The hypothesis that viruses can cause cancer has fallen in and out of fashion since the early 1900s. Former US President Richard Nixon declared war on cancer in 1971, at which time many held the view that cancer was caused by infective agents; however, it is now known that only a few cancer types can be directly attributed to viruses. Despite this, work on RNA tumour viruses (retroviruses) led to many important discoveries in cancer research — not least the discovery of some of the first cellular oncogenes.
Peyton Rous is surely the grandfather of the field. His ground breaking work in this area began in 1910, when he discovered an avian tumour that could be transplanted to other individuals — the first of its kind. The tumour was a spindle-cell sarcoma that originated in a Plymouth Rock hen. Rous inoculated bits of this tumour into the breast and peritoneal cavity of other hens, and found that they could be successfully transferred and propagated through subsequent transplants.
A year later, Rous published another paper, which took this work a giant step further. He made cell-free filtrates from the tumour using various protocols, and found that they were sufficient to induce tumour growth. So, a biological agent in the cell-free filtrate could cause tumour development; this agent was subsequently shown to be a virus, and was named after its discoverer as Rous sarcoma virus (RSV). The importance of this finding was not fully appreciated for some time, and it was only in 1966, at the age of 77, that Rous was awarded the Nobel Prize for this research.
In 1969, Robert Huebner and George Todaro reported a series of experiments that led to their proposal that “there exists a unique class of viruses present in most, and perhaps all, vertebrates that plays an important etiologic role in the development of tumours in these animals”. Their hypothesis was that C-type retroviruses — of which RSV was the most famous example — could be vertically transmitted from animal to progeny animal, and from cell to progeny cell, and that their activation by host genetic factors or environmental factors results in oncogene expression and cell transformation.
They found virus particles in almost all of the vertebrate species that were examined, and showed that tumour incidence corresponded with viral expression in several murine strains. They consequently proposed that normal cells had the capacity to activate latent tumour viruses, and that the spontaneous or induced de-repression of a viral oncogene would lead to cancer.
Although their hypothesis that most cancers were caused by expression of retroviral genes was not strictly correct, their work did lead to the identification of the first retroviral oncogene src , the realization that these viral genes were derived from functional cellular genes or proto-oncogenes and, finally, the identification of cellular proto-oncogenes as precursors of transforming cancer genes (see Milestones 15, 16 and 17). So, this collection of papers was truly ground breaking, and paved the way for other important discoveries in cancer research.
ORIGINAL RESEARCH PAPERS
Rous, P. A transmissible avian neoplasm (sarcoma of the common fowl). J. Exp. Med. 12, 696–705 (1910)
Rous, P. Transmission of a malignant new growth by means of a cell-free filtrate. JAMA 56, 198 (1911)
Huebner, R. J. & Todaro, G. J. Oncogenes of RNA tumor viruses as determinants of cancer. Proc. Natl Acad. Sci. USA 64, 1087–1094 (1969)
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Greenwood, E. From hens to eternity. Nat Rev Cancer 6 (Suppl 1), S9 (2006). https://doi.org/10.1038/nrc1846