There’s been some buzz about the recent paper on the contagious tumor of Tasmanian devils.1 Clearly the thing is a ghastly disease that’s threatening the Devils with extinction — but from a technical viewpoint, the paper last year on a different transmissible tumor was much more interesting.
The other tumor I’m talking about is canine transmissible venereal tumor (CTVT), and the paper is:
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 .
Most people haven’t heard of CTVT. (I had, but then I’m a veterinarian originally.) It’s just what it sounds like from the name: A sexually-transmitted cancer that spreads between dogs. (And it does seem to be a pure cancer, not a virus that causes cancer.) Until the Tasmanian Devil contagious tumor, that made CTVT essentially unique; no other tumors are known to be transmissible. (Actually, the Tasmanian Devil paper cites a tumor of Syrian hamsters2 that is apparently transmissible — but I’d never heard of that before, and I’m not clear that it still exists or if it has died out in the past 40 years.)
It turns out that the Tasmanian Devil tumor apparently can spread because it is essentially a self graft. Apparently Devils are highly inbred, and show very little polymorphism at the major histocompatibility complex (MHC) region. As I’ve been pointing out (ad nauseum) lately (see here and the links therein) this is really unusual, as in most vertebrates the MHC region is normally by far the most diverse region of the genome. The MHC region is important in graft rejection — duh, that’s what “histocompatibility” means. Essentially, then, it seems that the Devil tumor can “take” on virtually any other Devil, because it’s recognized as “self” MHC. 3 This is interesting, of course, but there’s nothing surprising about it. Endangered species are commonly inbred — inbred animals lack variation at the MHC4 — and matching MHC allows grafts to take. This is all known.
The canine tumor story is very different. This tumor does not match the recipient dogs’ MHC. The same tumor can infect unrelated dogs, with virtually any MHC; Murgia et al looked at tumor-bearing dogs from around the world (“None of the host dogs showed close relatedness to any of the others, consistent with the fact that they came from three locations in Europe, Asia, and Africa and were mongrels”), and they all carried the same tumor. So why is CTVT not rejected as an allograft?
Most, if not all, tumors in humans show evidence of having been edited by the immune system. That is, the tumors have altered their MHC expression in some way that probably allows them to evade the immune system. That’s one reason that tumors themselves are not rejected. (Presumably, there are many more proto-tumors that arise during our lifetime, that fail to alter their MHC and are destroyed by our immune systems before there are more than a half-dozen abnormal cells. We only see the successful ones.) CTVT has done this, as well, and expresses very low (but detectable) levels of MHC. Also, again like many other tumors, CTVT expresses an immune modulator, TGFβ. 5 Murgia et al suggest that these are enough to make the tumor invisible to the immune system and allow it to engraft.
But I’m not at all convinced. These changes — low MHC expression, high TGFβ — are very common, if not universal, tumor adaptations, yet CVTV is unique — extraordinarily, spectacularly, unique — in its ability to spread and persist within a highly outbred species. CVTV has persisted for hundreds, if not thousands or even tens of thousands of years:
The precise date when CTVT first occurred is difficult to determine. From its indistinguishable histopathology and its ability to grow as an allograft, it is likely that Novinski (1876) studied the same clone, and CTVT could have become established centuries before this date. Our analysis of divergence of microsatellites indicates that the tumor arose between 200 and 2500 years ago. Whether this time period represents the time the tumor first arose or whether it represents a later bottleneck in the tumor’s dispersion as a parasite cannot be resolved. While this estimated date indicates a relatively recent evolutionary origin, CTVT represents the oldest known mammalian somatic cell in continuous propagation, having undergone countless mitoses and host-to-host transfers.
In fact, the tumor may even predate dogs. The figure to the right from Murgia et al shows the relationship between the tumor and dogs and wolves (click for a larger version)– the thing is even closer to wolves than it is to dogs.
Frankly, the thing is damn creepy, and I kind of hope I’m right and there’s much more to its ability to persist than the really very common changes that have been pointed at so far, because I wouldn’t want to think that every tumor was capable of this kind of behaviour. Whatever it is, though, is more novel and scientifically interesting than the Tasmanian Devil tumor. Hopefully the Devil tumor is easier to deal with than the canine one.
- Siddle, H. V., Kreiss, A., Eldridge, M. D., Noonan, E., Clarke, C. J., Pyecroft, S., Woods, G. M., and Belov, K. (2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proc Natl Acad Sci U S A 104:16221-16226 [↩]
- Copper, H. L., Mackay, C. M., And Banfield, W. G. (1964). Chromosome Studies Of A Contagious Reticulum Cell Sarcoma Of The Syrian Hamster. J Natl Cancer Inst 33, 691-706.[↩]
- This is apparently the same mechanism as with the Syrian hamster transmissible tumor; hamsters are highly inbred as well. Streilein, J. W., and Duncan, W. R. (1983). On the anomalous nature of the major histocompatibility complex in Syrian hamsters, Hm-1. Transplant Proc 15, 1540-1545.[↩]
- Though not inevitably. The San Nicolas Island foxes I used as an example were inbred, yet had significant MHC diversity.[↩]
- The Devil paper states that CTVT also “up-regulates nonclassical class I expression to avoid the natural killer cell response” — but I don’t know where they get this from. It’s not in the reference they cite, and I can’t find evidence for it anywhere (but that doesn’t mean it’s not correct) [↩]
Ian…
Take a look at ref’s 21 and 22 from the original article. They’re referenced lower down in the discussion. I’m still looking at them now, so I can’t say yet whether they will explain the problem, but the abstracts look hopeful.
Neither ref. 21 nor 22 is directly relevant. Both are reviews about human tumors, and neither mention CTVT at all. There are comments about NK inhibition by non-classical MHC, but that’s a generic statement that has been known for a long time — not support for the specific comment in question.
Agreed, but from ref 22:
blockquote>MHC class I molecules comprise the classical (class Ia) human leukocyte antigens (HLA)-A, -B, and -C antigens in humans and H-2K, D, and L in mice, and the nonclassical (class Ib) E, F, and G, in humans and Qa and Tla antigens in mice (Bjorkman et al., [1987]). They form a trimolecular complex consisting of a 45-kDa heavy chain (HC), peptide antigen, and the nonpolymorphic 12-kDa 2-microglobulin (2-m) light chain. The HLA-A, -B, and -C and the H-2K, D, and L HCs are highly polymorphic (Bjorkman and Parham, [1990]). In humans, the class I HCs are encoded by genes located within the MHC region on chromosome 6, whereas 2-m is encoded by a gene mapped on chromosome 15. In mice, these antigens are encoded in chromosome 17 and chromosome 2, respectively. The classical HLA/H-2 class I molecules are expressed on the surface of most mammalian cells with only a few exceptions (Le Bouteiller, [1994]). It is estimated that there are up to 250,000 of each HLA class I molecule on the surface of a somatic cell (Parham and Ohta, [1996]).
It’s a good guess that if it works for mice and men, it works for dogs. From ref 10:
It’s pretty clear that Murgia et al are thinking in large clade terms. They are probably assuming that the reduced class I expression was all non-classical, but don’t say so because the research necessary to confirm it was not performed.
Siddle et al seem to be jumping to conclusions here (poor peer review), but it’s a pretty obvious conclusion in view of ref 22.
You’ve got their argument completely backward, and you’re making a really really forced interpretation of a very clear statement in the paper. Here is what they say: “CTVT passes across MHC barriers by down-regulating MHC class I and class II expression and up-regulating nonclassical class I expression to avoid the natural killer cell response.”
So they are not arguing that non-classical MHC is DOWN-regulated but rather that it’s UPregulated, and they are very clearly refering to the CTVT, not a generic effect. What’s more, when they make that claim they only cite a single reference, and that reference does not supprot their claim. Nor is there any claim anywhere in the literature that CTVT upregulates non-classical MHC.
I’m not claiming that non-clasical MHC doesn’t block NK, nor that it’s not a tumor immune evasion pathway — those are both trivial observations in that they’re widely known. I’m specifically saying that they’ve made an unsupported claim. And specifically it’s not an obvious conclusion for CTVT; there are lots of tumors that do NOT upregulate non-classical MHC, yet manage to be resistant to NK as well as classical CTL.
They also say:
Your quote comes from the introduction, the one above comes from the discussion section. Presumably, they thought a summary in the introduction was OK when the detail was in the discussion. The question is why they include CTVT in that class.
From ref 10 discussion:
Backing up to the results section:
Now as I understand the last paragraph, there is a reduction of the amount of Class I expression. Nothing is said whether the remaining Class I is classical or non-classical. Siddle et al are clearly taking it to be non-classical, that is a complete elimination of classical and upregulation of non-classical. But Murgia et al‘s results appear to be equally consistent with a reduced amount of classical and no non-classical. Agreed?
So the question is, what is there about ref’s 21 and 22 (see above) that justifies assuming the presence of non-classical.
I can’t even get into ref 21 without buying it for $30, which I don’t intend to do, but ref 22, which is pointed to humans, is describing a set of 7 “major altered HLA class I phenotypes have been defined in different tumor tissues” of which the last is “Phenotype VII: Downregulation of classical HLA A-B-C molecules and appearance of HLA-E molecules” which corresponds to what Siddle et al seem to be assuming. The others phenotypes seem to me (so far) to be human specific, so perhaps Siddle et al are assuming number 7 must be the explanation (which would be a distinct error).
OTOH perhaps the other results in ref 10 imply, or may imply, that option 7 is the correct one. I’m still trying to figure it out, myself.
I’m sorry, but you are really confused. Let me repeat my point here. Siddle et al claimed that CTVT evade the immune system because it downregulates classical MHC and upregulates non-classical MHC. There is nothing in the literature that supports that. Period, end of story.
You are apparently trying to support the claim that non-classical MHC can be upregulated on tumors. Yes, it can; that’s widely known, it doesn’t need support. But since not all tumors do that (again, a widely known point), it means nothing at all for CTVT; it’s not relevant. You can’t look at reviews on broad trends in human tumors and expect them to explain everything about one specific and very unique tumor of dogs.
You’re also making points about classical MHC downregulation on tumors. Again, this is widely known, and has been convincingly shown to be down-regulated on CTVT. It’s not my point.
I repeat: There is nothing in the literature that looks at non-classical MHC on CTVT. Siddle et al are making the claim that there is something about non-classical MHC on CTVT, and they are wrong. It’s that simple. It’s not a big deal. They made a throwaway comment in their intro, probably mis-remembering something or conflating two different tumors, and the comment got missed in peer review.
The reason I pointed it out, though, is that it’s very relevant for the point of my blog post here. The point I wanted to make is that for CTVT — unlike Tasmanian Devil tumors — the reason the tumor can spread between individuals is not known. Siddle et al — again, this was a throwaway statement in their intro — claimed that the reason is known, and they’re wrong, it’s not; the mechanism they pointed to, has not been demonstrated.
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