divulgatum está dedicado a la difusión de conocimiento científico en español e inglés, mediante artículos que tratan en detalle toda clase de temas fascinantes pero poco conocidos.
divulgatum is devoted to the dissemination of scientific knowledge in Spanish and English, through articles that go into the details of all sorts of fascinating, if not
widely known, subjects.

Sunday, December 6, 2015

The unleashed cancer

The most ancient and widespread tumour on Earth reveals unwonted aspects of cancer.

Canine transmissible venereal tumour cells are an infectious parasite of dogs from all around the world. (Credit: Olga Glebova.)

CANCER is the cause of one in eight deaths worldwide, and its treatment is generally complex and riddled with side effects. All this has turned cancer into the most feared disease of the developed world. The term ‘cancer’ actually encompasses more than a hundred different diseases, each sharing an identical origin. Cancer is an almost unavoidable consequence of natural selection at the cellular level; sporadically, a single cell can acquire the ability to replicate itself uncontrollably, due to alterations in its DNA, hence being gifted a selective advantage in the face of its neighbours. It could be said that this cell is ‘better adapted’ to its microscopic environment, a fact that increases its likelihood of success. But what is beneficial for a single cell is not always so for a whole organism. The immune system, in consequence, swiftly eradicates any cell that has lost control of its own proliferation.

Some cells, however, go much further. They are able to develop molecular counter-measures that avoid their detection or defeat by the hand of this army that patrols every micrometre of the body. These cells thus obtain the go-ahead to exploit natural selection mechanisms, growing, reproducing, spreading and invading the organism. The cancer, made up of increasingly ‘better’ — more aggressive — cells, takes over the body, giving no chance for defence. Because cancer cells have the ability to reproduce indefinitely, they are usually said to be immortal. Paradoxically, cancer itself turns out to be, however, a very short-lived biological entity. The emergence of a tumour normally leads to two possible endings: the death of the tumour, thanks to treatments of ever-increasing efficacy, or the death of the entire organism. Some types of cancer, on the other hand, have managed to escape this fate of self-destructive voraciousness. Due to an extraordinary series of biological circumstances, these tumours developed adaptations that allowed them to leave the body wherein they originated and to infect many others, thereby adopting a parasitic way of life that has granted them a condition of true immortality. These are the so-called transmissible cancers.

Canine transmissible venereal tumour (CTVT) was the first cancer recognised as being transmissible. This tumour, present in at least 90 countries of all the inhabited continents, arose in a dog of a breed closely related to the Siberian Husky, which lived and died around eleven thousand years ago. This places the birth of CTVT at the end of the ‘ice age’, in the time of the last mammoths, not long after the domestication of the first dogs. The cells that escaped the body of this dog kept living and multiplying in others, as they still do today, after the spread and colonisation of humans and dogs across the world. The total number of CTVT cells that have existed and exist since then far exceeds the number of cells comprising the body of the animal wherein they initially arose. This makes CTVT not only the most widespread and ancient cancer known, but surely the oldest living organism on Earth.

CTVT is common in tropical and subtropical countries, and is frequently found in stray dogs, guard dogs or hunting dogs, rather than in domestic animals. Its appearance ranges from microscopic nodules to masses of more than fifteen centimetres in diameter. As the name indicates, it is usually located in the genital area; during coitus, the tumour promptly tears and bleeds, allowing the transfer of living cancer cells that will seed a new tumour in a new host. Nevertheless, the progression of the disease is closely linked to the animal’s immunological condition. In dogs with a weakened immune system or in poor general state of health, the cancer can advance to the phase of metastasis, aggressively invading different areas of the body and causing the host’s death. But metastasis is not the only cause of death related to this disease; the fragility of the tumour and its exposure to the environment can lead to severe infection, while, in certain cases, the tumour reaches such dimensions that it completely obstructs the urinary duct of the animal. Fortunately, most CTVT cases are easily treatable with chemotherapy or surgery; in dogs with a robust immune system, the tumour can even remit without treatment.

CTVT developing inside a female dog's vagina. (Credit: Anna Czupryna.)

The eleven-thousand-year-old DNA of this cancer suggests that its links with mankind, through the omnipresent canine company, go back much farther than previously thought. Supporting this is the first written mention of this venereal tumour by the veterinarian Delebere Blaine, who depicted it as a common condition in stray dogs of the Georgian London. Although the history of CTVT stretches back to a much more distant past — it is known that its worldwide spread coincided with the time of the conquest of new continents by European powers — its transmissible nature was not conjectured until decades ago. Thanks to the impressive advances in fields such as molecular biology, genomics and DNA analysis technologies, today we know not only that this cancer requires no intermediary to go from one dog to another, but also that its origin corresponds to well-known mutational mechanisms, and that CTVT and certain human cancers are not as different as it might seem.

It is evident that a succession of implausible events allowed CTVT to surpass the multiple barriers that exist between any tumour and the ability to spread between individuals, to the point of becoming a real parasite of thousands of animals the world over. The first such barrier, the need for physical contact, was resolved with the settling — perhaps since the first moment, or during the first stages of its evolution — of CTVT as a venereal tumour that thrives around the genital region of infected animals. The second barrier, imposed by the immune system of the recipient animal (the new host), is similarly outsmarted by means of mechanisms that remain partially unclear. CTVT is capable of aborting the organism’s response in the face of cells that are evidently alien and invasive. The study of these immune-suppression mechanisms could spark great advances in areas such as organ transplantation, where it is necessary to neutralise the recipient’s immune system for the foreign organ not to be rejected.

Eleven millennia of life on Earth add a new hurdle to those already mentioned: maintaining a complement of genes (genome) sufficient to keep living, despite the unavoidable accumulation of mutations over the centuries. The genome of CTVT contains about two million mutations, hundreds of times more genetic alterations than would be observed in a typical cancer. The accumulation of mutations, which is initially cancer’s fundamental tool for evolving into a more aggressive form, at some point — a point that cannot be attained by a human cancer — turns itself into a serious threat to tumour survival. Even though mutations have the potential to improve the cancer’s adaptation to its environment, the likelihood that the next modification will be lethal to the cell necessarily increases over time, especially in such a long-lived genome. In this scenario, natural selection again exerts its influence on the cancer, favouring those cells that acquire new mutations more slowly. It is likely that less aggressive tumours, with less capacity to put their host’s health at risk, also benefitted in the long term. This idea is supported by the exceptionally stable genetic profile of today’s CTVT, which makes it possible that tumours found in dogs from Australia, Venezuela, United States, Cape Verde, Malawi, Russia, Ukraine or South Africa present a nearly identical genome. As a consequence, CTVT provides a way to study a stage of evolution that has been denied to any other cancer type. This peculiarity has made the oldest living cancer into an object of special scientific attention. Researchers from different countries study CTVT with the aim of shedding light on the evolutionary processes that affect any cancer, but which are normally undetectable due to the short life of this disease.

A transmissible cancer is an extremely unusual natural phenomenon, which has been described only three times in the animal world. In humans, transfer of tumours has occurred on a few notable occasions: from mother to foetus during pregnancy, or by means of a surgical accident or an organ transplant. A case of particular scientific and ethical interest is that of the experiments performed by Chester Southam in the United States during the sixties and seventies, which proved that cancer can be transferred between humans under certain conditions. However, the spontaneous emergence of a cancer capable of transmission between individuals demands specific adaptations and unwonted natural situations. Thanks to a series of events so astonishingly extraordinary that they defy imagination, cancer, this ‘mere’ genetic disease, has evolved to become a parasitic organism of admirable efficacy, perhaps with a much greater historical impact on the evolution of the animal immune system than we now imagine. If the ability of canine transmissible venereal tumour to remain one step ahead of its host is sustained over time, the fate of this ageless cell lineage is to become the oldest, most successful life form on the planet.


If, as a veterinary professional, you believe that you may have identified a CTVT case, please contact the Transmissible Cancer Group on ab2324@cam.ac.uk.

Special thanks are due to Isobelle Bolton for her invaluable help with translation.

Stratton, M.R. et al. The cancer genome. Nature (2009).
Strakova, A., Murchison, E.P. The cancer which survived: insights from the genome of an 11000 year-old cancer. Curr. Opin. Genet. Dev. (2015).
Ganguly, B. et al. Canine transmissible venereal tumour: a review. Vet. Comp. Oncol. (2013).