Canine Venereal Tumor phylogeny
Canine Venereal Tumor phylogeny

Bayman commented, after reading this post:

So isn’t the real question why can’t all tumors be transmissible? If you believe the tumor immunologists, all tumors should be capable of avoiding T cell attack…no??

I don’t have answers, but I can speculate a little. 1

Very quick background: In general, tumors are unique. They arise independently each time, and when their host dies, the tumor dies too. That’s in contrast to pathogens, whic may or may not kill their hosts, but which survive and are transmitted to a new host; pathogen infections are not unique, they have a long evolutionary history reaching back through many individual hosts. Tumors can’t do this, for the same reason that skin grafts are rejected by unrelated animals — tumors are essentially unrelated grafts, and should be very rapidly rejected by the new host.

But in very rare circumstances — there are two known instances, and a couple of other possible ones — tumors have arisen that can be transmitted from one host to another.  The two cases are canine transmissible venereal tumor, and Tasmanian Devil facial tumor.  There have been suggestions that these tumors are unique in some immunological way, but I am not convinced by those arguments: See this post and this one for more background.  That’s not to say that these tumors have no ways of evading the immune system; what I am saying, is that virtually all tumors have some way of evading the immune system, and the functions that have been convincingly described for the transmissible tumors don’t seem all that exceptional for tumors in general.

So, if these tumors can be transmitted, and they aren’t all that extraordinary immunologically, what does make them extraordinary?  As I say, I don’t know, but based on tumor immunology as I understand it, I can make some guesses.

The most important factor, I suspect, has nothing to do with immunology.  These tumors are unusual in that they have a built-in way of contacting new hosts. TDFT is spread through bites, CTVT is spread sexually.  There’s no similar way that, say, a liver tumor, or a brain tumor, could be spread.  So that immediately rules out the vast majority of tumors; even if they could survive after transmission, there’s no chance of a transmission chain. 2  But still, most tumors would be rejected even if they did manage to be transmitted.

The Three E's of tumor immunity
The Three E’s of tumor immunity

What seems to happen with most tumors3 is that proto-tumors appear quite early, but are controlled by the immune system – perhaps for years — and never become detectable.  Many such proto-tumors are completely eliminated by the immune system, and we have no way of telling that they even existed.  Many more are controlled at the half-dozen cell stage, much too small to detect; they aren’t eliminated by the immune system, but they can’t escape and grow either.  A very small percentage of these equilibrium tumors, though, eventually find a way of at least partially escaping from immune control, and begin to grow. (Perhaps the immune system kills 99% of the new cells, but a 1.01% growth rate compounds itself fast enough to be eventually detectable.)  This is the “Three E’s” theory of tumor growth (discussed more here and here) — “Elimination, Equilibrium, Escape”.

Regulatory T cells
Regulatory T cells and cancer

The Three E’s apply to the very small proto-tumors. But there is probably another factor that kicks in once the tumor becomes larger.  Tumors are themselves immunosuppressive — they shut down immunity throughout the entire body, to some extent, but they shut down immunity to themselves very powerfully.  The immune system has powerful safeguards that prevent it from attacking its own body; broadly speaking, tumors are their own body, and in many cases tumors probably also have been selected to massively amplify the normal protective signals. 4 (See this post, and this one, for more on that.)

So here5 is my speculation.  We suspect that the ability to be transmitted is present in several tumors, but they never get the opportunity to transmit.  Of those rarities that do get transmitted, most are rapidly rejected, as foreign grafts.  But a tiny minority of this minority may be able to survive because they have powerful immune suppression abilities on top of their common immune evasion abilities.

Tasmanian Devil crossing
Why did the Tasmanian Devil cross the road?

Were CTVT and TDFT just lucky — just happened to have the right immune suppressive abilities?  I don’t think so.  I think they were in the right place at the right time.  They were tumors that had a mechanism for transmission, and that had some ability to immune suppress, but they would normally have been rejected as foreign grafts.  Except that both of these tumors, I think, arose at a time and place where their population was highly inbred.  CTVT arose, we speculate, as dogs were becoming domesticated; probably a small, inbred, closely-related population.  Tasmanian Devils in general may not be closely related, but I suspect there are sub-populations6 that were closely related and that would not have rapidly rejected skin grafts.  The early version of the respective tumors would not have been rapidly rejected by these closely-related new hosts, giving them a chance to establish their own immune suppressive regime.

Now we have the chance for natural selection of the tumors.  Variants with more powerful immune suppression could spread to a wider range of hosts; variants with standard immune suppression died out with their victims.  In dogs, this natural selection could occur over time; as dogs became gradually more variable, there would be continuous new selection for new tumors that could keep up with the dogs. 7 With the Devils, the selection would be over space: The tumors would be selected for their ability to spread within new sub-populations of the Devils, perhaps through gradually more distantly-related subgroups. Eventually, we see the tumors as being capable of transmission and growth throughout the entire population, but the original tumor might not have had this ability.

Channel Island Fox
Rapid MHC diversity in Channel Island Foxes

This model suggests that humans are probably not at great risk of having a transmissible tumor spread in us; and the same is true for most species.  You need the combination of an inbred sub-population with a mechanism of tumor spread and the right kind of tumor. And inbred populations are usually a transient thing; MHC becomes diverse very rapidly, and then the window for tumor establishment is closed.

But this is just a guess, so don’t be too comforted.

  1. And by the way, I disagree with Bayman’s suggestion here (“Tumor Immunology Is A Waste of Time”) that he “find[s] it impossible to believe that effective therapy will ever achieved by artificially stimulating the immune system to attack weak and largely self antigens.” But this post is already too long, so I’ll save my answer for another time.[]
  2. There’s at least one case of a surgeon who apparently contracted a patient’s tumor after cutting himself during surgery — given the option, perhaps many more tumors could be transmissible, but don’t get the chance.[]
  3. Not necessarily those induced artificially, with high doses of carcinogens or with powerful oncogenes, but with those that arise naturally, in older individuals[]
  4. I suspect that tumors have many ways of achieving this localized immune suppression.  I also suspect that different tumors have different dependence on this localized immune suppression.  Those tumors that were highly successful as proto-tumors might already be very good at avoiding immunity — for example, they may secrete tons of TGF?, or otherwise have very powerful TReg-inducing abilities — and only need to shut down a little.  Those that barely squeaked by as proto-tumors, may have very potent immune suppression.  I don’t think the mechanisms for this tumor-based immune suppression are very well understood, though over the next couple years they probably will be. []
  5. Finally![]
  6. Subpopulations that are now, probably, extinct, because of the tumors[]
  7. I’m told that CTVT is eliminated faster or slower in different dogs.  It would be very interesting to correlate this with MHC types, to see if there’s still some effect of rejection even after 50,000 years of selection on these tumors.[]