmung- these ideas have since found wide acceptance ignored — association between aberrant mitoses seinrichtungen”), tumour-suppressor genes and molecular explanations. and malignant tumours. One of his impor- (“teilungshemmende chromosomen”) and onco- Subsequent work by several investigators tant innovations was to devise experimental genes (“teilungsfoerdernde chromosomen”). showed that known carcinogens, such as ion- manipulations of sea urchin eggs that allowed He further envisaged that ‘poisons’ (including izing radiation, acted as mutagens, which fur- him to induce multipolar mitoses and, therefore, nicotine), radiation, physical insults, pathogens, ther underscored the genetic basis of cancer. A aberrant chromosome segregation. Boveri, chronic inflammation and tissue repair might consistent chromosomal abnormality that was for example, found ways to generate cells with all be linked to the development of cancer by found in 1960 in chronic myeloid leukaemia multiple copies of the centrosome — an organelle indirectly promoting aberrant mitoses or other — the Philadelphia chromosome (see Milestone that organizes the poles of the mitotic spindle, events that cause chromosome imbalances. 10) — lent further support to this idea. MILESTONE 3 From these and subsequent studies arose showed that spontaneous tumours were not the belief, summarized by Harold Hewitt and inherently deficient in tumour antigens, but colleagues, that naturally arising tumours were instead failed to stimulate an effective immune Hide and seek not immunogenic. Moreover, Osias Stutman response. This failure could be overcome by had reported in 1974 that athymic mice do vaccination, a strategy that has since been The immune system has an amazing ability to not have an increased frequency of tumours adopted in numerous clinical trials. seek out and destroy that which is deemed induced by a chemical carcinogen, implying In a technical feat by Pierre van der foreign, and generally leaves ‘self’ alone. Yet, that the concept of immune surveillance Bruggen and colleagues, the Boon group later tumour cells, thanks to accumulated mutations providing protective immunity was incorrect. reported the first identification of a tumour- and altered patterns of gene expression, differ Yet, in 1982, enthusiasm for tumour specific antigen recognized by cytolytic T cells from their normal counterparts. Could the immunology was rekindled by the landmark in humans, reinforcing the idea that tumour same killing power that eradicates infection be discovery by Aline van Pel and Thierry antigens can elicit a detectable tumour-specific harnessed to destroy cancer cells — cells that Boon that specific immunity to spontaneous response. Whether that response can induce, are nevertheless self? tumours could be induced by vaccinating mice or be manipulated to induce, rejection of the Paul Ehrlich thought so. In 1909, he with mutagenized tumour cells. Their study tumour remains unclear. Yet Robert Schreiber suggested that, thanks to the immune system, and co-workers, in 2001, prompted renewed tumour development was usually suppressed. interest in immunosurveillance, showing that Yet, attempts to target tumours by immunodeficient mice are more susceptible immunotherapy have been less successful to chemically-induced, as well as spontaneous, than the Ehrlich hypothesis might predict. tumours. This proves to be a ‘catch 22’, Richmond Prehn and Joan Main, in 1957, however, for the immunocompetent mouse: showed that tumours induced by chemical in recognizing cancer, the immune system carcinogens in mice could stimulate tumour- exerts a selection pressure