Devil facial tumour disease

Devil facial tumour disease causes tumours to form in and around the mouth, interfering with feeding and eventually leading to death by starvation.

Devil facial tumour disease (DFTD) is an aggressive non-viral transmissible parasitic cancer among Tasmanian devils.[1][2][3][4]

The first official case of DFTD was described in 1996 in Australia. In the subsequent decade the disease ravaged Tasmania's wild devils, with estimates of decline ranging from 20% to as much as 50% of the devil population, across over 65% of the state.[5][6] Affected high-density populations suffer up to 100% mortality in 12–18 months.[7] The disease has mainly been concentrated in Tasmania's eastern half. Visible signs of DFTD begin with lesions and lumps around the mouth. These develop into cancerous tumours that may spread from the face to the entire body. Devils usually die within six months from organ failure, secondary infection, or metabolic starvation as the tumours interfere with feeding.[8] DFTD affects males and females equally.[9] At present the population has dwindled by 70% since 1996. As of 2010, 80% of population is infected.

The most plausible route of transmission is through biting, particularly when canine teeth come into direct contact with the diseased cells.[10] Other modes of transmission include, but are not limited to, the ingesting of an infected carcass or the sharing of food, both of which involve an allogeneic transfer of cells between unrelated individuals.[11]

Six females have been found with a partial immunity. Breeding in captivity has begun in an attempt to save the population.[12]

Characteristics

Tasmanian devil cells have 14 chromosomes, while the oldest-known strain of the tumour cell contains thirteen chromosomes, nine of which are recognizable and four of which are mutated “marker” chromosomes.[13] More recently evolved strains have an additional mutant marker chromosome, for a total of fourteen chromosomes.[14][15] Researchers identified the cancer as a neuroendocrine tumour, and found identical chromosomal rearrangements in all the cancer cells.[16] The karyotype anomalies of DFTD cells are similar to those of cancer cells from canine transmissible venereal tumour (CTVT), a cancer of dogs that is transmitted by physical contact.[16] Among the different alterations present in the tumour genome can be found several single base mutations or shorts insertions and deletions (indels) like deletions in the chromosomes 1, 2 and 3 or trisomy in 5p. Some of the mutated or deleted genes in DFTD are RET, FANCD2, MAST3 and BTNL9-like gene.[17]

The theory that cancer cells themselves could be an infective agent (the Allograft Theory[18]) was first supported by the researchers A-M. Pearse, K. Swift, and colleagues. In 2006, Pearse and Swift analyzed DFTD cells from several devils in different locations, and determined that all of the DFTD cells were not only genetically identical to each other, but also genetically distinct from their hosts, and from all known Tasmanian devils. Thus the cancer must have originated in a single individual and spread, rather than arising separately within each animal.[18][19][20] Twenty one different subtypes have been identified by analyzing the genomes (mitochondrial and nuclear) of 104 tumours from different Tasmanian devils.[17] Later researchers witnessed a previously-uninfected devil develop tumours from lesions caused by an infected devil’s bites, confirming that the disease is spread by allograft, and that the normal methods of transmission include biting, scratching, and aggressive sexual activity between individuals.[21] During biting, infection can spread from the bitten devil to the biter.[22] Since June 2005, three females have been found that are partially resistant to DFTD.[23]

Further research from the University of Sydney has shown that the infectious facial cancer may be able to spread because of low diversity in devil immune genes (MHC class I and II).[24] The same genes are also found in the tumours, so the devil's immune system does not recognize the tumour cells as foreign.[25][26] There are at least four, and most likely more, strains of the cancer, showing that it is evolving, and may become more virulent.[27] Increased levels of tetraploidy have been shown to exist in the oldest strain of DFTD as of 2014, which correlates with the devils involved being subjected to a DFTD removal programme. Because ploidy slows the tumour growth rate, Ujvari et al. posit that the DFTD removal programme selected for slower-growing tumours, and that disease eradication programmes may result in the evolution of DFTD.[28] The strains may also complicate attempts to develop a vaccine, and the mutation of the cancer may mean that it could spread to other related species, like the quoll.[29]

In a paper published in the January 2010 issue of Science,[30] an international team of researchers announced that devil facial tumour disease likely originated in the Schwann cells of a single devil.[14] Schwann cells are found in the peripheral nervous system, and produce myelin and other proteins essential for the functions of nerve cells in the peripheral nervous system.[31][32] The researchers sampled 25 tumours and found that the tumours were genetically identical.[31] Using deep sequencing technology, they then profiled the tumours' transcriptome, the set of genes that are active in tumours. The transcriptomes closely matched those of Schwann cells, revealing high activity in many of the genes coding for myelin basic protein production.[32] Several specific markers were identified by the team, including the MBP and PRX genes, which may enable veterinarians to more easily distinguish DFTD from other types of cancer, and may eventually help identify a genetic pathway that can be targeted to treat it.[32]

Due to the decreased life expectancy of the devils due to DFTD, they have begun breeding at younger ages in the wild, with reports that many only live to participate in one breeding cycle.[33] A study has suggested that Tasmanian devils have changed their breeding habits in response to the disease. Females previously started breeding at the age of two, then annually for about three more years until dying normally. Now they commonly breed at the age of one, and die of tumours shortly thereafter. It is speculated that the disease is spread by devils biting each other during the mating season.[34] Social interactions have been seen spreading DFTD in a local area.[35] It is one of three known contagious cancers.

In 2015, a variant form of the cancer was described which was tetraploid, not diploid like the main form of the cancer. The tetraploid form has been linked to lower mortality rates.[36]

Pathology

Growth of large tumours impedes feeding, and starvation is a common cause of death in affected devils. Organ involvement and additional infections may also be a factor in death, as regional lymph node involvement and systemic metastasis is common. The cancer invades the heart.[37]

The tumours are capable of dissolving parts of the skull.[38]

The tumours are "large, solid, soft tissue masses usually with flattened, centrally ulcerated, and exudative surfaces", which are "typically multicentric, appearing first in the oral, face, or neck regions". The tumours are "circumscribed to infiltrative nodular aggregates of round to spindle-shaped cells, often within a pseudocapsule and divided into lobules by delicate fibrous septae".[39]

Preservation response

Wild Tasmanian devil populations are being monitored to track the spread of the disease and to identify changes in disease prevalence. Field monitoring involves trapping devils within a defined area to check for the presence of the disease and determine the number of affected animals. The same area is visited repeatedly to characterise the spread of the disease over time. So far, it has been established that the short-term effects of the disease in an area can be severe. Long-term monitoring at replicated sites will be essential to assess whether these effects remain, or whether populations can recover.[6] Field workers are also testing the effectiveness of disease suppression by trapping and removing diseased devils. It is hoped that the removal of diseased devils from wild populations should decrease disease prevalence and allow more devils to survive beyond their juvenile years and breed.[6] A study felt that the current system of culling did not impede the disease's spread.[40]

Two "insurance" populations of disease-free devils are being established at an urban facility in the Hobart suburb of Taroona and on Maria Island off the east coast of Tasmania.[41] Captive breeding in mainland zoos is also a possibility. The decline in devil numbers is also seen as an ecological problem, since its presence in the Tasmanian forest ecosystem is believed to have prevented the establishment of the red fox, illegally introduced to Tasmania in 2001.[42] It is believed that Tasmanian devil young would be vulnerable to red fox predation, as they are left alone for long periods of time.[43]

In response to the impact of DFTD on Tasmanian devil populations, 47 devils have been shipped to mainland Australian wildlife parks to attempt to preserve the genetic diversity of the species. The largest of these efforts is the Devil Ark project in Barrington Tops, New South Wales; an initiative of the Australian Reptile Park. This project aims to create a set of one thousand genetically representative devils, and is now a major focus of the insurance policy.[44] In addition, the Tasman peninsula is being considered as a possible "clean area" with the single narrow access point controlled by physical barriers. The Tasmanian Department of Primary Industries and Water is experimenting on culling infected animals with some signs of success.[45][46]

In 2008, a devil named Cedric was thought to have a natural immunity to the disease, but in late 2008 he developed two tumours on his face. The tumours were removed[47] and officials thought Cedric was responding well until September 2010 when it was discovered that the cancer had spread to his lungs. He was euthanized upon the discovery.[48] A diagnostic blood test was developed in mid-2009 to screen for the disease.[49] In early 2010, scientists found some Tasmanian devils, mostly in the north-west of Tasmania, that are genetically different enough for their bodies to recognise the cancer as foreign. They have only one Major Histocompatibility Complex, whereas the cancerous cells have both.[50]

At present with the population reduced by 70% since 1996, if a cure is not found then scientists predict they will become extinct by 2035.[12]

A study recommended oocyte banking be used in the conservation effort for Tasmanian devils, as the survival rate of the oocytes in their study was 70%.[51]

In 2010, there was hope that EBC-46, a drug which cures facial tumours in dogs, cats, and horses, may be a cure for DFTD.[52]

Vaccination with irradiated cancer cells has not proven successful.[53]

Research published in the Proceedings of the National Academy of Sciences on June 27, 2011, suggests picking a genetically diverse breeding stock, defined by the genome sequence, for conservation efforts.[54]

In 2011, Principal Investigator David Phalen, (Wildlife Health and Conservation Centre, University of Sydney) and Stephen Pyecroft (Department of Primary Industries and Water in Tasmania) along with Antony Moore and Angela Frimberger (Veterinary Oncology Consultants) were awarded a Tasmanian Government Project Management Grant for their project Investigation into Chemotherapy Agents Effective Against the Tasmanian Devil Facial Tumour.[55]

In 2013, a study using mice as a model for Tasmanian devils suggested that a DFTD vaccine or treatment could be beneficial.[56]

In 2015, a study which mixed dead DFTD cells with an inflammatory substance caused an immune response in five out of six devils injected with the mixture. This has created hopes for a vaccine against DFTD.[57][58] Field testing of the potential vaccine is being undertaken as a collaborative project between the Menzies Institute for Medical Research and the Save the Tasmanian Devil Program under the Wild Devil Recovery program, and aims to test the immunisation protocol as a tool in ensuring the devil's long term survival in the wild.[59]

History

Spread of the disease as of 2007.[60]

In 1996, a photographer from The Netherlands[61] captured several images of devils with facial tumours near Mount William in Tasmania's northeast. Around the same time, farmers reported a decline in devil numbers.[62] Menna Jones first encountered the disease in 1999 near Little Swanport, in 2001 capturing three devils with facial tumours on the Freycinet Peninsula.[63]

The devil population on the peninsula decreased dramatically. In March 2003 Nick Mooney wrote a memo to be circulated within the Parks and Wildlife Services calling for more funding to study the disease, but the call for funding was edited out before the memo was presented to Bryan Green, then Tasmania's Minister for Primary Industries, Water and Environment.[64][65] In April 2003, a working group was formed by the Tasmanian Government to respond to the disease.[66] In September 2003, Nick Mooney went to the Tasmanian daily newspaper The Mercury, informing the general public of the disease and proposing a quarantine of healthy Tasmanian devils. At the time, it was thought that a retrovirus was a possible cause. David Chadwick of the state Animal Health Laboratory said that the laboratory did not have the resources needed to research the possibility of a retrovirus. The Tasmanian Conservation Trust criticised the Tasmanian government for providing insufficient funds for research and suggested that DFTD could be zoonotic, posing a threat to livestock and humans.[38] On 14 October 2003, a workshop was held in Launceston.[67] In 2004, Kathryn Medlock found three oddly shaped devil skulls in European museums and found a description of a devil in London Zoo dying, which showed a similarity to DFTD.[68]

A virus was initially thought to be the cause of DFTD,[38] but no evidence of such a virus could be detected in the cancer cells. Calicivirus, 1080 poison, agricultural chemicals, and habitat fragmentation combined with a retrovirus were other proposed causes.[69] Environmental toxins had also been suspected.[70] In March 2006 a devil escaped from a park into an area infected with DFTD. She was recaptured with bite marks on her face, and returned to live with the other devils in the park. She wounded a male and by October both devils had DFTD, which was subsequently spread to two others. This incident helped test the viability of the allograft theory of transmission.[71] In 2006, DFTD was classed a List B notifiable disease under the Animal Health Act 1995.[72] Also in 2006, the strategy of developing an insurance population in captivity was developed. It was reassessed in 2008.[73] A 2007 investigation into the immune system of the devils found that when combatting other pathogens, the response from the immune system was normal, leading to suspicion that the devils were not capable of detecting the cancerous cells as "non-self".[74] In 2007, it was predicted that populations could become locally extinct within 10–15 years of DFTD occurring, and predicted that the disease would spread across the entire range of the Tasmanian devils. This study also predicted that Tasmanian devils would become extinct within 25–35 years.[75]

In 2008, high levels of potentially carcinogenic flame retardant chemicals were found in Tasmanian devils. Preliminary results of tests of fat tissue revealed high levels of hexabromobiphenyl (BB153) and "reasonably high" levels of decabromodiphenyl ether (BDE209).[76]

In other animals

Transmissible cancer, caused by a clone of malignant cells rather than a virus, is extremely rare, with only two other known transmissible cancers—canine transmissible venereal tumour (CTVT), which is sexually transmitted among dogs, and contagious reticulum cell sarcoma of the Syrian hamster,[77] which can be transmitted via mosquito bites of Aedes aegypti.[78] CTVT mutes the expression of the immune response, whereas the Syrian hamster disease spreads due to lack of genetic diversity.[79]

See also

References

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  2. ↑ Loh, Richmond. 2003. Tasmanian Devil (Sarcophilus harrisii) facial tumour (DFT). Paper prepared for the Devil Facial Tumour Disease Workshop, Sir Raymond Ferrall Centre, University of Tasmania, Newnham, 14 October 2003, p. 2.
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  4. ↑ Weiss, Rick (11 August 2006). "Study Finds That a Type of Cancer in Dogs Is Contagious". The Washington Post. Retrieved 11 August 2006.
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  31. 1 2 Kinver, Mark (1 January 2010). "Tasmanian devil facial cancer origins 'identified'". BBC.
  32. 1 2 3 Walsh, Bryan (1 January 2010). "Decoding the Tasmanian Devil's Deadly Cancer". Time.
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  34. ↑ Kinver, Mark (15 July 2008). "Tumours 'alter devils' sex lives'". BBC News.
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  36. ↑ http://www.abc.net.au/worldtoday/content/2015/s4304667.htm
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  38. 1 2 3 Wood, Danielle (1 September 2003). "Tassie devil under threat". The Mercury (Hobart Town, Tasmania). p. 1.
  39. ↑ Loh, R; Bergfeld, J; Hayes, D; O'hara, A; Pyecroft, S; Raidal, S; Sharpe, R (November 2006). "The pathology of devil facial tumor disease (DFTD) in Tasmanian Devils (Sarcophilus harrisii).". Veterinary pathology 43 (6): 890–5. doi:10.1354/vp.43-6-890. PMID 17099145.
  40. ↑ Lachish, Shelly; McCallum, Hamish; Mann, Dydee; Pukk, Christy E.; Jones, Menna E. (2010). "Evaluation of Selective Culling of Infected Individuals to Control Tasmanian Devil Facial Tumor Disease". Conservation Biology 24 (3): 841–851. doi:10.1111/j.1523-1739.2009.01429.x. PMID 20088958.
  41. ↑ Zimmer, Carl (22 January 2013). "Raising Devils in Seclusion". New York Times.
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  45. ↑ Scientific American, March 2007
  46. ↑ Contagious cancer: the evolution of a killer, David Quammen, Harper's Magazine, April 2008.
  47. ↑ BBC – Fence hope for Tasmanian Devils. Retrieved 5 January 2009.
  48. ↑ "Cancer-related death for Cedric the devil – ABC News (Australian Broadcasting Corporation)". ABC.net.au. 2010-09-01. Retrieved 2010-09-11.
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  51. ↑ Czarny, N.A.; Rodger, J.C. (2010). "Vitrification as a method for genome resource banking oocytes from the endangered Tasmanian devil (Sarcophilus harrisii)☆". Cryobiology 60 (3): 322–5. doi:10.1016/j.cryobiol.2010.02.007. PMID 20219455.
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  53. ↑ "Hopes of a tumour test for Tasmanian devils". nature.com.
  54. ↑ Miller, Webb; et al. (27 June 2011). "Genetic diversity and population structure of the endangered marsupial Sarcophilus harrisii (Tasmanian devil)". Proceedings of the National Academy of Sciences 108 (30): 12348–12353. doi:10.1073/pnas.1102838108.
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  56. ↑ Pinfold, Terry L.; Brown, Gabriella K.; Bettiol, Silvana S.; Woods, Gregory M. (27 May 2014). "Mouse Model of Devil Facial Tumour Disease Establishes That an Effective Immune Response Can be Generated Against the Cancer Cells". Frontiers in Immunology 5. doi:10.3389/fimmu.2014.00251.
  57. ↑ "Tasmanian devil facial tumour vaccine a step closer, researchers say". ABC News.
  58. ↑ Kreiss, A.; Brown, G.K.; Tovar, C.; Lyons, A.B.; Woods, G.M. (February 2015). "Evidence for induction of humoral and cytotoxic immune responses against devil facial tumor disease cells in Tasmanian devils (Sarcophilus harrisii) immunized with killed cell preparations". Vaccine (journal). doi:10.1016/j.vaccine.2015.01.039.
  59. ↑ "Save the Tasmanian Devil Program moves closer to immunised devil trial". 25 February 2015. Retrieved 14 April 2015.
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  61. ↑ http://www.radiolab.org/story/91714-devil-tumors/
  62. ↑ Owen and Pemberton, pp.170–171
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  64. ↑ Owen and Pemberton, p.177
  65. ↑ "Tasmanian Devils - Spread of Disease". Parliamentary Debates (Hansard). Tasmania: House of Assembly. 29 October 2003. Part 2: pp. 31–104. (part 2) 3:30 pm (Jeremy Rockliff, Shadow Minister for Primary Industries, Water and Environment; Nick McKim, Tasmanian Greens; Bryan Green, Minister for Primary Industries, Water and Environment).
  66. ↑ Bryan Green, Minister for Primary Industries, Water and Environment (20 August 2003). "Tasmanian Devils and the Spread of Cancer". Parliamentary Debates (Hansard). Tasmania: House of Assembly. Part 1: pp. 1–29. (10:58 am) (part 1)
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  71. ↑ Research priorities in the Tasmanian devil facial tumour debate
  72. ↑ Frequently Asked Questions About Devil Facial Tumour Disease
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  75. ↑ McCallum, Hamish; Tompkins, Daniel M.; Jones, Menna; Lachish, Shelly; Marvanek, Steve; Lazenby, Billie; Hocking, Greg; Wiersma, Jason; Hawkins, Clare E. (2007). "Distribution and Impacts of Tasmanian Devil Facial Tumor Disease". EcoHealth 4 (3): 318–325. doi:10.1007/s10393-007-0118-0.
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