Dogs & Wolf (Gotthilf Heinrich von Schubert)
Dogs & Wolf (Gotthilf Heinrich von Schubert, 1872)
Naturgeschichte der Säugethiere: mit colorirten
Abbildungen zum Anschauugs-Unterricht für die
(Esslingen : Schreiber, 1872)

Cancer is a creepy disease. Your own cells turn on you, mindlessly and blindly destroying themselves — because the only way a cancer can survive is for its host to survive; unlike viruses, cancers don’t spread from their original carrier to new hosts. Each cancer is a new and unique event, and each cancer is a terminal event, with no future, no children, no transmission. 1 Cancers don’t spread between individuals, because they would essentially be tissue transplants; if you try to transplant skin (or whatever) between two animals, the skin will be rapidly rejected because of mismatched MHC alleles, and the same is true for tumors.

In theory, tumors could spread from one identical twin to another (I don’t know of cases where this has occurred, though). Tumors might also theoretically spread within a population that has little MHC diversity. Cheetahs, for example, notoriously don’t have much MHC diversity,2 probably due to a genetic bottleneck some 10,000 years ago,3 and tolerate random skin grafts very well;4 it’s conceivable that a tumor that arose in one cheetah could spread throughout the population. But MHC is generally diverse, and becomes diverse very rapidly, so these sort of low-diversity populations are unusual (though they may be more common than generally realized). And so, as I say, tumors are dead ends and don’t spread from their original host.

But there are always exceptions, and we know of a couple exceptions for this principle as well. Tasmanian Devil Facial Tumor is one; canine transmissible venereal tumor (CTVT) is the other. The last time I talked about this, I said that there wasn’t anything particularly surprising about TDFT. I’ve changed my mind about that, for reasons I’ll talk about later. Here I want to give a quick update on CTVT, which is still even more interesting than TDFT.

CTVT is just what it sounds like: an infectious tumor of dogs. It can be transmitted from one dog to the next, mainly during sex. There’s no sign of a viral agent, and in fact the tumor cells are distinct from the host — that is, the tumor cells are not host cells that have been transformed by, say, a virus, but are foreign agents altogether, cells from an ancient animal that have been passed along in this way, generation after generation, spreading throughout the world. Cells from a CTVT on a German Shepherd in Italy are virtually identical to those from a CTVT on a poodle in Brazil, but the tumor’s cells are very different from their hosts’: “… the differences in genome content between dog and CTVT are substantially greater than those between different CTVT samples.” 5

Dog and wolf phylogenyThe last time I talked about this I cited a paper6 that showed that the original host of CTVT was actually very ancient: “Our analysis of divergence of microsatellites indicates that the tumor arose between 200 and 2500 years ago.6 Amazingly enough,  it seemed that the tumor had been passed between dogs perhaps for a couple of thousand years.

But it turns out that it’s even more amazing than that: The 2500 year estimate turns out to be an underestimate. “The estimated time of origin of CTVT is 6500–65,000 years ago. … The cycle of infection currently takes about six months; if this has been true for, say, 15,000 years, then there have been 30,000 transmission events.5 That spans the age where dogs were domesticated and diverged from wolves , about 10,000-15,000 years ago; and in fact, based on genome analysis of the tumors, the tumors did arise in wolves, not dogs. 7

This raises a fascinating scenario (which I didn’t see spelled out in Reddeck et al, though I think they were hinting at it). It’s still mysterious how CTVT spreads between hosts. As I said, tumors should act like tissue grafts, which are very rapidly rejected if they’re not MHC matched (as is the case with the CTVT and modern dogs). But tumors could, theoretically, spread within a population that has minimal MHC diversity — that is, an inbred population, that has recently undergone a genetic bottleneck. Such a bottleneck very likely happened during the domestication of dogs, as they evolved from wolves. Was the original CTVT a tumor of one of the very first domesticated proto-dogs — an inbred proto-dog,8 a member of a small and inbred population — a spontaneous, fairly ordinary tumor that then spread to the first host’s MHC-matched neighbours in the small and inbred population? That would not be so mysterious; we know tumors can be transplanted between genetically identical hosts, that’s done with lab mice all the time. Then, as the domestic dog population expanded and spread over the world, the tumor would expand and spread along with it, and would have the opportunity to undergo natural selection, adapting to the newly-diverse MHC and to the immune responses that arose after the tumor did. We don’t know, in molecular terms, how the tumor has adapted — we don’t know why it’s able to spread in grow in spite of host immune responses. But at least we can now imagine how the tumor could have reached this point. Thirty thousand transmission events — a couple of million cell divisions — is a long time for a cancer to adapt.

  1. Even most viral cancers are probably dead ends, because many viral cancers represent abortive viral replication.[]
  2. DNA variation of the mammalian major histocompatibility complex reflects genomic diversity and population history.
    Yuhki N, O’Brien SJ
    Proc Natl Acad Sci USA (1990) 87:836–840.[]
  3. Molecular Genetic Insights on Cheetah (Acinonyx jubatus) Ecology and Conservation in Namibia
    Laurie L. Marker, Alison J. Pearks Wilkerson, Ronald J. Sarno, Janice Martenson, Christian Breitenmoser-Würsten, Stephen J. O’Brien, and Warren E. Johnson
    Journal of Heredity 2008 99(1):2-13; doi:10.1093/jhered/esm081[]
  4. Genetic basis for species vulnerability in the cheetah.
    O’Brien SJ, Roelke ME, Marker L, Newman A, Winkler CA, Meltzer D, Colly L, Evermann JF, Bush M, Wildt DE.
    Science. 1985 Mar 22;227(4693):1428-34

    It was suggested at the time, and is widely believed, that cheetahs are particularly susceptible to infectious diseases for this reason, but I think the evidence for this is very weak. Cheetahs have high mortality when infected with feline infectious peritonitis virus, but it’s not unusual for viruses infecting new species to have a high mortality — think SARS and avian influenza in hunans, canine distemper in seals, and feline (or something) parvovirus in dogs, all of which had high mortality in their new, MHC-diverse, host[]

  5. Rebbeck, C., Thomas, R., Breen, M., Leroi, A., & Burt, A. (2009). ORIGINS AND EVOLUTION OF A TRANSMISSIBLE CANCER Evolution DOI: 10.1111/j.1558-5646.2009.00724.x[][]
  6. Murgia, C., Pritchard, J. K., Kim, S. Y., Fassati, A., and Weiss, R. A. (2006). Clonal origin and evolution of a transmissible cancer. Cell 126, 477-487 .[][]
  7. To be fair to Murgia, they pointed out that their 250-2500 year estimate was for the divergence of the tumor, not its origin, and they specifically raised the possibility that the tumor originated earlier than dogs.[]
  8. Reddeck et al. point out that the tumor did, in fact, arise from an inbred animal[]