Contagious cancer in dogs: A tumor thousands of years old

Contagious cancer in dogs has existed for thousands of years. Countless generations of dogs have lived and died, yet the cells of one original tumor are still alive. They move from one animal to another, establish themselves in a new body, and continue multiplying. The dog in which this cancer first appeared is long dead. Its cancer has survived.

The disease is called canine transmissible venereal tumor, or CTVT. It is one of the rare forms of cancer that behave almost like an infectious parasite. What passes between animals is not a virus that causes cancer, but the living cancer cells themselves.

And those cells carry an extraordinary genetic record. By reading the mutations accumulated in their DNA, scientists have reconstructed a journey spanning millennia and continents.

A cancer that outlived its original host

Most cancers have a biological deadline. They can grow, invade surrounding tissues, and spread to distant organs, but they remain within the body where they first developed. When that organism dies, its cancer cells ordinarily die as well.

CTVT found a way around this limit.

During mating, tumor cells can enter damaged mucosal tissue in another dog. If they establish themselves, a new tumor begins to grow. Genetically, however, those cells remain descendants of a cancer that originated in an entirely different animal.

Each dog does not develop CTVT independently. All tumors belonging to this lineage trace back to a common ancestral cancer cell.

In 2014, Elizabeth Murchison and colleagues at the University of Cambridge sequenced two CTVT genomes. They identified approximately 1.9 million somatic substitutions and estimated that the original tumor arose in a dog living around 11,000 years ago.

A much larger study later revised that estimate.

In 2019, an international team led by Adrian Baez-Ortega published a study in Science based on the exomes of 546 CTVT tumors collected worldwide.

The exome comprises the protein-coding regions of the genome. By comparing mutations in these regions, the researchers constructed an evolutionary family tree of the cancer.

The result was a genetic history extending thousands of years into the past.

Their analysis placed the origin of CTVT approximately 6,220 years ago, with a 95% uncertainty interval of roughly 4,100 to 8,500 years. Central or Northern Asia emerged as the most likely region of origin.

The exact date remains uncertain. The central finding does not: this cancer lineage has survived for several millennia.

How cancer cells traveled around the world

Every time CTVT cells establish themselves in another animal, they continue accumulating mutations. Some of those changes are inherited by subsequent generations of tumor cells.

Shared mutations reveal relationships between tumors collected in different locations. More recent changes can help reconstruct when particular branches separated and where they may have traveled.

Using this information, the researchers found that CTVT probably remained geographically restricted for much of its early history.

Around 1,900 years ago, lineages that survive today began diverging from a common ancestor. The cancer subsequently spread through parts of Asia and Europe.

Its most dramatic expansion began roughly 500 years ago, when human maritime travel increasingly moved dogs between continents.

The tumor traveled with them.

Over the following centuries, CTVT spread through the Americas, Africa, Australia, and other regions. By the twentieth century, the cancer was established in dog populations around the world.

Its genome also preserves traces of environmental exposure.

The researchers identified mutations associated with ultraviolet radiation, along with evidence of an unusual mutational process that operated early in the cancer's history and later disappeared.

These findings turn the cancer genome into something resembling an evolutionary archive. It preserves evidence of events that occurred long before any living dog was born.

Why doesn't the immune system reject these foreign cells?

The remarkable longevity of CTVT raises a basic immunological question.

Vertebrate immune systems are equipped to distinguish the body's own cells from foreign tissue. This is why transplantation between genetically different individuals commonly requires measures to prevent immune rejection.

CTVT is effectively a transplant of foreign cancer cells.

Part of this recognition system involves major histocompatibility complex molecules, or MHC molecules, which help immune cells monitor the molecular contents of other cells.

CTVT can reduce the expression of these molecules, limiting immune recognition and allowing the tumor to establish itself.

Yet this immune evasion is not necessarily permanent.

Some CTVT tumors enter a regression phase, during which their growth slows or stops and the tumor shrinks. Immune cells can play a central role in this process.

A 2018 Cancer Cell study investigated the molecular events accompanying CTVT regression during treatment with vincristine, a chemotherapy drug.

By analyzing serial tumor biopsies, the researchers identified a sequence involving inflammatory signaling, immune-cell infiltration, changes in gene expression, and alterations in DNA methylation.

The findings showed that successful tumor clearance involves an active response from the host immune system.

There is an important distinction, however. These tumors were treated with chemotherapy. The study therefore does not establish how frequently untreated CTVT disappears on its own.

Spontaneous regression has been described, but its frequency under natural conditions remains uncertain. Untreated CTVT can progress and cause serious disease. Fortunately, the tumor generally responds well to veterinary chemotherapy.

Why is contagious cancer so much more dangerous in Tasmanian devils?

Dogs are not the only animals affected by transmissible cancer.

Tasmanian devils develop a contagious facial tumor disease in which living cancer cells spread between animals, usually through biting.

The basic transmission mechanism resembles CTVT. The consequences are very different.

One of the devil cancer lineages, DFT1, is usually fatal and has contributed to severe population declines in parts of Tasmania.

Like CTVT, DFT1 can interfere with immune recognition. Its cells suppress surface expression of MHC class I molecules, helping them avoid rejection as foreign tissue.

Research has shown that this suppression involves reversible changes in gene regulation, including epigenetic mechanisms.

But the immune defenses of Tasmanian devils are not completely ineffective.

Rare cases of tumor regression have been documented, and experimental immunotherapy has demonstrated that an antitumor immune response can be induced under certain conditions.

The contrast between the two cancers cannot be reduced to one species having effective immunity and the other lacking it.

The cancer lineages differ in origin, tumor biology, mechanisms of immune evasion, and the duration of their evolutionary relationships with their hosts.

CTVT has persisted for millennia. The known transmissible facial tumor lineages in Tasmanian devils emerged only in recent decades.

One possibility is that prolonged coexistence between CTVT and dogs has favored a particular balance between tumor growth, transmission, and immune control. This remains an evolutionary interpretation rather than an established causal explanation.

There is also a broader evolutionary constraint. A transmissible cancer that kills its hosts too quickly may reduce its own opportunities to spread.

CTVT illustrates an extraordinary way for cancer cells to escape the usual limits of an individual organism.

For most cancers, the death of the host ends the lineage. For CTVT, survival has depended on reaching another host before that happens.