A new study in the August 11, 2006 issue of the journal Cell provides evidence that a form of cancer afflicting dogs has spread from one individual to another by the transmission of the tumor cells themselves. The disease demonstrates how a cancer cell can become a successful parasite with a worldwide distribution, according to the researchers.
The findings may have broad implications for conservation biology and for scientists' understanding of cancer progression, the researchers said.
Robin Weiss of University College London and his colleagues traced the origin of so-called canine transmissible venereal tumor (CTVT) to a single clone. They estimated that the parasitic cancer arose at least 200 years ago in either a wolf or a closely related ancient dog breed. That makes the tumors the oldest cancer known to science, and possibly the longest continually propagated mammalian cell lineage in the world.
"Our results, based on several independent genetic markers in tumor-bearing dogs living on five continents, show that CTVT arose from a common ancestral cancer cell," Weiss said. "The cancer escaped its original body and became a parasite transmitted from dog to bitch and bitch to dog until it had colonized all over the world." Early in its evolution, the clone diverged into two separate lineages, each of which now has a broad geographic range, he added.
CTVT, also known as Sticker's sarcoma, is apparently transmitted among dogs through sexual contact but may also spread through licking, biting, and sniffing tumor-affected areas, the researchers said. Earlier studies found that the cancer could be transmitted only by experimental transplantation of living tumor cells, not by killed cells or cell filtrates. Scientists had also noticed similar chromosomal abnormalities in tumor samples collected in different geographic regions. However, several reports of virus-like particles in CTVT had led some to suspect that a cancer-causing virus might play a role.
"The idea that this cancer in dogs might be caused by the transmission of tumor cells themselves has been around for some time--30 years or more," said Weiss. "But the actual truth wasn't there."
The idea that cancer may be spread by cell transfer has attracted renewed interest due to the recent emergence of a facial tumor apparently transmitted by the bite of the Tasmanian devil, an endangered marsupial species, he added.
In the current study, the researchers applied forensic science to the study of CTVT, systematically examining tumor and blood samples from 16 unrelated dogs in Italy, India, and Kenya. They also examined tumor samples taken from animals in Brazil, the U.S., Turkey, Spain, and Italy.
They quickly found that DNA isolated from the tumor and blood samples were not a match.
"We saw that the tumor cells didn't belong to the dogs," Claudio Murgia, the veterinarian who is first author on the study said. Rather the tumors collected from dogs around the world were closely related to one another, stemming from a single cancer clone.
The researchers traced the origin of the CTVT cancer by comparing the sequences of tumor genes to the related genes of gray wolves and dogs. They found that CTVT clustered most closely with gray wolves, suggesting that the disease originated in wolves or a closely related East Asian breed of dog. Based on genetic variation among the very similar CTVT samples, the researchers estimated that the disease has been transmitted among dogs for two centuries or more.
The team further found evidence that CTVT has adapted to evade dogs' immune responses. Otherwise, the unrelated tumor tissue "ought to be rejected," Murgia said.
Interestingly, he added, most dogs infected with CTVT develop a tumor that then regresses several months later and disappears.
"It looks like there is an aggressive phase of growth as the foreign tumor initially isn't recognized by the immune system," Murgia said. "In the long run, the immune system gets the better of it."
"As a sexually transmitted cell, CTVT would not have been able to colonize dogs worldwide if it killed them too quickly; the host must survive in a fit state long enough to transmit the tumor, which in the case of females probably entails an estrous cycle."
The findings in CTVT might lead to new insights for cancer more generally, they said.
"It's a curiosity of nature, but apart from that, it might also raise important new ideas about the instability of cancer," Weiss said.
It has become dogma that as cancer develops, it tends toward greater genomic instability and becomes "more and more aggressive," he added. After the gross chromosomal rearrangements soon after its emergence, however, CTVT--the longest lived of all known tumor clones--bears "no evidence of genome loss or progressive instability."
The findings challenge the idea that there is "an inevitable progression of cancer towards more instability," Weiss said.
The study also raises important issues for conservation biology, said Elaine Ostrander in an accompanying preview of the article.
"At present, CTVT can enter the wild canid population through physical contact between individuals (licking and biting) or mating between closely related species," she said. "For highly endangered canids, exposure to CTVT could theoretically create an immediate threat to the population's survival."
It's also possible that the small population sizes of endangered species like the Tasmanian devil might leave them generally more prone to developing other forms of transmissible cancer.
"It has not yet been checked thoroughly, but the Tasmanian devil tumor looks as if it might be the same phenomenon," Weiss said.
"The low numbers of these animals has led to inbreeding. Therefore, the tumor probably isn't recognized as foreign," he speculated.
Although difficult to study, Weiss said that the possibility of sexually transmitted tumors--for example, prostate or cervical cancer--may have merit in humans, particularly among people with compromised immune systems such as organ transplant recipients and those with AIDS. In humans, occult tumors in donor organs have been known to emerge on rare occasions in immunosuppressed transplant recipients, Weiss noted.
The researchers include Claudio Murgia of University College London in London, UK and University of Glasgow Veterinary School in Glasow, UK; Jonathan K. Pritchard and Su Yeon Kim of the University of Chicago in Chicago, IL; Ariberto Fassati and Robin A. Weiss of University College London in London, UK.
C.M. was a Wellcome Trust Clinical Veterinary Research Training Fellow, and A.F. is a Wellcome Trust University Research Fellow. R.A.W. was supported by grants from the Special Trustees of the Middlesex Hospital and the Medical Research Council.
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
Related Preview by vonHoldt et al.: "The Singular History of a Canine Transmissible Tumor."