Oldest known cancer cell line originated in ancestral dogs and spreads via tumor cells
By Melissa Lee Phillips | August 10, 2006
A cancer in dogs is spread by the tumor cell itself, according to a study in this week's Cell. All cases of this cancer originated from a single cancerous cell in a dog or wolf ancestor hundreds of years ago, the researchers report.
"That means it's the oldest known cancer cell line known to science, much older than HeLa cells," senior author Robin Weiss of University College London told The Scientist.
During the study, the authors sampled canine transmissible venereal tumor (CTVT) cells from dogs all over the world. They found that the tumors are genetically distinct from the host animals, but closely related to each other -- a finding that challenges current thinking that cancer cells are inherently unstable, and gather more mutations over time.
CTVT is usually transmitted sexually between dogs but can also spread through biting, licking, or sniffing. Healthy dogs who develop the tumor often recover on their own, but not before expressing the tumor for several months and possibly spreading it to other animals.
Veterinarians have long suspected that CTVT is transmitted through the cancerous cells themselves, but immunologists and cancer cell biologists have remained skeptical, Weiss said. Previous research had shown that CTVT can only be induced experimentally with living tumor cells and that tumors isolated from different dogs have common genetic characteristics. But some scientists had suggested that an oncogenic virus, rather than direct transmission, might be the causal factor.
To pin down CTVT's mode of transmission, University College London researchers led by Claudio Murgia teamed up with University of Chicago scientists to compare normal and tumor tissue from dogs in Kenya, India, and Italy. They analyzed highly polymorphic regions of the dog major histocompatibility complex (MHC) and found that genetic patterns differed between tumors and host animals but were identical among tumors. Genotyping of microsatellites and mitochondrial DNA also confirmed that the tumors were genetically separate from the canine hosts but closely related to each other.
The researchers also found that all CTVT cells derive from a single cancerous clone, and that this clonal line later split into two distinct genetic clades. This split "must have happened early in its evolution," Weiss said, "because both of those are widespread across the world."
Next, Weiss and his colleagues analyzed microsatellites found in the tumor cells and compared them to microsatellites characteristic of different breeds of dogs. Using this analysis, CTVT cells appear most closely related to a gray wolf -- the ancestor of all of today's domestic dogs. It's also possible, Weiss said, that the cancer originated in an old breed of dog first domesticated in East Asia, such as the Siberian husky, Pekingese, or Shih Tzu.
Members of "the veterinary community have surmised that CTVT is a clonal cell that arose in an ancestral population for a long time," Jaime Modiano of the University of Colorado in Denver, who was not involved in the study, told The Scientist in an Email. "This paper cements that quite well. Maybe the most interesting part is how it assigns the origin more precisely -- although still not quite nailed down -- to an Asian wolf or an early domesticated dog."
The authors' microsatellite data show that CTVT likely originated between 200 and 2,500 years ago, Weiss said, which means that its genome has been remarkably stable for hundreds of years.
"The current view -- almost a dogma -- in cancer cell biology is that, as a cancer evolves in a person or an animal, it clocks up more and more mutations, more and more abnormal chromosomes, and becomes more virulent," Weiss said. The CTVT genome, on the other hand, "obviously went through a great deal of chromosome rearrangement early in its evolution, but then it became stabilized," he said, "so the idea of progressive instability of cancer cells is challenged by this tumor."
The researchers also found that canine MHC genes are expressed at a much lower level in CTVT cells than in a dog's own cells -- indicating that CTVT has adapted to evade host immune responses. This result came from only one dog, Weiss cautioned, "so it should be regarded as rather preliminary," although another study found that CTVT cells may suppress the host immune system by secreting a growth factor.
"I am not sure how much the impact of these genetic findings will be for cancers of other kinds," Reamin Chu of National Taiwan University in Taipei told The Scientist in an Email. "But CTVT is a great tumor model to study the immune evasion mechanisms by which a tumor escapes from host immunosurveillance."
CTVT transmission may share similarities with a cancer thought to spread among Tasmanian devils through biting, according to Weiss. In that case, however, the cancer is much more virulent than CTVT and often kills the host.
"It will be interesting to follow the course of the tumor of devils," said Modiano, "to see if the tumor will eventually stabilize and evolve into a 'benign parasite' rather than a deadly disease."
Melissa Lee Phillips
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