A Dead Dog Lives On (Inside New Dogs)

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Can a tumor become a new form of life?

This is the freaky but serious question that arises from a new study in the journal Cell. Scientists from London and Chicago have studied a peculiar cancer that afflicts dogs, known as canine transmissible venereal tumor (CTVT) or Sticker’s sarcoma. It is a cancer of immune cells called histiocytes, and dogs typically develop grapefruit-sized tumors that disappear after a few months.

Some scientists have suggested that Sticker’s sarcoma can be transmitted from dog to dog, either by mating or by licking or touching a tumor. They noted that the tumor cells appeared to share a unique genetic marker. But skeptics noted that virus-like particles are often found in or around Sticker’s sarcoma. There’s lots of strong evidence that viruses can trigger cancers (such as cervical cancer), possibly as a strategy to spread themselves rapidly. Dogs that were struck with Sticker’s sarcoma could just be acquiring a cancer-causing virus from other dogs.

To sort out just what’s going on with this cancer, the authors of the Cell paper made a big survey of dogs with Sticker’s sarcoma, examining sick pooches from five continents. They analyzed the DNA from normal cells in the dogs, as well as the DNA from their tumors. They put the tumor cells in dishes to observe how they interacted with dog cells. The picture they got was remarkably detailed and–please allow me to use the word again–freaky.

All of the tumor cells shared the same genetic marker. A virus-like stretch of DNA, called a LINE-1 element, had been moved to a new location in the genome of all of the tumor cells. None of the non-tumor cells from the dogs had this LINE-1 element in this particular spot. Other genetic markers also revealed the tumor cells to be closely related to one another–and not closely related to the dogs in which they had been found.

At some point in the past, the tumor cells must have originated from normal cells. To figure out their heritage, the scientists drew up an evolutionary tree, based on comparisons of their DNA to that of dogs and wolves. The cancer cells descend either from a gray wolf (the closest relatives of dogs) or from one of the older East Asian breeds of domesticated dog. That ancestral cell probably existed in a dog or wolf that lived several centuries ago. The scientists came to this conclusion by studying the mutations that have arisen in the cancer cells. Based on estimates of how fast mammal cells mutate, the scientists estimate that the mutations arose over the past 2500 to 250 years ago. But since cancer cells tend to mutate faster than normal cells, they favor a date at the recent end of the range.

The scientists propose that several centuries ago, a histiocyte cell in a dog or a wolf turned cancerous. A mutation may have caused the cell to become abnormal–perhaps that LINE-1 element that marks Sticker’s sarcoma cells today. But natural selection would have favored other mutations as well that allowed its descendants to become more effective at growing into a tumor. During mating, some of the cancer cells managed to spread to the dog’s partner, where they could continue to proliferate.

Scientists have proposed parasitic cancers in a couple of other cases in the past. In the 1960s, there was a report of histiocyte tumors in a colony of hamsters; the scientists even argued that mosquitoes could spread the cancer from rodent to rodent. Earlier this year, scientists reported that Tasmanian devils were spreading a face tumor by biting each other. There are a couple differences between the Tasmanian devil cancer and the dog cancer. One is just a matter of methods; no one has yet looked for genetic markers in the Tasmanian devil cancer the way that scientists have in Sticker’s sarcoma.

But if the Tasmanian devil cancer proves to be a genuine infection, it must behave very differently than Sticker’s sarcoma. When Tasmanian devils get the face cancer, the tumor grows until it blocks their mouths and they die. Dogs, on the other hand, generally only develop a temporary tumor. Once the tumor clears, they acquire immunity from any further infection with the cancer. The scientists found that the Sticker sarcoma cells make very few of the surface proteins that vertebrates use to distinguish self from non-self. It appears that the tumor cells can avoid an all-out attack from the immune system. Instead, the immune system reins in the cancer cells, which can survive in the dogs even after their tumor disappears.

The parallel between these two kinds of cancer and different sorts of parasites is very striking. The Tasmanian devil cancer is a virulent parasite, like smallpox, that kills its hosts but can race quickly to new hosts. It’s a risky strategy for the cancer, because it may kill off its hosts faster than they can breed. Sticker’s sarcoma has taken a different route, establishing a more peaceful relationship with its hosts, like Toxoplasma does with us. As a result, it has managed to survive and spread for centuries. With a booming population of stray dogs to infect, it has a rosy future. “It represents the evolution of a cancer cell into a successful parasite of worldwide distribution.”

So here’s the big question which the authors don’t tackle head on: what is this thing? Is it a medieval Chinese dog that has found immortality? If so, then it resembles HeLa cells, a line of cancer cells isolated from a woman named Henrietta Lacks who died in 1951. After her death, scientists have propagated her cells, and in that time they have have adapted to their new ecological niche of Petri dishes, acquiring mutations that make it grow aggressively in the lab. One biologist even suggested that the cells should be consider a new species.

Sticker’s sarcoma has, without any intervention from scientists, become a cell line as well, and one that has survived far longer than HeLa cells have. It is distinct from its dog ancestors, and has acquired adaptations that allow it to manipulate its hosts for its own advantage as effectively as a virus or a blood fluke. A parasite evolved from a dog, perhaps.

One question the scientists do raise is how common such cancer parasites may be. Scientists have reported tumors that spread from transplanted organs, but these don’t have a way to sustain their spread for centuries. Still, between mating, biting, and otherwise making contact, vertebrates provide plenty of opportunities for cancers to spread. And it is striking that our immune systems–and the immune systems of other jawed vertebrates–are equipped to battle so strongly against foreign tissues. What for? It’s not as if Devonian-era sharks were giving each other liver transplants 400 million years ago. Perhaps, the scientists suggest, our ancestors had to fight against a different sort of tissue donation: cancer parasites.

Reference: Murgia et al.: “Clonal Origin and Evolution of a Transmissible Cancer.” Publishing in Cell 126, 477-487, August 11, 2006. DOI 10.1016/j.cell.2006.05.051

Update, 8/10 9:45 am: I unintentionally broke an embargo for this story. For some reason, I thought it lifted yesterday at noon, instead of today. I apologize to Cell for my error. (Thanks to commenter John Travis for pointing out my mistake.)