Canine tumor appears immortal, spreads from dog to dog across all boundaries

A new study has revealed that the oldest and most widespread cancer cell line in the world is the contagious dog cancer called CTVT. This is among the few transmissible cancers. The canine transmissible venereal tumor (CTVT) has been found to cause sexually transmitted tumors in dogs for over 8,500 years.

According to evolutionary biologists Carlo Maley and Darryl Shibata, it is fascinating because these tumor cells survive the death of their host. They can thus undergo endless mutations, and in addition this seems to show that there is no inbuilt restriction on the number of times a mammalian cell can divide – it could theoretically be immortal.

CTVT first emerged in a dog that lived 4-8.5 thousand years ago. All CTVT tumours carry the DNA belonging to this “founder dog”. By counting and analysing the mutations acquired by CTVT tumours around the world, researchers can piece together how and when CTVT emerged and spread.   Artist’s impression of the “founder dog” that first gave rise to CTVT. This dog’s phenotypic traits were interpreted from the genetic variation found in the DNA of the cancer that it spawned.     [Image credit: Emma Werner]   Download Photo  A contagious form of cancer known as canine transmissible venereal tumor (CTVT) has been affecting dogs for thousands of years. The evolution of this disease could hold vital insights for the study and treatment of human cancers.
A contagious form of cancer known as canine transmissible venereal tumor (CTVT) has been affecting dogs for thousands of years. The evolution of this disease could hold vital insights for the study and treatment of human cancers.

The study of CTVT mutations could help scientists understand how cancer cells change their genome over time, and how a multicellular organism like a dog cancer transformed into an obligate asexually reproducing parasite specific to its host of origin. It also reflects the different types of mutation inducers it has been exposed to during its long journey, such as sunlight.

While cancers have been known to spread from human to human, they are very uncommon, usually in the form of transplanted tissue from a donor who had cancer, or from mother to child during fetal life. However, the spread always stops with the second host. The immune system deals with these foreign cells in healthy individuals, wiping them out quickly enough that they cannot establish cancer clones. In animals, it seems, there is no such limit. Eight instances of contagious cancers are known.

In Tasmanian devils, for instance, a fatal and disfiguring facial tumor began to spread rapidly in 1996. At first thought to be viral in origin, it was found to be due to a single clone of foreign tumor cells. In other words, every tumor showed the same genetic make-up though they were not related to the host dog’s cells themselves. In other words, this aggressive tumor was a transmissible one.

The CTVT is the prime focus of the current research. This ugly, oozing but non-fatal tumor occurs in the genital area in dogs, persists for a few months and is typically cleared by the immune system without treatment.

In the current study, the tumor cells from almost 550 dogs around the world were sequenced, and the results were the same as in the tumor-affected Tasmanian devils. All the CTVT cells had the same set of almost 2 million mutations, which were not observed in the healthy cells. These were observed in dogs as far apart as Australia and Brazil, and of different breeds. In other words, this is a single disease of antiquity, which has come down through the ages from animal to animal.

CTVT is supposed to have arisen first in a single founder dog somewhere in Asia, and has since jumped from dog to dog without any major change in its genome. From an isolated group of dogs in Asia, it spread slowly but widely, eventually reaching Europe about 2,000 years ago. The pace picked up just about 500 years ago as it spread via sexual contact between American native breeds and the dogs brought over by European colonists, and just 200 to 300 years ago it traveled back to Europe and infected all kinds of African and European dogs. In fact, this strain has become the ancestor of most of the modern CTVT cells.

These tumor cells are very interesting because they allow biologists to trace the appearance of various mutations in the somatic chromosomes (non-sex determining chromosomes) over time. This helps them discover how a cancer cell acquires malignant characteristics.

Another expert, Carlo Maley, comments on these findings, “Cancers evolve, and our strategies for managing cancer need to take that into account. In the future, we hope to maintain long-term control over these evolving tumors. CTVT is fascinating because it shows us how cancers might evolve over the long term.”

One important finding is that CTVT cell genomes have reached a stable state, unlike the vast majorities of cancer cells which are, almost by definition, genetically chaotic. Most tumor mutations are neutral (neither helpful nor harmful) while a few are harmful to tumor survival. Some are the important ‘driver mutations’ that help the tumor cell to persist and reproduce at high rates. Thus the most successful and resistant cancers are those that accumulate the most driver mutations. However, CTVT does not seem to have acquired more driver mutations, but rather those that do not impact its fitness, or neutral mutations.

Baez-Ortega explains the peculiar pattern seen with CTVT: “Whereas human cancers evolve thanks to the continuous acquisition of mutations which confer an advantage on some of the cancer cells, making them fitter to their environment (this is known as “positive selection”), CTVT has really ceased to evolve in any particular ‘direction,’ and so its evolution is largely undirected or, if you like, ‘random’ (this is known as ‘genetic drift’).”

This means that CTVT needed only some small adaptations to persist and develop well in dogs. It doesn’t show natural selection, which would indicate, in the words of Baez-Ortega, that “The tumor and the dogs aren’t competing against each other anymore. They’re coexisting. The cells behave like cancer cells, but the ecology of the tumor is that of a parasite.”

CTVT’s biology extends hope of future adaptive therapies for slow-growing but eventually deadly cancers. Such treatments restrict tumor growth, allowing it to survive but not harm the host, rather than eradicating the tumor cells themselves. The advantage is that this doesn’t allow resistant and lethal mutations to be selected. Studies to test this approach will soon come up.

Maley, in his commentary on the findings of Baez-Ortega et al., says, “Most cancers can only evolve for a few decades before they die with their host. CTVT is an incredible natural experiment, which showed us that it doesn't take much for a cancer to reach an optimal state. It is amazing that it did not discover additional adaptations over thousands of years, even as it infected all different breeds of dogs in all different environments around the world.”

This could also mean that CTVT hasn’t been able to come up with ways to adapt to rapid changes such as current chemotherapies. In fact, CTVT is extremely curable even with metastatic tumors. Another unsolved mystery is how these cancer cells manage to infect different hosts, something not achieved by human tumor cells to any significant extent so far. Baez-Ortega says, “We would like to look into the early history of CTVT in more detail and find out how its early genome looked like, and how it changed, during its first years and decades … about the mechanisms by which these tumors are able to counteract the immune system in so many different kinds of dogs.”

The findings and the commentary were published in the journal Science in August 2019.

Journal reference:

'Cancer cell evolution through the ages', Carlo C. Maley, Darryl Shibata, Science  02 Aug 2019:
Vol. 365, Issue 6452, pp. 440-441, DOI: 10.1126/science.aay2859, https://science.sciencemag.org/content/365/6452/440

Dr. Liji Thomas

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Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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