Tasmanian Devils: Contagious Cancer Drives the Risk of Extinction
By Roberta Attanasio
In November 2013, a team of biologists scattered 15 plastic cylinders in the fields of Maria Island, three miles off the east coast of the Australian island state of Tasmania. Each cylinder contained a healthy Tasmanian devil, a marsupial species that until then lived only in Tasmania. Soon, the 15 devils emerged from the containers, becoming the first ever to inhabit Maria Island. The biologists were planning to take more devils to the island. Why? To establish a healthy colony, needed for the survival of the entire species.
The Tasmanian devil is on the brink of extinction because of an unusual disease — a contagious cancer that is spreading very quickly. In some areas, more than 90% of the population has been wiped out. The disease is called Devil Facial Tumor Disease, or DFTD for short, and is characterized by malignant tumors — around the mouth and head — that behave as parasites and have caused an epidemic of cancer. The tumors are directly transmitted when the devils bite each other faces during fights — sometimes they bite off little pieces of tumor. When this happens, the cells reach the attacker’s bloodstream and, from there, its face. Once in the face, they start growing, producing a new tumor. Because the growth of tumors is not controlled by the devils’ immune system, the disease causes 100% mortality among infected devils.
Tasmanian devils (Sarcophilus harrisii) are dog-sized carnivorous marsupials known for their black color, spine-chilling screeches and bad temper — they look and sound fierce.
Today, the devil is a Tasmanian icon set to disappear. However, if the devils become extinct in Tasmania, the disease will disappear with them, as they are the only animals affected by this type of contagious cancer. At that point, the healthy devils from Maria Island could be introduced back in the wild.
Carl Zimmer wrote that when the tumor disease was first discovered in 1996, many scientists assumed it was caused by a rapidly spreading virus. Instead, in 2006, Anne-Maree Pearse and Kate Swift (Department of Primary Industries, Water and Environment in Tasmania), discovered something strange about the tumor cells. The chromosomes looked less like those in the animal’s normal cells and more like those in the tumors growing in other Tasmanian devils.
Pearse and Swift proposed that the disease is transmitted when an infectious cell line is passed directly between the animals through bites they inflict on one another. They thought that the low genetic diversity and high degree of kinship among devils might help to reduce their immune response to cancer cells implanted during biting.
In 2007, Katherine Belov and her collaborators published a study showing that the tumor DNA was similar in different animals, but was different from the DNA present in the normal cells of the animal with the disease. This finding indicated that the cancer was contagious, spreading from one animal to another. The researchers wrote: “This novel disease arose as a direct result of loss of genetic diversity and the aggressive behavior of the host species. The neoplastic clone continues to spread through the population and, without active disease control by removal of affected animals and the isolation of disease-free animals, the Tasmanian devil faces extinction.”
Finally, in 2010, a team of Australian and American scientists confirmed that DFTD is a transmissible cancer. But why is this type of cancer not controlled by the immune system? Findings from a study published in 2013 show that DFTD cells do not express cell surface MHC molecules, which are a type of identity badge present in mammals. In absence of MHC molecules, the immune response directed to the cancer is very limited — the cancer cells “escape” and survive. The absence of MHC molecules is the result of down-regulation of genes essential to the antigen-processing pathway, such as β2-microglobulin and transporters associated with antigen processing, which all work together to allow killing of the cancer cells by specialized cells.
DFTD continues to spread through wild populations in Tasmania. However, there are now a total of 28 devils on Maria Island. In addition, The Tasmanian Devil Program has established a captive Insurance Population of Tasmanian devils in partnership with the Zoo and Aquarium Association. Over 600 healthy devils are being held in 36 zoos and wildlife parks across Australia, as well as five overseas zoos under the Tasmanian Devil Ambassador Program. Sadly, one of the devils under the program was killed in October by an unidentified individual at the Albuquerque Bio Park Zoo, New Mexico. The animal suffered a fractured skull and brain trauma caused by a block of asphalt.
On November 23, the Tasmanian Government and the Commonwealth Government announced the new Wild Devil Recovery Project. The project places greater emphasis on population monitoring, field research and testing of possible vaccines and immunization techniques to control DFTD.
Major Histocompatibility Complex (MHC) is a mechanism to present protein peptides on self-surface to T cells. The MHC is a great way to differentiate what is self and non-self in the body because it always presents peptides on self-surface, even self-peptides. During a viral infection, the presentation of MHC1 and peptides on cell surface is very crucial because cytotoxic T cells scan the body and destroy the cells that present MHC with viral peptides. In this mechanism we have both T helper cells that help other immune cells of body to be activated and cytotoxic T cells to destroy virally infected or messed up cells like cancerous ones. However, like mentioned above, the devil facial tumor disease (DFTD) does not allow the cancerous cells to present MHC on self surface. Based on research presented by Nature, it is seen those genes for production of proteins: TAP 1, TAP2 and beta-microglobulin have been turned off. This is a very smart way of this disease taking over the body because without these proteins, MHC cannot be found on cell surface and without an MHC plus a peptide, there is no way for the T cells to recognize these harmful cells and kill them. In this pathway, the disease overtakes the body and kills the devils. However, what is really fascinating to me is how these cancerous cells are contagious for the rest of the devils because normally cancer cells are not contagious and do not infect others. There has been a lot of research going into this field not only to save the remaining of these endangered species but to also find a good explanation and research in this type of contagious cancer in spreading in the human population.
In order to further study the Devil Facial Tumor Disease (DFTD), I believe it is important to also look at other forms of contagious cancers such as Canine Transmissible Venereal Tumor (CTVT). I found a paper suggesting that the over-expression of chemokine ligand 7 can lead to the progression of CTVT. CTVT is a unique tumor thats transmitted via injured mucosa and skin. These tumor cells can evade MHC barriers in the progression (P) phase by secretion of Transforming growth factor-β (TGF-β) that inhibits the ability for MHC molecules to present antigens. The immune system usually rejects the tumorous cells in the regression (R) phase by use of interleukin (IL)-6 counteracting TGF-β activities.
Chemokine ligand 7 (CXCL7) has been associated with pro-inflammatory responses, and now this study shows that it plays a role in cancer development. Western blot and PCR analysis demonstrated that CXCL7 was expressed in high levels in the P phase and down-regulated in R phase suggesting that over-expression of CXCL7 may play a role in the progressive growth of CTVT. These findings can be used to further study the role CXCL7 can play in the progression of DFTD.
Chiang, Hsin-Chien, et al. “Overexpression Of Chemokine Ligand 7 Is Associated With The Progression Of Canine Transmissible Venereal Tumor.” BMC Veterinary Research 8.(2012): 216. MEDLINE with Full Text. Web. 10 Dec. 2014.
The concept of a contagious cancer is very interesting, and so is the research on the mechanisms at the basis of it. However, this will not solve the problems related to the still likely extinction of this species. Other animals may be in theory affected by this cancer. The issue here is transmission. The Tasmanian devils are aggressive, fight with each other, and bite pieces of cancer off the devil they’re fighting with, that’s how they get infected. Other animals do not have this type of behavior, and if they have the same cancer, it won’t be identified in the population, as the transmission rate will be very low and only a few individuals will be infected. If the devils learn to be less aggressive (just a joke here) the problem will migrate to outer space.
I think this story is still fascinating. Even if the devils’ behavior is responsible for transmitting the disease, it’s worthwhile to study this contagious cancer. I bet that if scientists that work with human cancer and don’t know anything about devils and DFTD get interested in it, and start looking at it, they may figure out a lot of new things about cancer. Unfortunately, scientists do not look outside the castle in which they live a limited life of very narrow knowledge and very narrow scientific interest.
The real question that should be asked is why this disease is even a problem in the first place. Yes, it is understood that only the Tasmanian devil is affected by this disease but has anyone taken the time to consider why only this animal is affected and no other animals that may inhabit the same area? Are they missing a gene that would otherwise protect them from developing these tumors or is this unknown? I believe that figuring out this concept is the key to potentially stopping infection or at least decreasing the rate of transmission.
According to Does the devil facial tumour produce immunosuppressive cytokines as an immune evasion strategy?
, it was shown that the tumors themselves are not the cause of rejection in the immune system and that instead other strategies used by similar cancers is what may allow them to avoid detection by the Tasmanian devil’s immune system. For instance, many researchers compare the DFTD phenomenon to the other only naturally occurring transmissible allograft disease, CVTV or Canine Transmissible Venereal Tumor. When compared to a similar disease such as CVTV the same cytokines that are responsible for suppression in this disease ironically are not used by DFTD. The expression of TGFB1 is an example of this according to the study conducted thus proving that DFTD does not use immunosuppressive cytokines to avoid immune rejection to begin
I was wondering the same when you asked why is this only affecting the Tasmanian devil species. I assume that this is occurring because they are competing for food resources which eventually leads to fighting or biting another Tasmanian devil. I did find an article that explains canine transmissible venereal tumor (CTVT) which is similiar to DFTD; however the only difference is that CTVT eventually expresses MHC on its surface allowing the immune system to recognize and clear the infection.
Siddle and his team treated these tumors with an antifungal medication called Trichostatin A. This allowed DFTD cancerous cells to express MHC on their surface in order for the immune system of the Tasmanian devil to trigger response to the infection. Another research found that the cancerous cells of DFTD are of Schwann cell origin. Schwann cells insulate nerve cells outside of the brain, so researchers are currently trying to understand how this cell was able to evolve into a parasitic form. So far, I feel that creating a vaccine is the most promising treatment for this deadly disease which will ultimately save the surviving Tasmanian devil population.
Thank you for your reply. I definitely did not take that into consideration but what I meant by that statement is why is it that these are the only species that we knowingly are affected by this disorder. Why is this particular species the carriers of this disorder and how long exactly has this been going on? According to this article,
Life history change in disease-ravaged Tasmanian devil populations we know that this has been a reported problem since 2001 and as stated earlier, I believe that if we find this link we can help to eradicate the problem. This is an unfortunate problem that has been affecting these creatures and if we are unable to find a causative agent soon this could possibly spread to other creatures in the surrounding areas ultimately reaching the human population if care is not taken.
It is very unfortunate that DFTD is sweeping out the dwindling population of Tasmanian devils in the wild. Since there is no cure for this transmissible cancer (or any cancer for that matter), scientists are left with a very few options to save what is left of this species. After some research, researchers have discovered a virus that kills cancer known as Ad5[CgA-E1A-miR122]PTD. Although it hasn’t been tested on humans, this virus has killed numerous tumor cells lines in animals. Scientists need to begin testing this virus on DFTD; if Ad5[CgA-E1A-miR122]PTD has shown a reduction in other cancer cells, hopefully it is successful with reducing the cases of Tasmanian devils infected with DFTD.
If Ad5[CgA-E1A-miR122]PTD is not successful in eliminating DFTD in Tasmanian devils, researches can continue relocating the species to Maria Island, and other regions with many similarities to the island of Tasmania. (Should species be relocated to prevent extinction?) Since the DFTD has a 100% mortality rate, it might be beneficial if DFTD kills off all of the Tasmanian devils remaining on the island of Tasmania. Once there are none left, DFTD-free Tasmanian devils should be relocated back to Tasmania; the population should grow exponentially without the presence of DFTD.
In a new study called: study Mouse model of Devil Facial Tumour Disease establishes that an effective immune response can be generated against the cancer cells give this disease another perspective. This article and this blog mentioned that it was though that low genetic diversity of the devil population enabled the transmission of DFTD. This blog also mentioned that DFTD is known for lacking MHC expression on cancer cells meaning that they are unable to trigger an immune response that could also be known as non-immunogenic. However, new evidence revealed that genetically diverse animals and the lack of immunogenicity of the tumor cells are the target of this disease. Therefore, this study focused on testing the immunogenicity by injecting DFTD cells to mice, in order to measure the anti-DFTD immune responses that could help develop an effective vaccine or immunotherapy. What they found really caught my attention because a range of antibody isotypes against DFTD was found, meaning that mice immune system responded to DFTD cells. This can give us the freedom to say that DFTD is immunogenic. Although the article demonstrated an immune response to DFTD, there are still some questions that need to be answered. The study mentioned that if MHC molecules are not present, then NK cells will do this job but the mechanism stills unknown. Furthermore, they discussed the role of TH2 in the immune response since it is considered that DFTD could be a tumor cell line that biases the immune response to a TH2 response leading to the suppression of TH1 anti-tumor responses. Overall, the few evidences are enough to start working on the immunotherapy side of this disease; however, this does not mean that research about this disease is done because there is still a need to find a vaccine to prevent the extinction of the Tasmanian devil.
I have one issue with this study (Mouse model of devil facial tumor) and that is why would use mice to study this disease? The mice studies might provide some insight into how this disease affects other organisms, however, mice are not closely related to Tasmanian devils. I would think it would be more relevant to use an animal or develop a cell line from an animal that is closely related to Tasmanian devils such as kangaroos or some other marsupial. This would give us more insight into why related species are not being affected by this disease. For instance, perhaps other marsupials have developed a way to prevent DFTD from downregulating MHC I expression. If so, maybe we could develop a treatment using this strategy. Another question I have, in response to the article on introducing MHC positive DFTD cells, is whether we could use some sort of adjuvant from some bacteria or virus that we know elicits an immune response in Tasmanian devils to elicit a little bit stronger response to clear the cancerous cells from the animals more effectively? For example, the gram positive bacteria Mycobacterium mageritense causes infection in Tasmanian Devils, so maybe we could attach a piece of the cell membrane to a DFTD peptide to elicit a stronger response.
I totally agree with your point, because Tasmanian devils and mouse belong to different species (maybe relatively remote species). We should compare MHC expression of DFTD within the same or related family. Here I just want to expand what is the related species to Tasmanian devils, and some feasible experiment plan for the DFTD research in Tasmanian devils.
The Tasmanian devil (Sarcophilus harrisii) belongs to the family Dasyuridae. Although the research that try to discover the relationship between Tasmanian devil and other species is not clear, . As we know, there are six species of quoll: The bronze quoll (D. spartacus), The western quoll or chuditch(D. geoffroii), The New Guinean quoll (D. albopunctatus), The eastern quoll (D. viverrinus), spotted tail quoll (D. maculatus), and The northern quoll (D. hallucatus). We can choose several number in each species, then directly inject DFTD cells to the experimental quolls. Of course the DFTD would not be infectious in quolls because DFTD only infected Tasmanian devil. Then we can find the mechanism why lacking of MHCI in DFTD can activate T-cells in the six species. We can also investigate the genetic diversity in the six quoll species.
The article states that, the absence of MHC molecules is the result of down-regulation of genes essential to the antigen-processing pathway, such as β2-microglobulin and transporters. These are associated with antigen processing, which all work together to allow killing of the cancer cells by specialized cells. As the down-regulation of β2-microglobulin has been found in the devil facial tumor disease (DFTD), this same situation has also occurred in canine transmissible venereal tumor (CTVT or Sticker’s sarcoma) in dogs. Researchers discovered that the DFTD is fatal within 6 months whereas in several cases the host dog rejects the CTVT, leading to a lifelong immunity. The difference between these two animals is in fact due to their genetic diversity, which is causing the lack of β2-microglobulin in the Tasmanian Devils not able to produce MHC molecules on its cell-surface. Another research states that β2-microglobulin is largely localized in the cytoplasm of advanced oral cavity squamous cell carcinoma (OCSCC). My question is why is β2-microglobulin largely localized in many OCSCC but not in DFTD? It is crucial to know if Tasmanian Devils cytoplasmic activity is lacking the production of β2-microglobulin. This is a main aspect to know so researchers can alter the cytoplasm, which will help more regulation of β2-microglobulin while DFTD is presented in the Tasmanian Devils.
Cancer cells that down regulate MHC on cell surface have been associated with other animals as well. You have brought up a good point about how canine transmissible venereal tumor that infects dogs also down regulates its expression of MHC. This is an interesting field to study because this type of disease, unlike the DFTD, eventually does make cell surface MHC when infecting another canine. The thought-provoking thing is why does this cancer eventually form the MHC in the new host unlike the devil facial disease? Researchers have also looked into finding a vaccine for diseases like this and one that they think will work well is by giving these animals cancerous cells that already have MHCs on cell surface. In this type of treatment, the body will start to recognize these new foreign MHCs with peptides and start a robust immune response that will target the pre-cancerous cells that were already in the body.
As the article stated, DFTD cells do not express MHC molecules which is why the immune system response to the cancer cells are very limited thus allowing the cancerous cell to survive and multiply. Since the growth of tumors can’t be controlled by the Tasmanian devil’s immune system it leads to 100% mortality rate. It’s found that the loss of gene expression isn’t due to a structure mutation in MHC but rather regulatory changes such as epigenetic deacetylation of histones. Therefore, if researchers can produce a vaccine that helps to restore the MHC molecules to the surface of DFTD cells, then T cells will be able to target DFTD cells. Researchers from Reversible epigenetic down-regulation of MHC molecules by devil facial tumor disease illustrates immune escape by a contagious cancer suggested that by priming Tasmanian devil’s immune system with MHC-positive and trichostatin A-treated DFTD cells it could potentially produce a vaccine against DFTD. The vaccine would alert the host T-cells to antigenic peptides from DFTD cells. The host cells will then activate against antigens found on the surface of DFTD cells or even intracellular antigens released by DFTD cells. This would initiate the immune response and the release of cytokines that would cause the wild-type DFTD cells to express MHC molecules. The expression of MHC molecules will lead to a stronger immune response and thus increasing the devil’s chance of survival.
In the study, Reversible epigenetic down-regulation of MHC molecules by devil facial tumor disease illustrates immune escape by a contagious cancer, it discusses how the DFTD (Devil Facial Tumor Disease) induces a mechanism which prevents the expression of MHC Class I molecules and therefore avoids the recognition of CD8 T-Cells. Due to the lack of recognition, the tumor cells have the ability to grow and spread in the facial regions of the Tasmanian Devils.
My question towards the research is; if the DFTD cells do not express any MHC Class I molecules, how come natural killer cells do not react to this lack of expression and activate to kill the DFTD cell? The lack of MHC Class I molecules on the cell surface of DFTD should indicate a strong enough stressor to cause the activation of the NK cell.
According to Natural Killer Cell Mediated Cytotoxic Responses in the Tasmanian Devil, when two healthy Tasmanian Devils were injected with irradiated DFTD, one only showed a small amount of cellular cytotoxicity and both had no antibody development. However when injected with other forms of xenogenic tumor cells, a strong cytotoxic response did occur. Therefore it proves that the immune system of Tasmanian Devils do have the ability to mount a cytotoxic response, except for DFTD unfortunately. This could be due to DFTD having the ability to either hide from NK cells or somehow fool them to think they are not “stressed” enough to be killed. It would be important to figure out how the DFTD cells are able to hide from the innate immune system and the adaptive immune system at the same time, so a viable vaccine or treatment could be made to save the species.