Prospects & Overviews

Review essays

Contagious cancer: Lessons from

the devil and the dog
Katherine Belov

Cancer is generally defined as uncontrollable growth of

cells caused by genetic aberrations and/or environmental factors. Yet contagious cancers also occur. The
recent emergence of a contagious cancer in Tasmanian
devils has reignited interest in transmissible cancers.
Two naturally occurring transmissible cancers are
known: devil facial tumour disease and canine transmissible venereal tumour. Both cancers evolved once and
have then been transmitted from one individual to
another as clonal cell lines. The dog cancer is ancient;
having evolved more than 6,000 years ago, while the
devil disease was first seen in 1996. In this review I will
compare and contrast the two diseases focusing on the
life histories of the clonal cell lines, their evolutionary trajectories and the mechanisms by which they have
achieved immune tolerance. A greater understanding of
these contagious cancers will provide unique insights
into the role of the immune system in shaping tumour
evolution and may uncover novel approaches for treating
human cancer.

Keywords:
canine transmissible venereal tumour; contagious cancer;
MHC; Tasmanian devil facial tumour disease

DOI 10.1002/bies.201100161
Faculty of Veterinary Science, University of Sydney, Sydney, Australia
Corresponding author:
Katherine Belov
E-mail: kathy.belov@sydney.edu.au
Abbreviations:
CNV, copy number variation; CTVT, canine transmissible venereal tumour;
DFT, devil facial tumour; DFTD, devil facial tumour disease; MHC, major
histocompatibility complex; NK cell, natural killer cell.

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Introduction
Generally we do not think about catching cancer. Cancer is a
disease which arises within one host and dies with that host. It
is caused by uncontrolled cell division which is brought about
by carcinogens, infectious agents and inherited predispositions. Within the individual, cancer is clonal and undergoes
Darwinian evolution, resulting in clones which are more
aggressive, with increased capacity to evade immune
responses and resist chemotherapy regimens [1, 2]. The concept of human extinction from cancer is inconceivable, yet the
Tasmanian devil, a carnivorous marsupial, is currently threatened with extinction due to the emergence of a contagious
cancer that is passed between animals by biting [3]. In this
review I summarise our understanding of Tasmanian devil
facial tumour disease (DFTD) and provide comparisons with
the only other naturally occurring transmissible cancer,
canine transmissible venereal tumour (CTVT). A striking common link between the two diseases is the involvement of the
major histocompatibility complex (MHC) [4], a key region of
the genome involved in immune response. In fact, these two
contagious cancers provide an ideal model for studying the
role of the immune system in shaping tumour evolution.

The major histocompatibility complex

plays a central role in defence against
disease and cancer
The MHC is a key region of the genome involved in immune
response to infectious diseases, immunosurveillance and self/
non-self recognition [5]. The MHC is the most highly polymorphic region of the vertebrate genome. Each MHC allele can
recognise a different range of pathogenic peptides and high
MHC diversity increases the chance that at least some members of each population will be able to mount an immune
response to a given pathogen [6, 7]. It naturally follows that
populations with low MHC diversity will be more vulnerable to
disease epidemics, but this link has been difficult to demonstrate [8].
There are two main classes of MHC molecules involved in
antigen presentation, MHC class I and class II [9]. MHC class I

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molecules are found on all nucleated cells and platelets and

are involved in the presentation of endogenous peptides to
CD8 cytotoxic T cells. MHC class I molecules are composed of
a heavy chain which is encoded within the MHC and a b2microglobulin, encoded outside the MHC. The number of MHC
class I genes varies greatly between species, and even within
species. Copy number variation (CNV) is a common feature of
MHC class I [10, 11]. The MHC class I genes can be divided
broadly into classical and non-classical genes, based loosely
on their expression patterns, levels of polymorphism and
genomic location [12]. Classical genes, including human
HLA-A, HLA-B and HLA-C present self and non-self peptides
to T cells and have a highly polymorphic peptide binding
region. Non-classical MHC class I molecules, including
HLA-G, are not necessarily involved in antigen presentation,
tend to have limited expression in different tissues and are not
necessarily polymorphic [13]. Non-classical class I molecules
can act as decoys, facilitating immune evasion [1420]. A
classic example of this involves expression of HLA-G at the
maternal-foetal interface [21]. By down-regulating classical
class I genes, the semiallogeneic fetus can evade destruction
by maternal T cells. Up-regulation of the structurally similar
non-classical HLA-G prevents destruction by natural killer
cells (NK), which kill cells that lack cell-surface MHC class I
molecules. As will be discussed in greater detail below, this is
also a common mechanism used by malignant cancers to
evade the immune response [1420].
MHC class II molecules are found only on a subset of
specialised antigen presenting cells, including B cells, some
macrophages and monocytes, Langerhans cells and dendritic
cells. MHC class II molecules present extracellular peptides to
CD4 helper cells resulting in the generation of an appropriate immune response. MHC class II molecules are composed of
an alpha chain and a beta chain, both of which are encoded by
genes within the MHC. The number of MHC class II family gene
families and genes differs between species, but not to the
extent of MHC class I [10, 11].
The dog and the devil MHC contain a unique gene
complement
Our understanding of the MHC of dogs and devils lags behind
that of humans. Lorna Kennedy and colleagues have generated a comprehensive dataset of canine MHC alleles, which is
available at http://www.ebi.ac.uk/ipd/mhc/dla/index.html.
One classical class I gene and three non-classical genes have
been characterised. Class II genes include DRA and DRB, DQA
and DQB, DPA and DPB1 and DPB2 and DOB. Dogs, wolves and
coyotes share MHC alleles [22]. Overall levels of MHC diversity
are lower in wolves than in dogs [23].
The devil MHC is more complicated. Our early work uncovered MHC class I CNVs between individuals [24]. Recent
sequencing of two MHC haplotypes using BAC-based sequencing has revealed up to five class I loci (-UA, -UB, -UC, -UD and UK) and four class II loci (DAA, DAB1, DAB2 and DAB3) per
haplotype [25]. We suggest that -UA, -UB and -UC have a
classical function,-UK is non-classical, while -UD may be
either classical or non-classical. More work is necessary to
confirm the exact functional roles of these genes. We identified
CNVs that extend into intergenic regions, meaning that as well

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as different numbers of loci per haplotype, expression of each

locus may be impacted by indels in promoter regions. MHC
diversity in devils is low at both MHC class I and class II, and as
discussed below, may have facilitated tumour transmission
through a lack of histocompatibility barriers in devil populations [26].
The genetic control of allorecognition differs
in vertebrates and invertebrates
In jawed vertebrates the MHC plays a critical role in immune
responses against non-self antigens [9, 27]. Graft rejection
occurs in MHC non-identical recipients and cumulative MHC
mismatches are associated with poor graft survival [28, 29].
But, allorecognition dates back to colonial invertebrates,
which do not have an adaptive immune response or MHC
genes [2831]. For example the tunicate Botryllus schlosseri
grows via asexual budding. Mobile stem cells can grow into
adjacent individuals. When the two individuals come into
contact the cells may either fuse and form a single chimeric
colony or rejection can occurs via a blood-based inflammatory
reaction. Once cells fuse the two stem cell lineages compete
and over time one lineage replaces the other in all germline
and somatic tissues. This process is called stem cell parasitism
[32]. Loci involved in fusion or rejection have been characterised. They do not share common evolutionary origins to
MHC [3335].
The MHC plays a central role in immune evasion
The most common mechanism by which malignant cells evade
the immune response is through changes in the expression
patterns of classical and non-classical MHC class I and class II
antigens [1420]. These changes can be brought about by
distinct mechanisms, including defects in b2-microglobulin
synthesis, loss of genes encoding MHC heavy chains,
mutations which inhibit MHC transcription or translation,
defects in regulatory mechanisms which control MHC expression or abnormalities in components of the antigen processing
pathway [36, 37]. There has been a recent focus on the role of
epigenetic events and MHC expression in malignant cells.
Readers are referred to an excellent review by Campoli and
Ferrone [36] which provides a comprehensive review on the
field.

Devil facial tumour disease threatens the

largest remaining marsupial carnivore with
extinction
The Tasmanian devil is the worlds largest remaining marsupial carnivore (depicted in Fig. 1A). The species was once
widespread on mainland Australia [38], but is now restricted
to the island state of Tasmania. Tasmanian devils have been
isolated in Tasmania for approximately 12,000 years and have
undergone additional population bottlenecks more recently
[39, 40], resulting in populations with low genetic diversity at
microsatellite markers [41], single nucleotide polymorphisms
[42] and at the MHC [26] (Table 1).

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Tasmanian devils are now listed as endangered, due to the

emergence of a contagious cancer, which has resulted in
90% population declines in eastern Tasmania (http://www.
tassiedevil.com.au/tasdevil.nsf/news/EFF829BABE84E1EFCA2578F000052FB1). The disease was first noticed in 1996 in Mt
William National Park in the east of the state. Animals with
DFTD have large ulcerating tumours, primarily on their face
and jaw [43] (depicted in Fig. 1B). The cancer metastasises in
over 65% of cases [43]. Prior to DFTD devils lived about five
years in the wild, breeding annually at 24 and sometimes five
years of age [44]. Today, most devils are infected by the age of
two and very few animals three years and over are found in
the wild [44]. There is 100% mortality within six months of
appearance of lesions [3]. The disease is expected to reach the
west coast of Tasmania within five years and could lead to
local extinctions in the wild within 25 years [45].
DFTD is transmitted as an allograft via bite wounds during
social interactions such as mating and feeding [46]. Molecular
and cytogenetic studies have shown that devil facial tumours
(DFTs) are clonal [47], that is the tumour arose once, most
likely from a Schwann cell or Schwann cell precursor [48], and
has since passed from animal to animal, rather than arising
independently in each animal. DFT cells have identical grossly
rearranged karyotypes [47] and share identical genotypes
which differ from that of the hosts [26, 48]. Next generation
sequencing also supports tumour clonality [42].
Devils are known to be prone to cancer [4951], but there
are no indications that they are immunologically compromised [52]. They are able to mount strong humoral immune
responses to horse red blood cells [53]. Lymphocyte proliferation can be triggered in culture [54]. NK cell responses have
been demonstrated [55]. However, our understanding of the
devils immune system is quite rudimentary. This is primarily
due to the fact that devil immune molecules are divergent from
those of humans and mice and commercial immunological

reagents do not cross react [56, 57]. Development of specific

immunological reagents based on genomic immune gene data
should allow a more comprehensive study of the immune
response of the Tasmanian devil in the near future.
The MHC plays a role in immune tolerance to DFTD
DFTs pass from animal to animal without invoking a detectable immune response [52]. Only 7% of DFTs contain infiltrating lymphocytes [58] and low MHC diversity in Tasmanian
devils contributes to a lack of non-self recognition of MHC
similar DFT cells [26]. However, as discussed below, DFTs
themselves may also contribute to immune tolerance [54].
Tasmanian devils can be broadly divided into two subpopulations based on microsatellite and MHC diversity: eastern and northwestern [24, 41]. Eastern devils have low MHC
diversity [26], while devils in the northwest of Tasmania are
genetically more disparate raising hopes that they might be
able to see DFTs as foreign [24]. Results in culture look
promising: mixing of eastern and northwestern lymphocytes
generates a strong mixed lymphocyte response demonstrating
that MHC diversity is sufficient for recognition of non-self
antigens [54]. Results from the wild also lend support the
notion that genetically disparate northwestern devils may
be more resilient to DFTD than their eastern counterparts.
A four-year study at West Pencil Pine, a population in the
genetic transition zone between the eastern and northwestern
sub-populations, has shown a marked difference in the
epidemiology and population impacts of DFTD compared to
other matched eastern populations [59]. Four years after
disease arrival, there is no evidence of a rapid increase in
DFTD prevalence in any age class, or changes to either the
population size or age structure of the populations [59]. A
study into the role of MHC in disease resistance is currently
underway.

Table 1. Comparison of devil facial tumour disease (DFTD) and canine transmissible venereal tumour (CTVT)
Disease
Species affected
Distribution
Origin
Primary tumours
Transmission
Metastasis
Mortality

DFTD
Tasmanian devil
Tasmania
Schwann cell
Face
Biting
65%
100%

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CTVT
Dogs, wolves, coyotes and jackals
Worldwide
Myeloid cell
Genitalia
Sexually transmitted
Rare
Rare

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Figure 1. A: A healthy Tasmanian devil. B: A

Tasmanian devil affected by devil facial tumour
disease. Photos by Rodrigo Hamede, University
of Tasmania.

K. Belov

Review essays

Lack of MHC diversity does not prevent allorecognition

in Tasmanian devils
Skin grafts were carried out on four MHC-matched skin graft
devil pairs from eastern Tasmania [54]. Three of the four pairs
had no amino acid differences in their MHC class I and class II
peptide binding regions and did not generate mixed lymphocyte responses in culture, while the fourth skin graft pair had
only two amino acid differences at MHC I, which led to a low
mixed lymphocyte response. In all cases, despite a lack of MHC
disparity, the grafts were rejected. The rejection in the MHC
mis-matched graft was no quicker than in the MHC-matched
grafts. In all four cases, the allografts were all infiltrated with
CD3 T cells [54], a marked difference from what is seen with
DFTD [58].
This experiment provides an important insight into DFTD
transmission: devils are capable of allorecognition despite low
MHC diversity, and low MHC diversity alone does not explain
tumour transmission.
So what drove allorecognition in these MHC-identical devils? In humans, MHC-identical twins still face a 40% risk of
graft-versus-host disease [60] and 2030% of MHC-identical
sibling renal allografts are lost to rejection [61]. Loss of skin
grafts between MHC identical mouse strains can be almost as
rapid as between strains that differ at their MHC [62]. The
major drivers of this rejection are MHC-restricted minor
histocompatibility antigens.
Minor histocompatibility antigens were originally
described by Snell as non-MHC genetic loci sufficient to
initiate allogeneic tissue rejection in congenic mouse
strains, that is animals bred to be identical at the MHC
locus but disparate at other areas of the genome [63].
Minor histocompatibility antigens are derived from
normal cellular proteins and are presented to cytotoxic T
lymphocytes by MHC molecules. Most autosomal minor
histocompatibility antigens are generated as a result of
non-synonymous coding SNPs, which lead to differences
in the amino acid sequences of homologous proteins between
donor and recipient cells [60]. Polymorphisms in cytokine
genes including IL10, TNF, IFNg, IL6, IL1 and TGFb1 are
known to be as important as MHC mismatches for triggering
graft rejection [60].
Autosomal minor histocompatibility antigens can also
arise when the recipient is confronted with a peptide for which
there is no allelic homolog in the donor. These arise through
structural variations including deletions, duplications, inversions and CNVs [60]. Many immune genes are subject to CNVs,
including MHC, NK receptors and genes encoding Fc and
immunoglobulin receptors. Our studies have recently shown
CNVs in the Tasmanian devil MHC [25], and the impact of
this on graft rejection should be explored. Several minor
histocompatibility antigens are encoded by genes on the Y
chromosome, which show significant polymorphism with
homologous regions on the X and are immunologically
relevant in sex mis-matched transplants [60]. More recently
minor histocompatibility antigens have been identified from
cryptic peptides from non-coding regions of the genome such
as untranscribed regions or introns [60].
Several hundred minor histocompatibility antigens exist in
mice and the number is probably similar in humans [60].

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Devils have roughly a quarter of the genetic diversity as

humans [42] so the number of minor histocompatibility antigens is likely to be significant.
In humans, skin grafts are particularly immunogenic
and are invariably rejected in an acute fashion [64, 65].
Immunosuppressive treatments, which can prevent early
rejection of organ transplants including kidneys, have little
or no effect in skin transplantation [65]. A striking example of
this includes burn victims, who are unable to accept skin from
others. The presence of dendritic cells and macrophages in
skin facilitates activation of T cells via MHC class II antigen
presentation. Lack of vascularisation of skin allografts at the
time of their placement increases immunogenicity of these
grafts, favouring dendritic cell trafficking via lymphatic
vessels [65]. Depletion of these cells from allografts is known
to cause marked reduction in immunogenicity and is worth
trialling on the devils.
Skin is also inherently non-sterile and ischemic and surgical trauma releases endogenous molecules capable of activating pattern recognition receptors (PRRs) [64]. Toll-like
receptors are a well-studied family of PRRs which play a major
role in activating immune responses and directing adaptive
immunity. They are expressed on dendritic cells, B cells, mast
cells and T cells and play a key role in graft rejection. NK also
play a role in graft rejection [66].
The role of minor histocompatibility, innate immunity and
choice of transplanted tissue all remain to be further investigated in the Tasmanian devil, but the transplantation results
do point towards the evolutionary adaptation of the DFTs to
prevent allorecognition. The study of the evolutionarily older
CTVT may provide some of the clues as to how DFTs avoids
recognition by the immune system.

The evolutionary ancient canine

transmissible venereal tumour provides a
unique contrast to the young devil facial
tumour disease
CTVT is the oldest recognised malignant cell line [67]. It is
believed to have evolved in wolves 6,000 years ago [68] and
since then has been passed between canine species during
coitus, licking, biting and sniffing tumour affected areas [69].
CTVT is characterised by lesion that occur primarily around
the genitalia. It can affect both sexes of any breed of dog and
has been seen on six continents [69].
CTVT is believed to have evolved from a histiocyte
(reviewed in [70]) and a recent report has uncovered evidence
of host mitochondrial capture by CTVT [71], to reduce
the accumulation of deleterious mutations in the clonal cell
line and potentially to optimise its metabolic machinery.
Evidence for CTVTs clonality comes from molecular genetic
and cytogenetic studies as well as the presence of a LINE
element insertion near the MYC locus in the CTVT genome
[68, 7275]. Extant tumours fall into two phylogenetic groups
[75]. CTVT genomes share many duplications and deletions,
which are not found in extant dog genomes [68]. These CNVs
could either have been selected due to functional advantage,
or tolerated [76]. Rebbeck et al. [68] estimate that CTVT has

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undergone up to 30,000 transmission events allowing plenty

of opportunity for adaptive evolution.

CTVT is believed to have evolved in wolves or an east Asian

dog breed with low MHC diversity [75]. Over time the tumour
evolved immune evasion strategies via down-regulation of cell
surface MHC class I and class II (reviewed in [4]). Only 25% of
CTVT cells express MHC class I during the progressive phase of
the disease and expression of b2-microglobulin is low [75, 77].
In healthy dogs, the tumour regresses within 69 months of
the appearance of tumours [69]. After tumour regression the
dog gains lifelong immunity to the disease. During the regressive phase approximately 40% of cells express MHC class I and
b2-microglobulin [75, 78]. CTVT does not completely suppress
MHC expression allowing it to escape rejection by NK cells,
which only kill cells when MHC is missing altogether [79].
CTVT cells can be induced to express cell-surface MHC by
exposing the cells to the supernatants of cultured regressive
phase CTVT cells and tumour infiltrating lymphocytes [80]
and regression of CTVT is accompanied by infiltration of
lymphocytes and macrophages into the tumour. Hsiao et al.
[81] suggest that regression is driven by cytokines produced by
tumour infiltrating lymphocytes. Fassati and Mitchison [79]
have suggested that based on the fact that CTVT is clonal and
genetically stable change from progressive to regressive CTVT
must be driven by epigenetics.
CTVT also provokes a humoral immune response [69].
MHC class II antigens, produced during the regressive phase
[80], are likely to promote the generation of antibodies against
CTVT, driving the rejection of the cancer. These antibodies are
then likely to protect against re-infection.
Metastases are common in DFTD and rare in CTVT
CTVT metastases in dogs are rare (approximately 7% of cases)
[69] and are most common in immunosuppressed dogs [82,
83]. It has been suggested that the growth of CTVT is enhanced
by the expression of the immunosuppressive cytokine TGF-b1,
which reaches appropriate thresholds in a solid tumour, but is
unable to reach such concentrations outside of the tumour
microenvironment [79] restricting the ability of circulating
tumour cells to establish elsewhere. This is in direct contrast
to DFTD, where metastases occur in 65% of cases [58].
Can the evolutionary history of CTVT help us to predict
the future of DFTD?
A recent review by Elizabeth Murchison [70] noted that devils
and dogs share behavioural and genetic aspects of their
biology that favour the transmission of a contagious cancer,
as devils are regularly bitten around the face during feeding
and mating and dogs engage in extended and rough sexual
intercourse. The similarities between the emergences of the
two diseases are striking. Both dogs and devils have undergone severe population bottlenecks: devils around the time of
the last ice age [41] and dogs around the time of domestication
and breed formation [84]. This low genetic diversity may have

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facilitated the initial transmission of cells between animals.

Over time, the canine tumours evolved additional strategies,
including down-regulation of MHC and mitochondrial capture, to assist them in becoming more adept parasites.
Preliminary evidence suggests that DFT is also evolving and
may be following a similar path to CTVT.
DFT is evolving its evolutionary trajectory is unknown
The identification of minor regional karyotypic differences
between DFT karyotypes suggests DFT is evolving [85].
Tumour strains are characterised by additional marker
chromosomes, translocations, deletions and inversions and
tetraploidy. The phenotypic consequences of these variations
are not yet known, but different morphology and growth rates
in culture have been observed. In addition, hypermethylation
of DFTs due to increased expression of the DNA methyltransferase 1 gene in tumour cells has recently been observed
(Ujvari and Belov, unpublished data). This hypermethylation
results in epigenetic variation between different DFTs, leading
to tumour plasticity. Different methylation patterns likely
result in the silencing of different genes, providing the raw
material on which selection can act.
What are the likely outcomes of DFT evolution? Firstly, we
might expect strong selection for a less lethal disease.
Secondly, in the presence of MHC-disparate hosts, we could
expect DFTs to evolve immune evasion strategies. Thirdly, the
DFT cells could become unstable and die out. Finally, we may
expect to see co-evolution of the tumour and the host [85].
CTVT is non-lethal and widespread. We do not know
whether the disease was originally more virulent, but evolution tends to favour less virulent disease strains [86]. Will
DFT follow the same route? CTVT has been evolving for over
6,000 years and has encountered over 30,000 hosts [68]. DFT
wont have the same evolutionary opportunities, as the number of remaining hosts is limited and restricted to Tasmania.
However, the appearance of a slow growing tetraploid strain
in West Pencil Pine [59, 85], and the apparent proliferative
advantage of triploid cells in the NOD/SCID mouse model of
DFT [87] suggest that polypoloidy may be advantageous.
If immunological recognition of DFTs does occur in West
Pencil Pine [59], then it follows that the DFTs would be under
strong pressure to evolve immune evasion strategies. As mentioned previously, alterations in classical and non-classical
MHC expression are the most common mechanism of evading
the host immune response. Epigenetic changes can impair the
expression of MHC genes and b2-microglobulin as well as
other genes involved in antigen processing, including TAP1,
Tapasin and LMP [36]. Cell surface MHC class I expression has
not yet been demonstrated in the Tasmanian devil due to a
lack of cross-reacting antibodies, but is critical to our understanding of tumour transmission in Tasmanian devils. CTVT
was transmitted across histocompatibility barriers due to MHC
down-regulation resulting in infection in foxes, coyotes and
jackals [88]. If DFTs are under strong selection to downregulate MHC in West Pencil Pine, then closely related marsupials, especially quolls, may be at risk and should be closely
monitored.
DFT arose from a single Schwann cell [48] and has been
undergoing asexual reproduction since then. Without sexual

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in CTVT

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reproduction the clonal cell is unable to override new deleterious mutations and may fall victim to Mullers ratchet [89, 90].
CTVT may have stepped around the loss of metabolic activity
through the capture of mitochondria from the host [71].
Whether DFT will do the same remains to be determined.
It is interesting to note that both CTVT and DFT are
remarkably stable cell lines [85]. Presumably daughter cells
that differ from their parent cell either die or are not transmitted. DFT metastases contain karyotypes with random
chromosomal arrangements and there is no evidence that
these variants are able to be transmitted [85]. Understanding
the limitations placed around tumour transmissibility is
important.
At present there is no evidence for co-evolution of DFTs
and their hosts. However, given enough time, and enough
devils, co-evolution of tumour and host remains a possibility.
In the short period of time since the emergence of DFTD, we
have already seen life history changes occurring to Tasmanian
devils [44]. Devils have transitioned from iteroparity (multiple
reproductive cycles over a lifetime) to semelparity (single
reproductive episode before death) [44]. Strong selection for
early breeding has led to a 16-fold increase in precocious
sexual maturity. Within eastern populations, increased
inbreeding, greater population genetic differentiation, changing selection regimens and reduction in the dispersal movement of females have also been documented [9193]. These
changes to host population dynamics and genetic structure
have occurred over only a couple of generations and just hint
at the changes that could occur over greater periods of time.

Contagious cancers provide unique

insights into immunosurveillance and
immune evasion
The immunosurveillance theory was first proposed by Burnett
and Thomas in 1957 [94, 95]. The theory proposes that lymphocytes within the immune system patrol the body for continuously arising cancer cells and eliminate them. It follows that
cancer variants are under strong selection pressure to evolve
immune evasion strategies to allow the cancer to establish,
progress and metastasise. The two contagious cancers discussed in this review provide a unique opportunity to study
the evolution of immune evasion strategies by cancers. DFTD
is a new disease, and at present we are not certain whether
devils can mount an immune response against it. The infiltration of T cells into allografts but not DFTs suggest that perhaps
the tumour is evading the immune response, but the mechanism behind this is not understood. On the other hand, CTVT
is an evolutionarily old disease, which can produce both cell
mediated and antibody responses in healthy hosts, as well as
hiding from the immune system during disease progression.
Again, the mechanisms behind these changes are not fully
understood.
A key difference exists between the immune systems of
dogs and devils. Dogs are eutherian (placental) mammals,
while devils are marsupials. The development of the marsupial
immune system differs quite drastically from that of eutherians [96]. Marsupials are born immunologically immature,

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without any immune tissues or organs, and without the

capacity to mount an adaptive immune response. During
immunological development the young remains in the pouch,
reliant on an extended lactation period, during which the
composition of the mothers milk changes and the young
receives passive protection via maternal antibodies and antimicrobial peptides [96100]. The young is also able to express
its own antimicrobial peptides [97], and possibly other innate
immune molecules. Young devils do not develop DFTD and
DFTs are not passed vertically from mother to offspring [101].
The reason for this is not yet clear. However, subadults, while
not sexually active, sustain biting injuries, indicating that
opportunities for infection exist [102]. Understanding protection in the pouch may provide new insights into defence
against DFT. Perhaps the young are able to generate immune
responses that their parents cannot?
Development of sensitive immunological reagents will
allow us to monitor whether immunological factors are transmitted from mother to young through lactation. Puppies of
mothers with CTVT are less susceptible to the disease [82] as
antibodies are passed from mother to offspring. Anti-DFT
antibodies have not been seen in affected adult devils, but
it is possible that these have simply not been detected with
existing tools or that there are other immunological factors
involved.
Development of a vaccine against DFTD requires a better
understanding of immunity and immune tolerance in
Tasmanian devils. The benefits to developing a vaccine
against a clonal tumour include the fact that the antigenic
targets will be conserved in each affected individual and that
genetic variation in Tasmanian devils is low, so a single
effective vaccine may protect the majority of devils with
low incidence of non-responders. However, DFT cells and host
cells are highly similar and vaccination could also lead to
autoimmunity.

Conclusions
DFT has only been around for 1520 years. In that time we
have witnessed devastating impacts on Tasmanian devil
populations. Populations on the east coast of Tasmania have
already lost 95% of their devils, and the disease front has
rapidly moved westwards to cover 85% of the devils range.
Currently there is no cure, no vaccine or no treatment for
DFTD. Without action, we are likely to lose this unique animal
from the wild within the next 25 years. Management of this
iconic wildlife species depends on informed scientific decisions. Here I have used the other contagious cancer,
CTVT, to help inform us of the likely evolutionary trajectory
of DFT and have suggested that CTVT became an ultimate
parasite by evolving immune evasion strategies, as well as
strategies to initiate disease regression after transmission but
prior to killing of its host.
CTVT and DFT provide unique models for understanding
cancer biology and immunobiology. Both cell lines have
existed long after the individuals that gave rise to them died,
and have been put under different selection pressures in
different hosts. The evolutionarily young DFT allows us to
monitor tumour evolution in real time, while the evolutionar-

Bioessays 34: 285292, 2012 WILEY Periodicals, Inc.

....

Prospects & Overviews

Acknowledgments
This research was supported by the Australian Research
Council and the Save the Tasmanian Devil Appeal. I would
like to thank my collaborators for their inspiring discussions,
especially Beata Ujvari, Anne-Maree Pearse, Menna Jones,
Hamish McCallum, Greg Woods, Alex Kreiss and Tony
Papenfuss. I am also grateful to students, postdocs, volunteers
and field teams, who are all fighting to save the Tasmanian
devil. This work would not progress without them.

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K. Belov

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