The Ancient Cancer that Crossed Continents (Devilish Diseases Part 2): Canine Transmissible Venereal Tumor
In the first installment of my “Devilish Diseases” series (https://vectorsofinquiry.substack.com/p/the-devils-burden) we looked at the series’ namesake, Tasmanian Devil Facial Tumor Disease (DFTD). This is a clonal cancer capable of passing directly from devil to devil through biting during fights or sexual interactions. It broke many conventional notions about cancer, showing that malignant cells could function in a way almost like an infectious agent, jumping from individual to individual across populations leaving ecological chaos in their wake. However, DFTD wasn’t the first or the oldest transmissible cancer to be found pulling off this dark trick. That distinction goes to Canine Transmissible Venereal Tumor (CTVT), an even more ancient lineage that has persisted for millennia and spread globally without typically killing its hosts..
CTVT has been quietly circulating among canid species for millennia, establishing itself as a stable, successful disease across the globe that thrives without killing its host 1,2 Thankfully, since it doesn’t usually kill its host, CTVT is a much less existential crisis for man’s best friend than DFTD is for the little Devils in Tasmania. Yet you, and many others, may have never heard of this disease either. The existence of these transmissible tumors like CTVT and DFTD raises some fascinating questions. How do these tumor cells avoid being recognized as foreign? What is their evolutionary history like? How can we understand more about CTVT guide us to further insights in cancer biology and immunology?
In this post we’ll dig into the evolutionary and ecological history of CTVT. We will look at its unique transmission strategy and the tricks it uses to dodge the canine immune system. By the end, you will see how a single tumor cell line has carved out a successful ecological niche and what that could mean for our own understanding of cancer and disease.
What is CTVT?
Canine Transmissible Venereal Tumor is, as implied by the name, a cancer passed between dogs primarily via sexual contact. Picture a mating encounter between wild or free-roaming dogs: as the animals bite and mount the infected tumor cells can transfer from an infected individuals genitalia onto the mucous membranes of the partner. This is not like HPV in people where a virus or other single-celled organism causes the cancer. These are actual canine tumor cells, descendants of a once-normal dog cell that lost its identity through continuous mutation and evolved into a lone entity capable of living beyond the original host 3.
CTVT’s typical presentation is as cauliflower-like masses on the external genitalia of both male and female dogs. Sometimes it can appear around the mouth or nose due to sniffing behaviors prior to mating. Clinically the disease is relatively responsive to chemotherapy4 and even regresses spontaneously in some dogs5. The condition is more common in free-roaming and stray dog populations, especially where veterinary care is more limited, and animals have little or no reproductive control. This has allowed the tumor to propagate widely across the globe1.
The parallels between CTVT and DFTD show that these transmissible cancers are rare, but not entirely unique. They represent a separate category of pathogen to me, one that blurs the lines of viruses being distinct organisms and cancer being a disease of the self. Here we have two examples of cancer acting more like a virus, and over millennia no less.
Understanding the basics of CTVT allows us to set the stage for some more complex questions. How did it originate? How old is it? How’d it spread so successfully? Next, we’ll look at its evolutionary history to see how this rogue cell line has survived the test of time.
Origins and Evolutionary History
In my reading of the literature, what shocked me most of all the astonishing insights about CTVT is how old it seems to be. Genetic analyses have placed its origin thousands of years in the past, with a best guess of just over 11,000 years ago3,6. Imagine a dog living on the outskirts of some ancient human settlement. In this dog, a single cell line has diverged from normalcy. It underwent mutations allowing it to survive even after that dog’s death by passing to another during mating. Over time, this lineage spread and persisted across contents achieving global distribution.
Scholars have compared CTVT’s genome against numerous other canid genomes. Analyzing the patterns of mutations and their estimated accumulation rate, researchers deduced that the tumor originated from a single ancestral host dog 7,8. Long before dog shows and carefully managed breeding, some proto-dog population gave rise to this transmissible tumor that has ripped across the world. The genome itself reveals footprints of adaption with analyses uncovering mutations and genetic patterns that enhance the cancer’s survival and transmission. Large scale genomic sequencing has shown that certain beneficial alleles that confer advantages in immune evasion and metabolic efficiency appear repeatedly across different geographic populations, suggesting selective pressures that favor variants lined to immune evasion or metabolic efficiency.
Mitochondrial DNA (mtDNA) analyses show that CTVT periodically acquires host mitochondrial haplotypes. This implies ongoing positive selection effect for mitochondrial variants that improve the tumor’s energy metabolism or adaptability to diverse canid hosts. These mtDNA studies9,10 also show that CTVT cells pick up mitochondria from the host dog from time to time. These horizontal transfer events indicate at the subcellular level, the tumor is engaged in a dynamic evolutionary dance within the hosts.
The ongoing interplay of mutation and selection has made CTVT extremely good at what id does, persisting. The tumor can’t kill its host too quickly or it loses its ride to the next host. It also can’t be so benign as to disappear without replicating. This lineage has found the balance.
The population genetics of clonally transmissible cancers helps us understand the evolutionary forces that shaped and continue to shape CTVT 2. It is akin to studying a parasite’s population structure, except the parasite is a clone of the host’s own cells. This allows us to understand how these ‘parasitic clonal lineages can emerge and spread.
Biology and Transmission Mechanisms
So how does CTVT move from one host to another? We established that the cancer itself is being transmitted like a virus and that sexual contact involving the genital mucosa is the primary route of infection. One dog with a tumor mates with another and during that period of contact cells slough off and implant themselves into microabrasions or the mucosal surfaces. The “receiving” dog’s tissues are the new habitat for the transplanted cells11,12.
But why doesn’t the receiving dog’s immune system recognize the foreign cells and destroy them like they would an infection? Typically transplanted tissues from unrelated individuals trigger immune reactions. And there lies the puzzle. CTVT cells have evolved ways to minimize this detection allowing for their engraftment in the new host and growth. Immune evasion will be covered more in the next section, but from a biological standpoint the tumor’s method of spread is brute simplicity, direct cell transfer.
As I mentioned, sexual contact isn’t the only way CTVT spreads. Sniffing, licking, and biting of the areas containing the tumors are all behaviors spreading the disease 13. While sexual contact is the main mechanism of action, the differences in male and female for these behaviors leads to some shocking differences in the presentation of the disease with male hosts being four to five times more likely to have oronasal presentation of the tumor 14. These alternative modes of transmission highlight a remarkable adaptability, ensuring even non-reproductive contact can facilitate the persistence of CTVT in a population.
This mode of transmission comes with tradeoffs. Unlike an airborne pathogen, CTVT relies on intimate physical contact. And dog populations without breeding control methods roam and interact more frequently. Over the centuries this has been enough to allow the disease to become widespread. Once established in the new host, the tumor cells form lesions that blead rather easily, increasing the chance that viable cells are available to infect the next unsuspecting dog.
Conceptually, CTVT’s transmission reminds me of grafting in plants. Imagine taking a small branch from one tree and placing it on another where it takes root and continues growing. CTVT does something similar with canine tissue, an unsettling demonstration that in nature, immune boundaries that keep bodies as safe and separate worlds are not impregnable in the least.
Immune Evasion and Host Interactions
For CTVT cels to thrive in their new host they must evade this dog’s immune defenses. Foreign cells are typically shredded apart by T-cells or natural killer cells, so how does CTVT slip through the cracks?
A key tactic for this evasion of the immune system is the downregulation of Major Histocompatibility Complex (MHC) molecules. These normally would precent antigens to T-cells 15. By reducing the presence of MHC on their surfaces, CTVT cells become less visible to the immune system. This is basically stealth cellular warfare, hiding the molecular flags that if noticed would have the immune system shouting out “foreign invader!” This method of immune evasion has been highlighted as appearing in other transmissible tumors, like the facial tumor of Tasmanian Devils16.
Another factor that allows for immune evasion is the tumor microenvironment. CTVT appears to have adapted to produce one that is more favorable for survival. CTVT cells implanted into immunodeficient mice showed that the tumor reprograms gene expression profiles to create this supportive niche17. The influence of local cytokines, infiltration of immune cells, and signaling pathways allow CTVT to foster conditions that weaken host defenses. This kind of immunomodulation could also help to explain why some tumors eventually regress, with hosts mounting delayed but robust immune responses once the cancer is eventually detected. Researchers have documented the molecular signatures associated with this regression, suggesting that while the stealth tactics of CTVT are good, they’re not perfect 5,18. Some dogs’ immune systems eventually wise up, controlling and sometimes clearing the tumor.
All of this to say that immune evasion in this case isn’t about making the host’s immune system weaker, it is about dodging detection as a foreign body. This is a delicate balance, with CTVT not being to immunologically invisible, lest it lever be cleared and cause more severe, and potentially host killing disease. This is an important point, if the tumor were invariably lethal it would fail as a transmissible parasitic entity. But if it is too flashy, it won’t survive long enough to spread. This is an important point, if the tumor were invariably lethal it would fail as a transmissible parasitic entity. The type of equilibrium at hand suggests a long co-evolution with the canid immune system that is confirmed by the genetic analyses.
CTVT’s Clinical Course and Outcomes
We’ve established that CTVT manifests as a distinct mass, most commonly on the genitals. Veterinarians typically recognize it by appearance with definitive diagnoses involving cytology or histopathology. Some tumors will regress spontaneously5, a testament to dog’s eventually achieving immune recognition of the foreign cells. Others persist in the dog and can cause discomfort, bleeding, or secondary infections which can lead to death.
The good news is that CTVT is highly treatable through chemotherapy, with vincristine sulfate being a common choice4. Better news, the treatment success rates are generally excellent. Even without aggressive treatment courses the tumor may enter a stable or regressive phase.
Epidemiological data from Grenada and the UK suggest that while CTVT can appear in clusters, it does not typically overwhelm dog populations11,13,19. The disease also may take advantage of what Is known as the “popular sire effect” in dogs, where one male dog will be the primary mating partner for many females in the area. While not shown in any research, it is plausible that an infected popular sire could cause the type of clustering seen in CTVT.
A Comparison of CTVT and DFTD
The transmissible cancer club has DFTD as its poster boy, but both it and CTVT are not alone. There is one more mammalian transmissible cancer in a hamster species and a transmissible leukemia like cancer in bivalves, both of which I plan to cover at a later point. But CTVT and DFTD share some surprising parallels with both having emerged from a single original host, both spread by direct cellular transfer, and both evolving to evade the host’s immune system16,20.
Yet the two also highlight some interesting differences. DFTD is severely more lethal, posting a truly existential threat to the Tasmanian Devil species whereas CTVT has developed a stable coexistence with its host species. This discrepancy may be due to the time each cancer has existed (devils and the cancer haven’t evolved together long enough for this type of coexistence but may in the future) or because of dynamics within host immune systems.
Examining the two side by side helps to clarify that transmissible cancers are a phenomenon that can play out differently depending on ecological and evolutionary conditions. Researchers have suggested that the strategies each tumor employs to escape immune detection may offer a window into how immune systems recognize (or fail to recognize) abnormal cells in the body.
The Evolutionary and Ecological Implications
CTVT is a natural experiment in evolution and ecology being done right before our eyes. We think of cancer as a breakdown of cellular cooperation within a single body, but CTVT shows that with a relaxation of certain constraints, like the requirement that the tumor die with its host, cancer acts as a transmissible parasite, essentially evolving like any other pathogen2.
CTVT appears to occupy a niche somewhere between a pathogen and a parasite. It requires a living host to survive and propagate. The studies on its geographic distribution show that it occurs worldwide, tracking the global expansion of domestic dogs1,19. Since dogs are among the most widespread carnivores, traveling by our side for tens of thousands of years, it’s not surprising that this lineage of cancer found a way to piggyback on that journey.
To me, CTVT challenges how we categorize life forms and diseases. Is CTVT a “cell line” or a separate organism now? It is genetically distinct from the hosts and long separated from the original dog genome by high levels of mutation. The multicellular clonal lineage is not unlike a lineage of microbes. It blurs the line between disease and organism, pushing scientists to reconsider what it means to be alive and to be a pathogen.
What we can learn from CTVT
Understanding CTVT illuminates some fundamental principles of cancer biology. Most tumors never leave the host. They accumulate mutations until the host either dies or successfully destroys them. This is why CTVT stands out, it shows what happens when that host barrier is breached. Free to colonize the new individuals, the cancer cells then face selective pressures like those of pathogens. This could give us a leg up on tricky concepts like metastasis and immune evasion in human cancers.
Research on MHC downregulation and immune escape might inspire new immunotherapy approaches15. If we can understand how transmissible cancers tweak antigen presentation to remain hidden we could better predict how human tumors might do the same, or how to prevent them from doing so. Signatures of regression could inform strategies that drive human tumors toward states where the immune system can play a larger part in clearing them 5,18.
While CTVT might seem like a niche research topic, these avenues of research show it to be a unique window into greater truths. Grappling with how this single cancer cell line and DFTD conquered time and space, we could get some lessons to shape our fight against cancer and at the very least we gain a better understanding of the astonishing adaptability of life.
A Final Note on CTVT
Canine transmissible venereal tumor is a riveting look at evolution, immunity, disease ecology, and dogs. A rogue cell line from a single ancient dog has managed to stay around for millennia, spreading across the globe and thriving. Its balance of stealth and aggression is unlike anything I have come across. This overview and the one into DFTD have taught me that cancer is not a dead-end byproduct of aging or simple genetic bad luck. The right circumstances can let it break free and act as a parasite, showing how fluid the boundaries we take for granted truly are.
Citations
1. Strakova A, Murchison EP. The changing global distribution and prevalence of canine transmissible venereal tumour. BMC Vet Res. 2014;10(1):168. doi:10.1186/s12917-014-0168-9
2. Ní Leathlobhair M, Lenski RE. Population genetics of clonally transmissible cancers. Nat Ecol Evol. 2022;6(8):1077-1089. doi:10.1038/s41559-022-01790-3
3. Murchison EP, Wedge DC, Alexandrov LB, et al. Transmissible Dog Cancer Genome Reveals the Origin and History of an Ancient Cell Lineage. Science. 2014;343(6169):437-440. doi:10.1126/science.1247167
4. Otter WD, Hack M, Jacobs JJL, Tan JFV, Rozendaal L, Moorselaar RJ a. V. Effective Treatment of Transmissible Venereal Tumors in Dogs with Vincristine and IL2. Anticancer Res. 2015;35(6):3385-3391.
5. Frampton D, Schwenzer H, Marino G, et al. Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor. Cancer Cell. 2018;33(4):620-633.e6. doi:10.1016/j.ccell.2018.03.003
6. Baez-Ortega A, Gori K, Strakova A, et al. Somatic evolution and global expansion of an ancient transmissible cancer lineage. Science. 2019;365(6452):eaau9923. doi:10.1126/science.aau9923
7. Decker B, Davis BW, Rimbault M, et al. Comparison against 186 canid whole-genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor. Genome Res. 2015;25(11):1646-1655. doi:10.1101/gr.190314.115
8. vonHoldt BM, Ostrander EA. The Singular History of a Canine Transmissible Tumor. Cell. 2006;126(3):445-447. doi:10.1016/j.cell.2006.07.016
9. Strakova A, Ní Leathlobhair M, Wang GD, et al. Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer. Ostrander E, ed. eLife. 2016;5:e14552. doi:10.7554/eLife.14552
10. Strakova A, Nicholls TJ, Baez-Ortega A, et al. Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer. Nat Commun. 2020;11(1):3059. doi:10.1038/s41467-020-16765-w
11. Hayes A, Schiavo L, Constantino-Casas F, et al. Transmission of canine transmissible venereal tumour between two dogs in the United Kingdom. J Small Anim Pract. 2023;64(9):590-594. doi:10.1111/jsap.13607
12. Canine Transmissible Venereal Tumor: Etiology, Pathology, Diagnosis and Treatment | IVIS. April 25, 2005. Accessed December 5, 2024. https://www.ivis.org/library/recent-advances-small-animal-reproduction/canine-transmissible-venereal-tumor-etiology
13. Schectman SJ, Khanam A, Walters MND, Kirwan E, Sylvester WR, Khan FA. A retrospective study of canine transmissible venereal tumour in Grenada, West Indies. Vet Med Sci. 2022;8(3):1008-1012. doi:10.1002/vms3.778
14. Strakova A, Baez-Ortega A, Wang J, Murchison EP. Sex disparity in oronasal presentations of canine transmissible venereal tumour. Vet Rec. 2022;191(5):e1794. doi:10.1002/vetr.1794
15. Taylor BC, Balko JM. Mechanisms of MHC-I Downregulation and Role in Immunotherapy Response. Front Immunol. 2022;13. doi:10.3389/fimmu.2022.844866
16 .Siddle HV, Kaufman J. A tale of two tumours: Comparison of the immune escape strategies of contagious cancers. Mol Immunol. 2013;55(2):190-193. doi:10.1016/j.molimm.2012.10.017
17. Ke CH, Tomiyasu H, Lin YL, et al. Canine transmissible venereal tumour established in immunodeficient mice reprograms the gene expression profiles associated with a favourable tumour microenvironment to enable cancer malignancy. BMC Vet Res. 2022;18(1):4. doi:10.1186/s12917-021-03093-4
18. Fassati A. What a dog transmissible tumor can teach us about cancer regression. Mol Cell Oncol. 2018;5(4):e1472059. doi:10.1080/23723556.2018.1472059
19. Gibson DN, Singleton DA, Brant B, Radford AD, Killick DR. Temporospatial distribution and country of origin of canine transmissible venereal tumours in the UK. Vet Rec. 2021;189(12):e974. doi:10.1002/vetr.974
20. Chale RS, Ghiam N, McNamara SA, Jimenez JJ. Transmissible Cancers and Immune Downregulation in Tasmanian Devil (Sacrophilus harrisii) and Canine Populations. Comp Med. 2019;69(4):291-298. doi:10.30802/AALAS-CM-18-000129