ArticlePDF AvailableLiterature Review

Abstract

Over 1.66 million humans (approx. 500/100 000 population rate) and over 4.2 million dogs (approx. 5300/100 000 population rate) are diagnosed with cancer annually in the USA. The interdisciplinary field of comparative oncology offers a unique and strong opportunity to learn more about universal cancer risk and development through epidemiology, genetic and genomic investigations. Working across species, researchers from human and veterinary medicine can combine scientific findings to understand more quickly the origins of cancer and translate these findings to novel therapies to benefit both human and animals. This review begins with the genetic origins of canines and their advantage in cancer research. We next focus on recent findings in comparative oncology related to inherited, or genetic, risk for tumour development. We then detail the somatic, or genomic, changes within tumours and the similarities between species. The shared cancers between humans and dogs that we discuss include sarcoma (osteosarcoma, soft tissue sarcoma, histiocytic sarcoma, hemangiosarcoma), haematological malignancies (lymphoma, leukaemia), bladder cancer, intracranial neoplasms (meningioma, glioma) and melanoma. Tumour risk in other animal species is also briefly discussed. As the field of genomics advances, we predict that comparative oncology will continue to benefit both humans and the animals that live among us. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
rstb.royalsocietypublishing.org
Review
Cite this article: Schiffman JD, Breen M. 2015
Comparative oncology: what dogs and other
species can teach us about humans with
cancer. Phil. Trans. R. Soc. B 370: 20140231.
http://dx.doi.org/10.1098/rstb.2014.0231
Accepted: 29 April 2015
One contribution of 18 to a theme issue
‘Cancer across life: Peto’s paradox and the
promise of comparative oncology’.
Subject Areas:
genomics, genetics, evolution,
molecular biology
Keywords:
comparative oncology, genomics, genetics,
cancer, canine, human
Authors for correspondence:
Joshua D. Schiffman
e-mail: joshua.schiffman@hci.utah.edu
Matthew Breen
e-mail: matthew_breen@ncsu.edu
Comparative oncology: what dogs and
other species can teach us about humans
with cancer
Joshua D. Schiffman1and Matthew Breen2
1
Department of Pediatrics and Oncological Sciences, Primary Children’s Hospital, Intermountain Healthcare,
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
2
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, Center for Comparative Medicine
and Translational Research, Center for Human Health and the Environment, Cancer Genetics, UNC Lineberger
Comprehensive Cancer Center, North Carolina State University, Raleigh, NC, USA
Over 1.66 million humans (approx. 500/100 000 population rate) and over
4.2 million dogs (approx. 5300/100000 population rate) are diagnosed with
cancer annually in the USA. The interdisciplinary field of comparative oncology
offers a unique and strong opportunity to learn more about universal cancer
risk and development through epidemiology, genetic and genomic investi-
gations. Working across species, researchers from human and veterinary
medicine can combine scientific findings to understand more quickly the
origins of cancer and translate these findings to novel therapies to benefit both
human and animals. This review begins with the genetic origins of canines
and their advantage in cancer research. We next focus on recent findings
in comparative oncology related to inherited, or genetic, risk for tumour devel-
opment. We then detail the somatic, or genomic, changes within tumours and
the similarities between species. The shared cancers between humans and
dogs that we discuss include sarcoma (osteosarcoma, soft tissue sarcoma, histio-
cytic sarcoma, hemangiosarcoma), haematological malignancies (lymphoma,
leukaemia), bladder cancer, intracranial neoplasms (meningioma, glioma)
and melanoma. Tumour risk in other animal species is also briefly discussed.
As the field of genomics advances, we predict that comparative oncology will
continue to benefit both humans and the animals that live among us.
1. Introduction
Comparative oncology is a quickly expanding field that examines both cancer
risk and tumour development across species. Characterized by interdisciplinary
collaboration, its goal is advancement of both human and animal health.
Nowhere has this been more evident than in the investigation and comparison
of canine and human tumours. The study of naturally occurring cancers in the
domestic dog provides a suitable model for advancement of the understanding,
diagnosis and management of cancer in humans [1–4]. There are over 70 million
pet dogs in the USA, residing in over 40 million households [5,6]. With over
100 million vet visits each year in the USA, our dogs provide a powerful
resource for closely monitored health data. Canine cancers occur spontaneously,
and have similar clinical presentation and pathophysiology to equivalent
human cancers. As such, they closely parallel the natural progression of
human cancer to a greater extent than is observed in induced cancer animal
models [79]; genomic analysis of canine tumours has revealed shared features
between both species, providing fresh insight into the genetic basis of tumour
development [10 12]. Additionally, society’s practice of dog breeding has
unwittingly created a high-risk model for breed-specific disease due to consan-
guinity and inbreeding [13,14]. The restricted genetic variation in many
purebred dog breeds allows for easier identification of the genetic basis of dis-
ease, including cancers, and the shorter lifespan of dogs facilitates timely and
efficient evaluation of new approaches to cancer diagnosis, treatment and pre-
vention. This review will discuss the domestic dog as a model for comparative
&2015 The Author(s) Published by the Royal Society. All rights reserved.
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oncology, with a focus on both inherited risk and tumour
genomics, along with a brief assessment of other species
relevant to the field of study.
(a) On the origin of dogs (and their cancer risk)
While there are probably over 400 breeds of dog recognized
worldwide, the number of breeds recognized by the dog
fancy in different countries varies. For example, in the USA
the American Kennel Club (AKC) now recognizes 184 breeds
of dog (including 21 varieties) and the United Kennel Club
(UKC) recognizes over 300 breeds. The characteristics of each
dog of a specific breed have been refined and maintained
to meet the stringent breed standards and be considered a
contender for selection as a champion.
Over 15 000 years ago, man’s relationship with the dog was
quite different, being one in which dogs were selected primar-
ily for their function. Dogs helped humans to survive, using
their fast pace to aid in hunting of animals and their strength
and boldness to serve as protectors. Over the course of sub-
sequent millennia, the relationship between man and dog
continued to be one of co-dependency. Around the time of
the industrial revolution, we started to breed dogs as much
for their form as their function, in an industrializing society.
In just the past few hundred years, intensive selection and
breeding of dogs for key desirable traits resulted in the devel-
opment of what we regard today as the major characteristics
of the breed. When considered as a species, the level of genetic
variation sampled across all dog breeds today is perhaps as
extensive as for human populations [15]. In individual pure
breeds, however, the level of genetic diversity is now variably
restricted [16]. The process of breed formation over just the past
23 centuries has been estimated to have resulted in sevenfold
greater reduction in genetic diversity than did the thousands of
years of early domestication [17]. This is compounded further
by the use of popular sires and gene pool decline during the
twentieth century. Since many of the key phenotypes are
characteristics of the particular breed, their presence in the
breed had been positively selected, resulting in high frequency
of the genes that cause these specific phenotypes. With such
intense selection, it is perhaps not surprising that there are
now over several hundred inherited diseases recognized in
dogs. While some diseases have simple inheritance patterns,
others, including cancers, are likely to be more complex. The
genetic background of some purebred dogs may predispose
the breed to a higher risk for specific cancers, or cancers in gen-
eral. It is this increased risk of cancer in purebred dogs that may
be leveraged to accelerate the process of cancer gene discovery
from a comparative perspective.
The histological and clinical presentation of numerous
canine cancers closely parallels that of the corresponding can-
cers in humans. The extended lifespan of the dog, combined
with the shared environment and development of spontaneous
cancers, places the dog in a unique position to better reflect
cancer development and progression than traditional rodent
models. As is the case for human and rodent models, the
advancement of genomic technologies and the development
of canine custom reagents and resources have facilitatedstudies
of both somatic and inheritedgenomic variation in the domestic
dog. As discussed in §2, canine cancers share evolutionarily
conserved genomic changes that are found in their human
counterparts. Man’s best friend is already providing scientists
with an opportunity to generate data beneficial to both species
[3,4,10,11,18,19].
2. Germline and cancer risk
Several purebreds of dog are known to have a high incidence
and elevated risk of specific cancer subtypes, sometimes
even more than one subtype. The high degree of expectation
has led veterinarians and pathologists to associate specific
cancers with certain breeds of dogs (table 1). Such breed-
specific risk reflects the underlying genetics of the different
breeds. The patterns of specific cancers found within dog
breeds is very reminiscent of the human cancer predispos-
ition syndromes, whereby inherited genetic mutations in
humans lead to very specific cancer risks in related children
and families [2125]. In humans, knowledge of specific
cancer risk leads to designated early cancer screening
approaches to decrease morbidity and mortality [2429].
High-risk breeds of dog can be thought of as if they carry a
hereditary cancer syndrome, although breed-specific screen-
ing in asymptomatic dogs has not yet become standard of
care. Interestingly, several of the human cancer predispos-
ition genes have been found in the constitutional (germline)
DNA of dogs with cancer; this includes BRCA1/BRCA2 germ-
line mutations in dogs [30,31] which leads to hereditary
breast and ovarian cancer syndrome in humans and TP53
germline mutations in dogs [32] which lead to LiFraumeni
syndrome in humans with multiple different cancers.
In addition to known deleterious mutations, more common
single nucleotide polymorphisms (SNPs) and copy number
variations (CNVs) (or combination of SNPs and CNVs) have
been associated with disease risk in specific dog breeds. The
approach of using genome-wide association studies (GWAS)
in humans to identify disease-risk alleles has been relatively
successful, with an explosion in published GWAS data over
the past decade [33,34], although admittedly, revealing
varying levels of clinically significant disease risk [35,36]. In
dogs, the rewards of GWAS can be more readily realized
owing to the genetic homogeneity readily found within dog
breeds [15,37]. Indeed, this has been the case for several
recent GWAS findings in canine cancer.
One of the first cancer GWAS to evaluate a canine cancer
explored the risk of histiocytic sarcoma (HS) in the Bernese
mountain dog (BMD) [38]. This exceedingly rare sarcoma in
humans occurs frequently in a few breeds of dog, including
BMD, flat-coated retriever, Rottweiler and golden retriever.
The lifetime risk of developing a HS in BMDs is 15– 25%
[38,39]. The authors performed the first GWAS in 111 BMD
cases and 117 BMD controls from North America, as well as
a second GWAS in 125 BMD cases and 117 BMD controls
from Europe. Independent and combined analyses identi-
fied a significant risk allele on dog chromosome (CFA) 11
(North American BMD: P
raw
¼1.41 10
29
, European BMD:
P
raw
¼1.50 10
26
, combined BMD: P
raw
¼1.11– 10
213
).
Follow-up fine mapping and targeted sequencing revealed a
shared haplotype in 96% of affected BMDs that included
MTAP and part of CDKN2A (two very well-described cancer
genes in humans). The exact mechanism leading to HS is still
under investigation. Humans with germline MTAP mutations
have been reported and these individuals develop diaphyseal
medullary stenosis with malignant fibrous histiocytoma (a
soft tissue sarcoma) [40]; humans with germline CDKN2A
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mutations develop melanoma and pancreatic cancer [41,42].
Clearly, the story of HS risk in dogs is only just beginning,
and when combined with tumour genomics (see §3), there is
still much to be learned to the benefit of both dogs and their
human owners.
The same group also investigated the very specific
increased risk for squamous cell carcinoma of the digit
(SCCD) found to be especially prevalent in standard poodles
(STPOs) [43]. This aggressive cancer causes lytic bone lesions
of a focal nature, but interestingly, SCCD almost always
occurs in dark-coated STPOs and rarely in their light-coated
counterparts. The authors performed a GWAS, comparing
31 SCCD cases in STPOs to 34 unrelated black STPO controls.
The GWAS identified a statistically significant peak SNP
localized to CFA 15 (P
raw
¼1.60 10
27
). Further genotype
mapping discovered a minimal region of less than 30 kilo-
bases (kb) that contained the KIT Ligand (KITLG) gene
locus with a CNV with at least four copies due to a tandem
repeat. Since both the light-coloured and dark-coloured
STPOs carry this KITLG tandem repeat, a subsequent
GWAS compared light and dark STPOs (N¼24 versus 24)
and identified the MC1R locus to be the only difference
between the groups ( p¼2.52 10
215
). The study authors
concluded that mutations found with MC1R may actually
be cancer protective for light-coloured STPOs, and that
MC1R may be interacting with KITLG CNVs as a genomic
modifier. In humans, KITLG is not associated with cancer
risk, although rare germline KIT mutations have been associ-
ated with familial gastrointestinal stromal tumours (GIST), a
type of gastrointestinal sarcoma [44]. Interestingly, there is
precedent for the role of MC1R as a modifier of disease, as
germline MC1R variants in humans affect pigmentation
[45,46] and seemingly function as genomic modifiers for sev-
eral human diseases [47– 51], in one study conferring risk for
BRAF-mutant melanoma [52].
A third canine cancer GWAS has been performed to
identify risk of osteosarcoma. Using a study cohort compris-
ing 492 dogs as 261 cases and 231 controls across three breeds
(greyhounds, Rottweilers and Irish wolfhounds), the GWAS
identified 33 different inherited risk loci that could explain
5585% of the phenotype variance in each breed [53].
The strongest association within the greyhounds was within
a 150 kb segment upstream from CDKN2A/B, one of the
most highly rearranged genes detected in canine osteosar-
coma tumour cells. This study revealed a polygenic series
of germline-risk factors that collectively highlighted specific
pathways as drivers of disease. Consistent with the biology
of the tumour, the candidate regions were enriched for
genes in bone differentiation and growth pathways.
A GWAS in human osteosarcoma also was recently published
by Savage et al. [54], but with different findings than in the
dog; they analysed 941 individuals with osteosarcoma and
3291 cancer-free adult controls of European ancestry and
found a very high statistical association with disease risk in
GRM4 located at 6p21.3 ( p¼8.1 10
29
) and two SNPs in
the gene desert at 2p25.2 ( p¼1.0 10
28
and 2.9 10
27
).
As Machiela & Chanock [37] discuss, although GRM4,
which is involved in intracellular signalling and inhibition
Table 1. Cancers associated with specific dog breeds (data from authors and [13,20]).
cancer subtype dog breed
lymphoma (unspecified)
— B-cell lymphoma
— T-cell lymphoma
Old English sheepdog, boxer, pointer, golden retriever, Rottweiler, St Bernard, Scottish terrier, bulldog
— Irish wolfhound, Siberian husky, shih tzu, Airedale terrier, Cavalier King Charles spaniel, Yorkshire terrier
— boxer, cocker spaniel, basset hound
osteosarcoma large and giant breeds, such as Irish wolfhound, Scottish deerhound, Great Dane, BMD, mastiff, St Bernard, Irish
setter, golden retriever, Rottweiler, Dobermann pinscher, greyhound
soft tissue tumours larger dogs, such as boxer, BMD, Airedale terrier, Great Dane, St Bernard, basset hound, golden retriever—all
with twice as many as the general canine population
hemangiosarcoma German shepherd, BMD, golden retriever, flat-coated retriever, Portuguese water dog, Labrador retriever, boxer,
Skye terrier, Australian shepherd
hs/malignant histiocytosis BMD, flat-coated retriever, Rottweiler, golden retriever
mast cell tumours boxer, pug, Labrador retriever, golden retriever, vizsla
meningiomas mesocephalic (medium) and dolichocephalic (long)-nosed breeds, e.g. Labrador, golden retriever, collies
gliomas (including glioblastoma
multiforme)
brachiochephalic (short-nosed) breeds, including boxers, bulldogs and terriers
testicular seminoma Norwegian elkhound
nasal cavity carcinoma golden retriever, beagle, Boston terrier, rough collie, Belgian shepherd
UC Scottish terrier, beagle, West Highland white terrier, Shetland sheepdog, American Eskimo dog,
standard schnauzer
lower urinary tract carcinoma Airedale terrier, beagle
squamous cell carcinoma (digit) STPO, giant schnauzer
melanoma
— oral melanoma
— cutaneous melanoma
— poodles
— schnauzers, beauce shepherds
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of the cyclic AMP signalling cascade, was not found to be
associated itself with canine osteosarcoma, GRIK4, another
glutamate receptor, was significantly associated with osteosar-
coma risk in greyhounds; also, the SNPs close to GRM4 were
fixed in Rottweilers with osteosarcoma [53]. This comparative
approach may provide novel insightand validation of signalling
pathways associated with osteosarcoma risk in both humans
and dogs. More comparison work is currently underway.
The most recent canine cancer GWAS explored the genetic
risk for haematologic malignancy in the dog, specifically
B-cell lymphoma and haemangiosarcoma in golden retrievers
[55]. These cancers occur at high rates in this breed (B-cell
lymphoma 6% and haemangiosarcoma 20%), and the investi-
gators looked at 148 haemangiosarcoma cases versus 41
B-cell lymphoma cases versus 172 cancer-free controls.
When the results from each GWAS were combined, two
associated loci were identified on CFA 5 and contributed
nearly 20% of the risk for haemangiosarcoma and B-cell
lymphoma (4.6 10
27
and 2.7 10
26
, respectively). Whole
genome sequencing (WGS) of nine cases and controls discov-
ered risk haplotypes without coding changes. The authors
investigated gene expression in B-cell lymphoma tumours
and concluded that these germline-risk alleles affect T-cell
regulatory pathways and immune-mediated responses.
Based on their canine GWAS findings, the authors conclude
that the immune system and malignant cells may interact in
tumour risk and development [55], a hypothesis that now
can be explored in other haematologic malignancy models
and even primary tumours in humans. In support of this con-
cept, recent human GWAS in diffuse large B-cell lymphoma
[56], follicular lymphoma [57] and marginal zone lymphoma
[58] have all demonstrated a role for immune recognition and
immune function, with lymphoma risk strongly linked to
HLA and other regions [5658].
A striking and recurrent theme in the analysis of canine
cancer GWAS data compared to comparable human GWAS
is the ability to analyse a much lower number of canine
cases and controls to identify risk factors compared to
human studies of identical cancers. The actual number of
cases and controls depends on a variety of factors, but, in
general, it is evident that the restricted level of genetic hetero-
geneity in purebred dogs provides opportunities for an
efficient means to identify risk loci for cancers that may be
of comparative value to human studies.
3. Somatic and tumour genomics
Identification of risk for developing cancer is a key factor in
health management of the individual and the population.
Once constitutional changes to the canine genome have
been determined, these data offer a powerful approach to
screen and stratify populations by risk. Within purebred
lines, knowledge of risk will play a key role in selecting
more informed breeding programmes designed to reduce
carefully the frequency of deleterious alleles in the popu-
lation. The inherited risk of a cancer may not be directly
related to the genome dysregulation associated with initiation
and/or propagation of tumour cells, and so be of little to no
value in making decisions about patient care once a cancer
develops. Genome-wide assessment of changes at the somatic
level istherefore another key area of active research in compara-
tive oncology. Identification of recurrent genome changes in
cancer cells is a key approach to identifying potential targets
for therapeutic intervention. The introduction of molecular
genetic tools has revolutionized the way we are able to interro-
gate cancer cells to identify specific changes in gene dosage,
organization and regulation. Numerical and structural changes
to the genome have been identified in over 65 000 cases of
human cancer, representing over 70 different types of can-
cer (see http://cgap.nci.nih.gov/Chromosomes/Mitelman).
Many of these recurrent chromosome aberrations initially
were associated with histopathological or immunological
subgroups, leading to their use as diagnostic signatures. More
recently the cytogenetic status of tumour cells has been demon-
strated to be of established clinical value for prognosis, guiding
therapy and assessing remission for a range of cancers, includ-
ing ovarian cancer [59], colorectal carcinoma [60,61], gliomas
[62], melanoma [63,64] and breast carcinoma [65]. From the per-
spective of comparative oncology, we may consider all animals
to be differentially organized collections of the same collection
of ancestrally related genes. As such, assessment of changes to
genome architecture in canine cancers has been an active area of
research, aimed at identifying regions of genome aberration
shared between canine and human cancers, suggestive of a
conversed mechanism of pathogenesis.
(a) Sarcomas
In the USA, it is estimated that approximately 500 new cases of
cancer are diagnosed per 100 000 of the population each year
(http://seer.cancer.gov), whereas in dogs the estimate is
approximately 5300 cancer diagnoses/100 000 population
(AVMA, 2011). These figures are striking in that they indicate
that 2.5the number of cancers are diagnosed in pet
dogs each year and that this represents an incidence of over
10that of the human population with which they live.
Approximately 50% of all human cancer-related deaths in the
USA in 2014 were the result of just four types of cancer, all of
which were carcinomas; pulmonary, prostate and colon carcin-
oma in males, and breast, pulmonary and colon carcinoma in
females (figure 1). While accurate numbers of cancers in pet
dogs are not known, extrapolation from extensive academic
records suggests that almost 60% of the estimated 1 500 000
diagnosed malignant cancers in dogs in the USA each year
are represented by a combination of sarcomas and carcinomas
(figure 1). The apparent lower numbers of pulmonary and
colon carcinoma in pet dogs may in part be due to the
human-specific influences (diet and smoking) affecting rates
of these prevalent cancers, both of which are associated with
factors not necessarily shared with pet dogs. Considering
some of the most prevalent cancers in human, the correspond-
ing canine cancers are highly evident also (figure 2) indicating
the potential for the role of the dog as an appropriate biological
model system.
(i) Osteosarcoma
Osteosarcoma isthe most common human bone tumour in ado-
lescents and young adults. This aggressive bone tumour has
been associated with germline TP53 mutations (Li– Fraumeni
syndrome), among other hereditary cancer syndromes [66].
With the introduction of combination chemotherapy and mul-
timodal approaches, the cure for human osteosarcoma has
risen to nearly 70%, although it still remains at less than 20%
for relapsed or recurrent disease [67,68]. Although relatively
rare in humans, with up to 75 000 cases of canine osteosarcoma
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diagnoses each year in the USA, the rate is as high as 75that
of humans. Breeds considered at high risk of developing canine
osteosarcoma tend to be some of larger and giant breeds,
including the Rottweiler, Great Pyrenees, mastiff, Dobermann
pinscher, Irish wolfhound, Scottish deerhound. Given its fre-
quency in canines, the dog model of naturally occurring
osteosarcoma has offered an unparalleled opportunity to
understand the genomic origins of osteosarcoma, to learn
about the role of metastasis in disease and to pilot new inves-
tigational drugs in trials that would otherwise take too long
to accrue in humans [12,69]. Several years ago, Scott et al. [70]
took advantage of the genetic homogeneity in dogs to identify
molecular subtypes of osteosarcoma based on genome-wide
gene expression profiling in a cohort of high-risk breeds of
dogs with osteosarcoma (N¼79). In this study, the authors
were able to divide samples into two distinct subgroups based
on gene expression that also correlated with overall survival.
Similar to human osteosarcoma, the two canine groups involved
‘G2/M transition and DNA damage checkpoint’ and ‘microen-
vironment-interaction’. As the authors conclude, the genomic
findings in canine osteosarcoma are of benefit for both dogs
and humans, and further investigation ‘may enhance prognosis
and prediction, and identify relevant therapeutic targets’ [70].
In a parallel study, Angstadt et al. [71] used high-reso-
lution oligonucleotide aCGH to interrogate copy number
alterations (CNAs) in canine osteosarcoma (N¼23, various
prostate (28%)
pulmonary (10%)
colon and rectum (8%)
breast (26%)
pulmonary (15%)
colon and rectum (9%)
lymphoma (12–18%)
urothelial carcinoma (4%)
adenocarcinoma (colon, kidney, rectum, mammary) (10%)
squamous cell carcinoma (7%)
soft tissue sarcoma (5%)
osteosarcoma (5%)
mucosal melanoma (5%)
mast cell tumour (grade 3) (4%)
(b)(a)
(c)
Figure 1. Frequency of cancer-related deaths in human and dog. Approximately 50% of all human cancer deaths in the USA each year are a consequence of four
cancers, two of which are common to males (a) and females (b) (human data from (http://www.cancer.org)). (c) The estimated annual frequencies of death-related
malignant cancers in pet dogs in the USA are shown (extrapolated canine data from US academic accessions). (Online version in colour.)
one medicine
brain
oral melanoma
leukaemia
lymphoma
cutaneous
melanoma
breast
bladder
prostate
bone
approx. 1.66 million diagnoses each year
(approx. 500 cases/100 000 population)
approx. 4.2 million diagnoses each year
(approx. 5300 dogs/100 000 population)
one patho
g
enesis
Figure 2. The remarkable similarity in cancers shared by human and dog. The cancers shown are found in both human and canine populations, and several
ongoing studies are highlighting the similarities at the genomic level. The incidence of cancers in both species is shown, highlighting the more than 2.5number
of cancers diagnoses in pet doges each year. Comparative oncology is a growing trans-disciplinary field that harnesses these data, adding evidence to support a
shared pathogenesis. (Online version in colour.)
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breeds) and compared the data directly with cases of human
osteosarcoma (N¼15). The authors demonstrated that even
though osteosarcoma is a cancer with enormous genomic
instability, the identification of common regions of conserved
genomic alterations between species provides a means to
narrow the search for genomic drivers versus passengers.
This study identified shared regions of CNAs that were
less than 500 kb in size between dog and humans and
then interrogated those regions for orthologous osteosar-
coma-associated genes. Genes with known association in
osteosarcoma were revealed (CDC5L, MYC, RUNX2 and
CDKN2A/CDKN2B) as well as new genes that had not been
described previously in osteosarcoma (ADAM15, CTC1,
MEN1, CDK7, along with several more genes) [71].
Primarily a cancer of children and young adults, osteosar-
coma is rare, with fewer than 1000 cases each year diagnosed
in the USA. As such, a major challenge to the progress of
human osteosarcoma clinical trials is low patient accrual.
The high number of canine osteosarcomas diagnosed each
year, combined with the remarkable motivation of dog
owners to enroll their pets in clinical trials offers a tremen-
dous opportunity to advance studies for this cancer. The
net result is that both biological and clinical studies can be
performed with pet dogs that would otherwise take an inor-
dinately long period of time to accomplish in humans. In the
study of osteosarcoma progression and metastasis, key
advances have been made by the Comparative Oncology Pro-
gram at the National Institutes of Health (NIH) through the
study of dogs, including the recognition of the role of ezrin
[12,72– 75]. Furthermore, early clinical trials are now ongoing
in dogs in conjunction with the Children’s Oncology Group
in North America, an approach that will quickly ascertain the
effectiveness of osteosarcoma therapy, owing primarily to the
much larger number of dogs with osteosarcoma compared
with humans [12,72,76–78]. With time and additional canine
trials, researchers believe the success of this approach will
become readily apparent.
(ii) Soft tissue sarcoma
In 2013, Caserto published a comprehensive review of canine
and human rhabdomyosarcoma (RMS) with an emphasis on
comparing the classification and pathogenesis of this soft
tissue sarcoma [79]. Not surprisingly, there were numerous
similarities between RMS in both species, including their
histological classification. Caserto described the ability to
diagnose RMS in dogs using immunohistochemical (IHC)
stains for desmin, a-actins, myogenin and MyoD1, in addition
to electron microscopic identification of sarcomeric structures
[79]. More recently, Milovancev et al. [80] have described
non-RMS soft tissue sarcomas in dogs and their comparison
to human non-RMS tumours. In this study, veterinary and
human pathologists interpreted 32 clinically archived, canine
soft tissue sarcomas. There was general agreement on the
diagnoses and their similarities to human tumours, including
low-grade spindle cell sarcomas (N¼13/32), undifferentiated
sarcoma (N¼32), liposarcoma with atypical desmin-
positive epithelioid cells (N¼5/32), spindle cell sarcoma
with myxoid features (N¼5/32) and myxofibrosarcoma
(N¼2/32). The comparative genomics of soft tissue sarcomas,
both RMS and non-RMS, is a field that will continue to grow
as technology advances and more of these rare tumours are
collected in canines.
(iii) Histiocytic sarcoma
Canine HS is a very aggressive and rapidly fatal sarcoma of
dendritic cell origin with a tendency to metastasize to the
spleen and lungs. This cancer is very commonly reported
in just two less abundant breeds of dog, the BMD and
flat-coated retriever, and also in large numbers of three of
the most popular breeds, including the Rottweiler, golden
retriever and Labrador retriever [81– 83]. The BMD is extra-
ordinarily susceptible to this sarcoma, with as many as 25%
of the breed diagnosed at a young age [38,39]. In humans,
the equivalent of HS is not quite so clear; human HS is a
very rare tumour, presents in lymph nodes, skin, and the
gastrointestinal tract, often will be misdiagnosed as non-
Hodgkin lymphoma (NHL), and is considered a diagnosis
of exclusion [84,85]. As is the case with osteosarcoma, com-
parative oncology of HS offers a unique opportunity to
leverage data from the canine disease to learn more about
a poorly understood human cancer [86].
Hedan et al. [86] used molecular cytogenetic profiling
with aCGH in spontaneously occurring HS from BMDs and
flat-coated retrievers (N¼104 total) [86]. The data indicated a
high level of genome disruption and instability, and the inves-
tigators identified that many of the highly recurrent CNAs were
shared between both breeds, suggesting a common underlying
pathogenesis. Specially, recurrent deletions were detected in
commonly described human tumour suppressor genes, includ-
ing CDKN2A/B, RB1 and PTEN [86]. Interestingly, the GWAS of
canine HS in BMDs (see above) localized a possible HS-risk
allele also to CDKN2A (in addition to MTAP) [38]. Hedan
et al. [86] also identified several private CNAs uniqueand recur-
rent to each breed, perhaps suggesting a difference in initiation
and/or progression leading to a more universal HS genomic
phenotype once the tumour develops. Molecular work
on canine HS continues, and this hopefully will inform our
understanding and treatment approaches to human HS.
(iv) Haemangiosarcoma
Angiosarcomas and haemangiosarcomas are an aggressive
group of tumours that have been studied extensively in both
canines and humans. Initially thought to be of endothelial cell
origin [87,88], there is now suggestion that these aggressive
sarcomas of blood vessels may be of haematopoietic origin
[89– 91]. In humans, angiosarcomas are a very rare, hetero-
geneous subgroup of soft tissue sarcoma, representing much
less than 1% of all tumours. These malignant vascular tumours
occur spontaneouslyas primary tumours and also as secondary
tumours followingradiation therapy or in the context of chronic
lymphoedema [92,93]. Almost half of angiosarcomas occur
in the head and neck, though these represent less than 0.1%
of all head and neck malignancies [94]. Insidious in nature,
clinical symptoms of angiosarcomas often do not manifest
until the disease is well advanced. In the dog, haemangiosarco-
mas frequently involve major vascular organs, (spleen, liver,
heart), and also can be subcutaneous. As in humans the
tumours are indolent and often remain undetected until
the point at which the vascular mass ruptures and the
dog suffers internal bleeding that can result in death. While
haemangiosarcomas can affect any breed, those of notably
high risk include the golden retriever, German shepherd,
Portuguese water dog and Australian shepherd.
Gorden et al. [95] performed genome-wide expression pro-
filing of a small number of primary canine haemangiosarcomas
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(N¼6 golden retrievers, N¼1 Rottweiler, N¼1 golden
retriever Great Pyrenees, N¼1 Portuguese water dog) and
determined three distinct haemangiosarcoma subtypes associ-
ated with: angiogenesis (group 1), inflammation (group 2) and
adipogenesis (group 3) [95]. The authors investigated haeman-
giosarcoma cell lines and discovered expression of multiple
and distinct markers for early endothelial, haematopoietic
and myeloid cells along with several phagocytic and adipo-
genic functional experiments [95], further supporting the
multipotent potential and origin of this blood vessel sarcoma.
Genome-wide DNA copy number profiling of canine haeman-
giosarcoma has also been performed using high-resolution
oaCGH [96]. In this study, primary intra-abdominal haeman-
giosarcomas (N¼75; golden retriever (n¼40), Australian
shepherd (n¼10), German shepherd (n¼10), flat-coated
retriever (n¼9) and BMD (n¼6)) were assessed and the
data revealed a relatively low rate of CNAs with small ampli-
tudes. Despite the presence of multiple passenger alterations,
potential recurrent driver alternations were seen in CDKN2A,
VEGFA and SKI. Interestingly, VEGFA gains were observed at
nearly half the rate in golden retrievers compared with the
other breeds (22 versus 40%) [96]. These datasupport an alterna-
tive origin of tumorigenesis among breeds and multiple
haemangiosarcoma molecular subtypes owing to alternative
activating pathways as demonstrated in the gene expression
studies. Further work comparing canine haemangiosarcoma
to human angiosarcoma is now awaited.
(b) Haematological malignancies
(i) Lymphoma
Haematological malignancies are common forms of cancer
in both dogs and humans. In 2014, approximately 71 000
new cases of human NHL were diagnosed in the USA
(http://www.cancer.org). In the domestic dog, key opinion
leaders estimate that over 250 000 cases of canine lymphoma
(comparable to NHL) were diagnosed in the same period.
The high degree of similarity between human and canine
lymphoma has been extremely helpful in understanding
this disease in both species [97 99]. The high similarity in
pathologic presentation of canine and human lymphoma
allows for use of World Health Organization (WHO) criteria
for accurate and reproducible classification of the canine
tumours [100,101]. In human NHL, the vast majority
(approx. 90%) of cases are of B-cell origin. In the domestic
dog, the proportions of B- and T-cell lymphomas across all
dogs is estimated to be approximately 2 : 1, but the immuno-
phenotype prevalence in individual breeds is highly variable
[102]. A large study of canine lymphoma characterized 608
cases based on cytomorphological, histomorphological and
immunological criteria and importantly included both epide-
miological and clinical data [103]; the majority of tumours
(76%) were classified as high-grade malignant lymphomas,
highlighting the clinical importance of understanding both
lymphoma risk and designing novel therapeutic approaches.
As is the case across all breeds, approximately two-thirds
of the canine lymphomas in this cohort were classified as
B cell (CD3, CD79aþ) with one-third classified as T-cell
lymphomas (CD3þ, CD79a) [103].
Diffuse large B-cell lymphoma (DLBCL) has been one
subtype of canine lymphoma that has been very well studied
with genomic profiling. Richards et al. used IHC and gene
expression profiling on canine DLBCLs (N¼49) and
identified similar profiles to human DLBCL, including acti-
vation of NF-kB pathway genes and immunoglobulin
heavy chain alterations [104]. Although some differences
with human lymphoma existed (lack of BCL6 and MIM1/
IRF4 protein expression), the authors concluded they could
identify germinal centre and post-germinal centre subtypes
in canine DLBCL, including different survival times, and
that their canine findings reflect human DLBCL [104].
Using a bivariate mixture model based on two-species data,
Su et al. [105] were also able to use gene expression profiling
to distinguish both the germinal centre B-cell-like DLBCL and
the activated B-cell-like DLBCL, including different clinical out-
comes based on survival. Another study used gene expression
profiling on 35 canine lymphoma samples to define three
major groups: (i) low-grade T-cell lymphoma, composed
entirely by T-zone lymphoma; (ii) high-grade T-cell lymphoma,
consisting of lymphoblastic T-cell lymphoma and peripheral
T-cell lymphoma not otherwise specified and (iii) B-cell lym-
phoma, consisting of marginal B-cell lymphoma, diffuse large
B-cell lymphoma and Burkitt lymphoma [106]. Similar to the
DLBCL studies, the genomic subtypes were associated with
different clinical outcomes. Remarkably, the authors distilled
their gene expression profiling into four genes whose expression
could reliably predict lymphoma subtype and survival (CD28,
ABCA5, CCDC3 and SMOC2) [106]. These findings now need
to be confirmed in larger studies in human lymphomas to
assess their universal clinical utility.
(ii) Leukaemia
Leukaemia is another haematological malignancy with shared
high incidence in dogs and humans. Genomic studies in
canine leukaemia are underway, although recent results display
similar mechanisms driving leukaemogenesis. RB1 deletions in
chronic lymphocytic leukaemia and BCR–ABL fusion in
chronic myeloid leukaemia (CML) were among the first cytoge-
netic aberrations detected in canine cancers that mirror the
corresponding human cancers [107]. The BCR–ABL tyrosine
kinase translocation (the so-called ‘Raleigh chromosome’ in
dogs and ‘Philadelphia chromosome’ in humans) has since
been demonstrated to be present in additional subtypes
[108,109] and proven useful for monitoring cytogenetic remis-
sion in CMLs [110]. Another canine study included acute
lymphoblastic leukaemia (ALL)/acute undifferentiated leukae-
mia (AUL) (N¼11) and chronic lymphocytic leukaemia (CLL)
(N¼12) and demonstrated increased c-KIT expression in
the ALL/AUL samples [111], offering the possibility of using
tyrosine kinase inhibitors as a treatment option in canine
leukaemia, an approach similar to that used for human
leukaemia with tyrosine kinase-affected pathways.
(c) Bladder cancer
Bladder cancer, also called transitional cell carcinoma (TCC), or
urothelial carcinoma (UC) is yet another tumour that affects
both humans and their pet dogs [112,113]. In humans, environ-
mental exposure, including tobaccosmoke, is a major risk factor
for UC. In dogs, however, the risk for UC appears to be mostly
genetic through predisposition [13]. Similar to osteosarcoma,
the molecular genetics/genomics of canine UC reflect human
UC, and the knowledge gained through canine therapeutic
trials in UC benefits both dogs and humans [114]. A recent
study explored aCGH in canine UC (N¼31), compared
canine data with comparable results in human TCC (N¼285)
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and discovered both large chromosomal and focal regions of
alterations shared between the species even among a large
amount of background genomic instability [18]. Given the
strong environmental risk for UC in humans and the prom-
inent genetic risk in dogs, the study of shared genomic
events leading to UC tumorigenesis will prove important for
both prevention and treatment across species. The introduc-
tion of sea lion genomic data for sea lion specific UC will
further hone candidate genes for clinical targeting (see §4).
(d) Intracranial malignancies
The clinical and histological presentation of intracranial
malignancies affecting human and dog are highly compar-
able, allowing similar diagnostic criteria to be used from
both species [115,116]. In support of the role of the pet dog
as a model for such cancers, canine and human intracranial
tumours share key histopathological features that are absent
in rodent models [117]. There is considerable potential to
exploit the dog as a preclinical model for development and
evaluation of novel brain tumour therapies [118]. It is
widely accepted that short-nosed (brachycephalic) breeds,
such as boxer, pug and bulldog, are predisposed to gliomas
[7,119,120], while longer nosed (dolichocephalic) breeds,
such a collies, golden retriever and Labrador retriever, are
more predisposed to meningiomas [11].
(i) Meningioma
While meningiomas represent approximately 25% of adult
primary intracranial tumours in human patients [116],
they are estimated to comprise almost 40% of all canine intra-
cranial neoplasms [121,122], which largely reflect the
enormous popularity of several medium/long-nosed dog
breeds. The elevated incidence of meningiomas in the dog,
as compared to human populations is of particular concern
in veterinary medicine and simultaneously offers a higher
caseload to investigate meningioma biology. Meningiomas
in both species are highly comparable and share similar phe-
notypes and gene expression profiles [116,121,123]. Genomic
profiling of canine meningiomas for DNA copy number by
Thomas et al. [11] indicated that canine meningiomas share a
limited extent of whole chromosome aneuploidy with their
human counterpart. Importantly, the authors hypothesized
that by considering the DNA copy number data from both
species, the shared aberrations should be the focus of research;
for example, in this study they were able to reduce the size
of conserved genomic segments by as much as 50-fold.
Interrogation of the minimally shared regions revealed genes
of interest that are now being investigated for their functional
significance in meningioma biology.
(ii) Glioma
Intracranial gliomas are the most common and lethal primary
brain tumours in both the human and canine populations.
These tumours are particularly detrimental to the paediatric
age group, accounting for 80% of malignant brain tumours in
children less than 18 years old. In human adults, gliomas pro-
gress from low-grade (III) tumours to high-grade (III– IV)
tumours and are often rapidly fatal once detected, with long-
term survival in grade IV glioblastoma multiforme (GBM)
averaging less than 1 year [124]. The molecular genetics of
human GBMs have been studied in depth [125,126], with
three main pathways identified as RTK/RAS/PI-3K, p53 and
RB signalling [125]. Human patients often present with neuro-
logical symptoms such as headaches and seizures, and despite
the vast amount of genomic data and novel therapies
now available, GBMs recur quickly and aggressively after
resection and often lead to death [124]. Several of the human
cancer predisposition syndromes include gliomas in their
clinical spectrum [127–133], supporting the genetic risk for
development of these tumours.
Among canines, gliomas are the second most common
brain tumour behind meningiomas and occur with the highest
frequency in brachycephalic dog breeds [7,119,120]. Published
and anecdotal incidences of brain tumours in boxers, mostly
gliomas, range from 5 to 25% incidence [119,120], while some
individual pedigrees can have even higher presentation rates.
Similar to humans, an untreated glioma in a dog will rapidly
progress to a stage IV GBM. Previous cytogenomic studies of
canine intracranial malignancies by Thomas et al. [11] revealed
genomic architecture similar to the human counterparts.
Similar to humans, survival in dogs with gliomas is extremely
poor despite treatment ranging from chemotherapy, radi-
ation therapy, hyperthermia, to gene and vaccine therapy
[134– 138]: most dogs (and humans) will present with neuro-
logical symptoms such as seizures [139] and unfortunately
die within months of diagnosis.
Genomic analyses of human gliomas reveal increasing
molecular complexity as the clinical tumour stage progres-
ses, along with accumulation of specific driver mutations
[125,126,140]. Our own genomic data demonstrate very distinct
patterns of genome-wide instability when measuring CNAs in
human GBMs (JD Schiffman 2015, unpublished data). Genomic
analysis of canine GBMs reveals a very similar pattern [11]. The
comparison of genomic changes in canine versus human
GBMs, and early- versus late-stage tumours, will permit the
continued identification of drivers versus passenger mutations.
(e) Melanoma
Human melanomas are the most common malignant
skin cancers, often occurring in sun-exposed areas due to
UV exposure [141,142], although the rarer mucosal melano-
mas also can occur in people [143145]. In humans, as
described previously (§2), germline mutations in CDKN2A
can lead to familial melanoma with presentation at a young
age regardless of sun exposure [42]. Dogs also develop melan-
oma, and similarly to all the other cancers discussed in this
review, these melanocytic canine tumours will very closely
resemble human melanoma, emphasizing the beneficial role
of the canine preclinical model in studying both UV and
non-UV pathways in melanoma [20,146]. Furthermore, the
dog has been extremely useful for clinical trials and has con-
tributed to a phase I study for DNA vaccination with
xenogeneic human tyrosinase for advanced malignant melan-
oma [147151]. Poorman et al. [152] used aCGH profiling to
compare cutaneous melanomas (often benign) with the more
aggressive oral mucosal form. Distinct patterns of CNAs
emerged in the malignant tumours including recurrent
gains of dog CFA 13 and 17 and loss of CFA 22, whereas
the more benign tumours were more copy number neutral,
presenting fewer CNAs (except for recurrent gain of
CFA 20q15.317) [152]; this pattern resembles that reported
with human melanoma, where malignant melanoma can be
differentiated from benign nevi using genomic microarray
based on number of CNAs [153]. Canine mucosal melanomas
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display specific and unique ‘sigmoidal patterns’ of copy
number loss followed immediately by a gain on CFA 30q14,
a characteristic feature conserved on HSA 15 in human muco-
sal melanoma [154]. In addition, both species show numerous
other CNAs including frequent gain of c-MYC and deletion of
CDKN2A [152]. Other recent studies have shown microRNA
(mi)R-203 to be a common tumour-suppressive miRNA in
both human and canine melanoma cell experiments [152].
Clearly, the study of canine melanoma, especially mucosal
melanoma, offers an opportunity to understand melanoma
biology and rapidly translate that information into both
veterinary and medical clinical care.
4. Other animals besides dogs (sea lions, whales,
bats and naked mole rats)
In addition to canines, many other animals offer their own
unique opportunity to betterunderstand the universal processes
involved in tumorigenesis. Some of these animals, such as
dogs, are more prone to develop cancer, while others seem to
be resistant to its development. By studying both ends of the
cancer-risk spectrum, it is hoped that the knowledge gleaned
will help with both the treatment and prevention of cancer.
For over half a century, marine mammals have been widely
accepted as highly suited sentinels for assessing the health of
the world’s oceans. The typical lifespan of marine mammals
is sufficient to allow assessment of the development of numer-
ous chronic diseases, including cancers [155,156]. The number
of marine mammals diagnosed with cancers has been increas-
ing over the past 30 years. Of the 500 live adult and sub-adult
free-ranging California sea lions (CSLs) that strand on the west
coast of the USA each year, 200–300 are admitted to the Marine
Mammal Center in Sausalito, California for rehabilitation.
Necropsy data indicate that approximately 20% have neo-
plasms, of which 85% are aggressive, widely metastatic
genitourinary carcinomas [157,158]. While the gamma herpes
virus, otarine herpesvirus-1 was initially thought to play a
key role in urogenital tumour pathogenesis [159,160], this
virus has been reported in the genital secretions of healthy
sea lions [161], questioning the roleof the virus in cancer patho-
genesis. Of key concern for all top-trophic predators (including
the sea lion) is the bioaccumulation of high levels of persistent
fat-soluble organic contaminants (OCs), including PCB and
DDT. Accumulation of high concentrations of these and other
persistent OCs are known to cause immune suppression, hor-
monal and metabolic disruption and genotoxicity leading to
cancer [162]. Such compounds remain as major contaminants
along the west coast of the USA and continue to pose a serious
health threat to the CSL and other marine mammals. Assess-
ment of the levels of DDT and PCB in CSLs with and
without genitourinary carcinoma revealed that there are stat-
istically higher levels of both of these OCs in the cancer
patients [162]. These cancers, which are not a feature of captive
bred and maintained CSLs, are progressive and cause slow
painful death in wild animals. Initial genomic investigation
of these aggressive urothelial neoplasms, as part of the larger
ongoing work by the Sea Lion Cancer Consortium has revealed
that they share conserved features with both canine and human
counterparts (M Breen 2015, personal communication). We
propose that a more detailed investigation of shared cancers
using this multi-species approach will highlight genes associ-
ated with uroethial carcinogenesis in the context of risk
related to both genetics and environmental exposure.
On the opposite side of tumour risk, bats may be protected
against cancer (although anecdotal, this seems to be a common
consensus in the field) [163]. Naked mole rats,another cancer-
free rodent, with an impressive 30-year lifespan, have evolved
hypersensitivity to cellular contact inhabitation mediated
through alternative INK4a/b splicing and very high molecular
weight hyaluronan [164– 166]. Bowhead whales, the longest
living mammal with a lifespan of over 200 years and reportedly
very low cancer rates, recently were described to harbour geno-
mic alterations associated with cancer, ageing, cell cycle and
DNA repair (e.g. ERCC1 and PCNA) [167]. Elephants represent
another large mammal that appears to be protected from
cancer [168,169], and various studies are underway to explain
the molecular basis for this phenomenon known as Peto’s
paradox (large and long-lived animals that appear to be
cancer resistant) [170–175].
The study of comparative oncology truly embraces all
cancer risks, great and small, including humans and all types
of animals, wild and domesticated. Working in a transdiscip-
linary setting, colleagues provide expertise across the basic
sciences, medical oncology, tumour biology, pharmacology,
evolutionary biology, epidemiology, patient care, drug devel-
opment, clinical trials and a series of other key disciplines.
Whether the primary research focus of the individual is to
seek benefit for the human or animal patient, the combined
goals of the field are to advance our overall understanding of
oncology and translate this towards improving the health
and welfare of all animals affected by cancer.
Competing Interests. We declare we have no competing interests.
Funding. We gratefully acknowledge support of Skippy Frank Fund for
Life Sciences and Translational Research/Rockefeller Philanthropy
Advisors (awarded to M.B./J.D.S.). J.D.S. receives support through
the Primary Children’s Hospital (PCH) Pediatric Cancer Program
funded by the Intermountain Healthcare Foundation and the PCH
Foundation. J.D.S. hold the Edward B. Clark, MD Chair in Pediatric
Research at the University of Utah, and M.B. holds the Oscar
J. Fletcher Distinguished Professorship of Comparative Oncology
Genetics at North Carolina State University.
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... According to the Global Cancer Observatory (GCO) from the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO), the cancer burden in humans is progressively increasing worldwide. The same trend is observed among companion animals, with over 4.2 million dogs diagnosed with cancer annually [1]. Dogs are considered unique models of human cancer because, among others, they develop cancers with similar morphological and biological features and share the same environment as humans [1]. ...
... The same trend is observed among companion animals, with over 4.2 million dogs diagnosed with cancer annually [1]. Dogs are considered unique models of human cancer because, among others, they develop cancers with similar morphological and biological features and share the same environment as humans [1]. This makes them promising translational models for human cancer therapy and potential sentinels of environmental exposure to carcinogenic agents [1]. ...
... Dogs are considered unique models of human cancer because, among others, they develop cancers with similar morphological and biological features and share the same environment as humans [1]. This makes them promising translational models for human cancer therapy and potential sentinels of environmental exposure to carcinogenic agents [1]. Therefore, canine cancer data may provide important information in a comparative oncology and One Health approach. ...
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Cancer registries are fundamental tools for collecting epidemiological cancer data and developing cancer prevention and control strategies. While cancer registration is common in the human medical field, many attempts to develop animal cancer registries have been launched over time, but most have been discontinued. A pivotal aspect of cancer registration is the availability of cancer coding systems, as provided by the International Classification of Diseases for Oncology (ICD-O). Within the Global Initiative for Veterinary Cancer Surveillance (GIVCS), established to foster and coordinate animal cancer registration worldwide, a group of veterinary pathologists and epidemiologists developed a comparative coding system for canine neoplasms. Vet-ICD-O-canine-1 is compatible with the human ICD-O-3.2 and is consistent with the currently recognized classification schemes for canine tumors. It comprises 335 topography codes and 534 morphology codes. The same code as in ICD-O-3.2 was used for the majority of canine tumors showing a high level of similarity to their human counterparts (n = 408). De novo codes (n = 152) were created for specific canine tumor entities (n = 126) and topographic sites (n = 26). The Vet-ICD-O-canine-1 coding system represents a user-friendly, easily accessible, and comprehensive resource for developing a canine cancer registration system that will enable studies within the One Health space.
... In the United States, it is estimated that 4.2 to 6 million dogs receive a new cancer diagnosis each year [57,58] out of a total population of approximately 65 to 77 million dogs [58,59]. Therefore, the estimated annual incidence of canine cancer is approximately 5.5% to 9.2% across all dogs. ...
... Validation studies specific to each of these post-diagnosis use cases will be required to demonstrate the performance of liquid biopsy methods in these clinical scenarios. Finally, canine and human cancers share many molecular features [57,107]; therefore, genomic data being generated from liquid biopsy testing in canine cancer subjects may provide benefits to human cancer patients via comparative oncology analyses. ...
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Cancer is the leading cause of death in dogs, yet there are no established screening paradigms for early detection. Liquid biopsy methods that interrogate cancer-derived genomic alterations in cell-free DNA in blood are being adopted for multi-cancer early detection in human medicine and are now available for veterinary use. The CANcer Detection in Dogs (CANDiD) study is an international, multi-center clinical study designed to validate the performance of a novel multi-cancer early detection “liquid biopsy” test developed for noninvasive detection and characterization of cancer in dogs using next-generation sequencing (NGS) of blood-derived DNA; study results are reported here. In total, 1,358 cancer-diagnosed and presumably cancer-free dogs were enrolled in the study, representing the range of breeds, weights, ages, and cancer types seen in routine clinical practice; 1,100 subjects met inclusion criteria for analysis and were used in the validation of the test. Overall, the liquid biopsy test demonstrated a 54.7% (95% CI: 49.3–60.0%) sensitivity and a 98.5% (95% CI: 97.0–99.3%) specificity. For three of the most aggressive canine cancers (lymphoma, hemangiosarcoma, osteosarcoma), the detection rate was 85.4% (95% CI: 78.4–90.9%); and for eight of the most common canine cancers (lymphoma, hemangiosarcoma, osteosarcoma, soft tissue sarcoma, mast cell tumor, mammary gland carcinoma, anal sac adenocarcinoma, malignant melanoma), the detection rate was 61.9% (95% CI: 55.3–68.1%). The test detected cancer signal in patients representing 30 distinct cancer types and provided a Cancer Signal Origin prediction for a subset of patients with hematological malignancies. Furthermore, the test accurately detected cancer signal in four presumably cancer-free subjects before the onset of clinical signs, further supporting the utility of liquid biopsy as an early detection test. Taken together, these findings demonstrate that NGS-based liquid biopsy can offer a novel option for noninvasive multi-cancer detection in dogs.
... Bearing in mind the p62-plasmid efficacy on breast cancer in dogs, it becomes logical to predict the p62-based curative potential within multi-therapy regimens in comparative oncology. Notably, only in the United States, the number of yearly canine cancer patients amounts to more than 4 million [73,74]. Research efforts revealed that dogs appear to develop bone and soft tissue sarcomas and hematopoietic cancers with a higher incidence than humans [73]. ...
... Notably, only in the United States, the number of yearly canine cancer patients amounts to more than 4 million [73,74]. Research efforts revealed that dogs appear to develop bone and soft tissue sarcomas and hematopoietic cancers with a higher incidence than humans [73]. The study of various canine tumors, such as urothelial carcinoma; glioma, melanoma, lung and breast cancers; lymphoma; and osteosarcoma, which share similar molecular aspects with humans, have had beneficial impacts on animals and translational research [74]. ...
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Inflammation is the preceding condition for the development of mild and severe pathological conditions, including various forms of osteopenia, cancer, metabolic syndromes, neurological disorders, atherosclerosis, cardiovascular, lung diseases, etc., in human and animals. The inflammatory status is induced by multifarious intracellular signaling cascades, where cytokines, chemokines, arachidonic acid metabolites, adhesion molecules, immune cells and other components foster a “slow burn” at a local or systemic level. Assuming that countering inflammation limits the development of inflammation-based diseases, a series of new side-effects-free therapies was assessed in experimental and domestic animals. Within the targets of the drug candidates for quenching inflammation, an archetypal autophagic gear, the p62/sqstm1 protein, has currently earned attention from researchers. Intracellular p62 has been recently coined as a multi-task tool associated with autophagy, bone remodeling, bone marrow integrity, cancer progression, and the maintenance of systemic homeostasis. Accordingly, p62 can act as an effective suppressor of inflamm-aging, reducing oxidative stress and proinflammatory signals. Such an operational schedule renders this protein an effective watchdog for degenerative diseases and cancer development in laboratory and pet animals. This review summarizes the current findings concerning p62 activities as a molecular hub for cell and tissues metabolism and in a variety of inflammatory diseases and other pathological conditions. It also specifically addresses the applications of exogenous p62 (DNA plasmid) as an anti-inflammatory and homeostatic regulator in the treatment of osteoporosis, metabolic syndrome, age-related macular degeneration and cancer in animals, and the possible application of p62 plasmid in other inflammation-associated diseases.
... Dogs are considered a useful, attractive, and complementary model of human cancer as sharing human physical, chemical environments, and approximately "650 Mb of ancestral genetic sequence" [3][4][5]. From a histological perspective, numerous cancer types, e.g., osteosarcomas, melanomas, non-Hodgkin lymphomas, bladder cancer, and mammary carcinomas are quite similar in dogs and humans [6][7][8][9][10][11]. ...
... Companion animals, due to their close coexistence with their owners, share the same environmental, social, economic and cultural characteristics that may influence the occurrence of neoplasms in particular regions or countries. Rural and urban environments also allow contact with different environmental factors that can influence the type and frequency of cancer [6,35,[44][45][46][47]. Since no exclusion criteria were performed on the data from both species come, haphazard, from the same territory. ...
Article
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The animal cancer burden is essential for the translational value of companion animals in comparative oncology. The present work aims to describe, analyze, and compare frequencies and associations of tumors in dogs and cats based on the Animal Cancer Registry created by Vet-OncoNet. With 9079 registries, regarding 2019 and 2020, 81% (n = 7355) belonged to dogs. In comparison, cats have a general one-year right advance in the mean age of cancer diagnosis compared to dogs. The multivariate topography group analysis shows a distinct pattern between the two species: dogs have higher odds of cancer in the genito-urinary system, spleen, soft tissue tumors and skin, while cats show higher odds for tumors in the eyes, digestive organs, nasal cavity, lymph nodes, bones and mammary glands. Regarding morphologies, dogs are overrepresented in mast cell tumors (MCT), melanomas, and hemangiosarcomas. While cats are overrepresented in fibrosarcomas, lymphomas (T and B-cell), in malignant mammary tumors, and squamous cell carcinoma (SCC). Females have greater odds only in the mammary gland, with males having greater odds in six of twelve topographies. This study is the first outcome of continuous animal cancer registration studies in Portugal.
... Approximately 50% of all dogs older than 10 years will be killed by cancer. Generally, dogs develop cancer with a similar frequency as humans [9]. Cancer development in dogs is of strong resemble that of humans. ...
Thesis
Cancer is one of the major causes of mortality in developed countries. In 2020, there were more than 19.3 million new cases of tumor malignancies worldwide, with more than 10 million deaths. The high rates of cancer cases and mortality necessitate extensive research and the development of novel cancer treatments and antitumor agents. In most cases, conventional treatment strategies for tumor therapy are based on chemotherapeutic treatment, which is supplemented with radiotherapy and/or surgical resection of solid tumors [1]. The use of chemotherapy for the treatment of cancer has significant side effects, the most dangerous of which is toxicity [2] [3]. Modern methods of treating tumors focus on specific drug delivery to the tumor site, actively targeting the tumor cells, as well as the reduction of side effects. One of the most promising current approaches is based on oncolytic viruses. Antitumor properties of viruses were documented at the beginning of the 20th century when some cancer patients recovered after acute viral infections, particularly influenza [4]. Vaccinia virus (VACV) is a member of the Poxviridae family, has natural antitumor properties, and provides a good basis for generating efficient recombinant oncolytic strains. Furthermore, VACV has never been shown to integrate into the host genome [5]. VACV is likely one of the safest and well-studied viruses due to extensive research being done in molecular biology and pathophysiology to investigate its potential as a vaccine for smallpox eradication programs. It has been administered to over 200 million people worldwide. VACV antitumor therapeutic effectiveness has been established in xenograft models with a variety of tumor types for human and canine cancers. Furthermore, recombinant oncolytic VACVs expressing genes encoding light-emitting proteins are a big improvement in a treatment strategy that combines tumor-specific therapies and diagnostics. Oncolytic virus treatments are effective in xenograft cancer models in mice, however, the significant improvements found in mice do not always translate to human cancer patients. These therapies should be tested in dogs with spontaneous cancer not only to offer well translatable information regarding the possible efficiency of viral therapy for human cancers but also to improve the health of our household pets as well. Spontaneous canine tumors are starting to be regarded as an essential model of human cancers that can reproduce the tumor microenvironment and immune response of cancer patients [6]. Just as data obtained in dog experiments can improve cancer therapy for human patients, these findings can also be used to improve treatment protocols in canine patients. Hundreds of studies and dozens of reviews have been published regarding the antitumor effects of various recombinants of VACV, but information on the anticancer features of initial, genetically-unmodified “naïve” VACV is still limited. In the first studies, we compared different wild-type, non-modified strains of VACV and tested their oncolytic properties on a panel of various cancer cells derived from different organs. In addition, we also tested a protection system based on the “Trojan horse” concept - using a combination of human Adipose tissue-derived Stem Cells (hADSC) and three different wild-type single plaque purified Vaccinia virus strains: W1, L1, and T1. We showed that all tested human cell lines (FaDu, MDA MB 231, HNT-13, HNT-35, and PC-3) are permissive to L0, W0, T0, L1, W1, and L1 infection. Furthermore, we tested the cytotoxicity of VACV in different cancer cell lines (A549, PC-3, MDA-MB 231, FaDu, HNT-13, HNT-25, and HNT-35). All strains lysed the cells, which was most visible at 96 hpi. We also showed that all tested strains could efficiently infect and multiply in hADSC at a high level. In our in vivo study, we tested the therapeutic efficacy of the wild-type Vaccinia viruses L1, W1, and T1 alone or in combination with hADSC. Wild-type VACV strains were tested for their oncolytic efficiency in human lung adenocarcinoma (A549) in a xenograft model. Treatment of A549 tumors with different doses of L1 and W1 as well as with a L1/ADSC or W1/ADSC combination led to significant tumor regression compared to the PBS control. Additionally, the treatment with L1 and W1 and the combination of L1/ADSC and W1/ADSC was well tolerated by the animals. In the case of the wild-type Tian Tan strain, results were not obtained due to the high cytotoxicity of this strain. Therefore, it should be attenuated for further studies. In the second part of the current study, we investigated the oncolytic effect of C1-opt1, W1 opt1, and L3-opt1 strains based on the wild-type Copenhagen, Wyeth, and Lister vaccines with additional expression of turboFP635. Replication and cytotoxicity assays demonstrated that all 3 viruses were able to infect, replicate in and kill canine tumor cell lines STSA-1 and CT1258 in a virus dose- and time- dependent fashion. Cytotoxicity and replication assays were also performed on cultured canine Adipose-derived Mesenchymal Stem Cells (cAdMSC). The results showed that the cells were lysed much slower than the tumor cells. It suggests that these cells can harbour the virus for a long-term period, allowing the virus to spread into the body and there is enough time to reach the primary tumor or metastases before the cell carrier is destroyed. The viral replication in cAdMSC in our study was lower than in canine cancer cells (STSA-1 and CT1258) at the same MOI. After being studied in cell culture, C1 opt1 and their combination with cAdMSC (C1-opt1/cAdMSC) were used in canine STSA 1 tumor bearing nude mice. We tested the oncolytic effect of the C1-opt1 virus alone and in combination with cAdMSC in the canine STSA-1 xenograft mouse model. Altogether, our findings have shown that both C1-opt1 and cAdMSC/C1-opt1 significantly reduced tumor size or eliminated the tumor. There was no significant difference between C1-opt1 alone and cAdMSC/C1-opt1. The virus particles were mostly found within the tumor after 24 dpi, some amount of virus particles were found in the lungs of mice injected with a combination of cAdMSC/C1-opt1 but not in the group injected with virus alone (cAdMSC might get stuck in the lungs and cause virus propagation there). Taken together, this study provided a proof-of-concept that hADSC/cAdMSC can be used as a carrier system for the “Trojan horse” concept. However, it should be confirmed in another experimental model system, such as canine patients. Moreover, these findings suggest that wild-type, non-modified strains of Vaccinia virus isolates can be considered promising candidates for oncolytic virotherapy, especially in combination with mesenchymal stem cells.
... Over the last decades, an increasing number of wild animals live in urbanized areas because of zoos and zoological gardens, and they are faced with the need to adapt to the urban ecosystem (1). In this environment, they are highly exposed to pollutants (e.g., chemicals, light, and noise), contaminants in the air, water, and food, and new infections that, in the literature, are reported as predisposing factors of cancer in both humans and animals (2,3). According to scientific literature, neoplastic diseases are an important cause of morbidity and mortality in several wildlife species (4). ...
Article
Full-text available
The aim of this study was to evaluate the frequency of neoplasms in captive wild felids in Southern Italy zoos over a 13-year period (2008–2021) and to investigate macroscopic and histologic tumor findings in these animals. A total of 24 cases were necropsied, 9 males and 15 females, with age ranging from 6 to 19 years, including 12 tigers (Panthera tigris), 7 leopards (Panthera pardus), 4 lions (Panthera leo), and 1 black jaguar (Panthera onca). Diagnosis of neoplasm was made in 14/24 cases (58.3%). Tumors diagnosed were two cholangiocarcinomas, two hemangiosarcomas of the liver, two uterine leiomyomas, a renal adenocarcinoma, an adrenal gland adenoma, a thyroid carcinoma, an oral squamous cell carcinoma, an osteoma, a meningioma, a mesothelioma, an esophageal leiomyosarcoma, a muscoloskeletal leiomyosarcoma and a thyroid adenoma. The malignant and benign tumors were 62.5 and 37.5%, respectively. Among malignant tumors, no metastasis was observed in 50% of cases; in 10% of cases metastasis involved only regional lymph nodes; and distant metastases were found in 40% of cases. Based on our findings, the liver was the most frequent primary tumor site (25%). The high rates of malignant and widely metastatic neoplasms suggest the importance of active monitoring and management of neoplasia in these threatened and endangered species.
... Unlike laboratory-induced cancer in rodents, dogs develop spontaneous neoplasms over a long period of time, which more closely mirrors cancer development in humans; and for many tumor types, canine cancers are remarkably similar to their human counterparts in microscopic appearance and biologic behavior. 23,24,72,87 Investigation of molecular pathways that are dysregulated in canine cancers can help researchers decide whether a canine cancer type is a suitable model for the study of human cancer. Nuclear factor kappa-light-chain-enhancer of B cells (NF-kB) is a transcription factor that is constitutively active in most human hematopoietic and solid tumor cell lines, and has also been demonstrated in diverse human tumor types. ...
Article
Spontaneous tumors in dogs share several environmental, epidemiologic, biologic, clinical and molecular features with a wide variety of human cancers, making this companion animal an attractive model. Nuclear factor kappa B (NF-kB) transcription factor overactivation is common in several human cancers, and there is evidence that similar signaling aberrations also occur in canine cancers including lymphoma, leukemia, hemangiosarcoma, mammary cancer, melanoma, glioma, and prostate cancer. This review provides an overview of NF-kB signaling biology, both in health and in cancer development. It also summarizes available evidence of aberrant NF-kB signaling in canine cancer, and reviews antineoplastic compounds that have been shown to inhibit NF-kB activity used in various types of canine cancers. Available data suggest that dogs may be an excellent model for human cancers that have overactivation of NF-kB.
Article
Oncostatin M receptor beta (OSMRβ) mediates signaling of Oncostatin M (OSM) and interleukine-31 (IL-31), two key cytokines involved in many important biological processes including inflammation and cancer progression. More importantly, OSMRβ might be a potential biomarker and therapeutic target for some diseases, such as inflammatory bowel disease, pruritus and ovarian cancer. In this study, soluble recombinant canine OSMRβ (cOSMRβ) was experimentally expressed as a native antigen to develop an effective cOSMRβ-specific monoclonal antibody (mAb), 2O2, using hybridoma technology. It was demonstrated that 2O2 is able to detect OSMRβ expressed on cell surface using immunofluorescence assay (IFA) and flow cytometry (FACS). This mAb has very high binding affinity to cOSMRβ with the KD and half-maximal effective concentration (EC50) values of 2.49 nM and 96.96 ng/ml, respectively. Meanwhile, it didn't show any cross-relativities with feline OSMRβ (fOSMRβ) and human OSMRβ (hOSMRβ). Moreover, we determined the binding epitope of 2O2, which localizes in the domain VI (DVI, amino acids 623–734) of cOSMRβ. In conclusion, this novel mAb, 2O2, can be used in immunoassays, including IFA, FACS and enzyme-linked immunosorbent assay (ELISA) to facilitate studies in dogs.
Article
The epidermal growth factor receptor (EGFR) is involved in tumor malignancy through gene amplification and/or protein overexpression. An anti-human EGFR (hEGFR) monoclonal antibody (clone EMab-134), which explicitly detects hEGFR and dog EGFR (dEGFR), was previously developed. The defucosylated mouse IgG2a version of EMab-134 (134-mG2a-f) exhibits antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in dEGFR-overexpressed CHO-K1 (CHO/dEGFR) cells and antitumor activities in mouse xenografts of CHO/dEGFR cells. In this study, it was shown that 134-mG2a-f reacts with a canine fibroblastic tumor cell line (A-72) using flow cytometry and immunocytochemistry. Furthermore, 134-mG2a-f exerted ADCC and CDC on A-72 cell line. The administration of 134-mG2a-f significantly inhibited the A-72 xenograft growth. These results suggest that 134-mG2a-f exerts antitumor effects on dEGFR-expressing canine fibroblastic tumors.
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Osteosarcoma (OS) is the most common malignant bone tumor in children. Despite efforts to develop and implement new therapies, patient outcomes have not measurably improved since the 1980s. Metastasis continues to be the main source of patient mortality, with 30% of cases developing metastatic disease within 5 years of diagnosis. Research models are critical in the advancement of cancer research and include a variety of species. For example, xenograft and patient-derived xenograft (PDX) mouse models provide opportunities to study human tumor cells in vivo while transgenic models have offered significant insight into the molecular mechanisms underlying OS development. A growing recognition of naturally occurring cancers in companion species has led to new insights into how veterinary patients can contribute to studies of cancer biology and drug development. The study of canine cases, including the use of diagnostic tissue archives and clinical trials, offers a potential mechanism to further canine and human cancer research. Advancement in the field of OS research requires continued development and appropriate use of animal models. In this review, animal models of OS are described with a focus on the mouse and tumor-bearing pet dog as parallel and complementary models of human OS.
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