Page 25 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

4 PART I The Biology and Pathogenesis of Cancer

associations between age, body mass, and disease risk under important to avoid the significant pitfalls that arise from assump-
conditions in which artificial selection has superseded natural tions of equivalence where none exists. The next section of this
chapter reviews the hallmarks of cancer that are shared by virtually
selection. Specifically, natural selective pressures in dogs were
VetBooks.ir replaced by artificial selection since the initial domestication every cancer from every species. The final section of the chapter
focuses on recent studies that elevate companion dogs as models
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events approximately 10,000 to 25,000 years ago. Changes
in demand for form, instead of function, drove the creation of for understanding the complex genetics of cancer through the use
more than 400 breeds in the past 300 to 400 years. This artificial of contemporary technology and cautious, deliberate interpreta-
selection, usually for a single or a few phenotypic traits, gives tion of data.
little chance for adaptation across the rest of the genome. Con-
sequently, the risks of mutation associated with normal processes The Hallmarks of Cancer
of cell replication during development, growth, and maintenance
into adulthood are enhanced in large dogs (more cells), making Forty years of research culminated in an insightful and a thor-
it possible to explain the disproportionate risk of certain cancers, ough review paper by Douglas Hanahan and Robert Weinberg in
such as appendicular OSA, by manipulation of their genomic 2011 that synthesized knowledge about cancer into 10 essential,
plasticity with extreme selection for size. This is also consistent acquired characteristics. 31
with the fact that the overall risk for axial OSA in dogs is simi- In 2000 the same authors had described six characteristics nec-
lar to that observed in other species, accounting for the effects essary for cellular transformation, which comprised the abilities
of size and functional/mechanical stresses on bone. The greater to (1) sustain proliferative signaling, (2) evade growth suppres-
risk for large and giant dogs to develop appendicular OSA can sors, (3) resist cell death, (4) enable replicative immortality, (5)
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be explained, at least in part, by the fact that more cell divisions induce angiogenesis, and (6) activate invasion and metastasis.
are needed to create and maintain large bones, especially as bone In this initial paper describing the hallmarks of cancer, Hanahan
tissues undergo continuous remodeling. Each round of replica- and Weinberg created a paradigm shift by providing the first ever
tion for an osteoblast, in turn, contributes to its mutational bur- comprehensive synthesis of the molecular events leading to can-
den and potential transformation. The late age of onset in dogs cer. The important concepts that were clarified included these:
is consistent with chronic selection for cells that accumulate a no single gene is universally responsible for transformation; five
critical complement of mutations. In humans, OSA is among or six critical (driver) mutations are the minimum theoretical
the cancers in which the R factor can explain virtually all of the number required to endow the cancer phenotype (an observation
risk; also, an association has been recognized that shows OSA is that has since been confirmed experimentally) ; each step in the
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more common in children in the higher percentiles of size for path toward transformation and cancer progression is regulated
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their age. 22–24 by multiple interactive biochemical pathways, and thus, muta-
Accounting for the risk of appendicular OSA (or other cancer tions of different genes along a pathway can result in equivalent
types) stochastically as a function of replication risk leaves another phenotypes and, conversely, mutations of the same gene can result
important question unanswered: Why does the risk for some dog in different cancers with distinct biology; tumors behave as tissues;
breeds seem to be higher (or lower) than expected based on their and the interactions between the tumor and its microenvironment
overall size? Partial answers to this question are available, and are major drivers of cancer behavior.
again, solid data is available for OSA. In terms of breed-specific The updated hallmarks of cancer added two “enabling” char-
risk, multiple heritable factors seem to influence the risk for OSA. acteristics, (7) genome instability and mutation and (8) tumor-
Data from a genome-wide association study (GWAS) in three promoting inflammation, and two “emerging” hallmarks, (9)
high-risk dog breeds indicates that the patterns of heritable risk deregulating cellular energetics and (10) avoiding immune
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for OSA are complex and incompletely penetrant. However, destruction.
selective breeding, especially for large size, seems to have enriched The effect of this unifying conceptualization of cancer genet-
risk alleles that are now fixed in certain populations. 14,25,26 Fixed ics and this level of understanding are clearly evident when one
alleles associated with risk are not unique to OSA; they have also considers how they have influenced the design, development,
been associated with breed-specific risk for canine mammary can- implementation, and success of new cancer therapies (Fig. 1.3). A
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cer, canine digital squamous cell carcinoma, and other cancer summary of the information with added refinements is provided
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types (discussed later in the chapter). later in the chapter.
In humans a GWAS identified two loci associated with the
presence of OSA and a single, distinct locus in the NFIB gene Sustaining Proliferative Signaling
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associated with the presence of metastasis at diagnosis. The risk
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alleles for humans and dogs are not located in orthologous regions Arguably the most important event in neoplastic transfor-
of the genome. It appears, then, that achieving a large size rela- mation is the capability of cells to proliferate in perpetuity.
tively rapidly, and not breed-specific (or individual) traits in the Under normal conditions, cells communicate with each other
germline, is the overwhelming contributor to OSA risk. It is thus and integrate environmental signals by sensing cues and gradi-
reasonable to conclude that Peto’s paradox arises as a result of bar- ents. For example, migration, metabolism, and proliferation of
riers of natural selection, and that when such barriers are removed mature hematopoietic cells are regulated in autocrine and para-
and the natural life span of an organism is extended, as is the crine fashions by locally secreted cytokines. The same cytokines
case for dogs, the paradox disappears, revealing the overwhelming may act systemically in an endocrine fashion. With the notable
influence of DNA replication errors on individual cancer risk. exception of steroid hormones that bind to intracellular recep-
The examples provided underscore that cancer risk and pro- tors, growth-promoting cytokines work by binding transmem-
gression have both shared and unique traits across species in brane receptors, which in turn initiate signaling cascades that
the animal kingdom. This creates opportunities to study the culminate in transcriptional changes. These transcriptional
natural history of cancer in a spontaneous setting. However, it is responses, in turn, allow cells to adapt their behavior to match