Genes, and Cancer:
Why Cancer Happens and
What We Can Do to Prevent and Treat It
Modiano (previously at the AMC Cancer Research Center in Denver, CO)
and now at the
University of Minnesota, Modiano Lab
Due to advances in veterinary
health care, dogs are living to older age when most cancer
types occur with greater incidence.
is now the leading cause of disease-related death in dogs, and as
such, it has gained exceptional importance in our society.
Genetic and environmental factors also have major effects
on the temporal occurrence of cancer and are the basis of research
on what causes cancer (pathogenesis), as well as prevention,
diagnosis and treatment. Thus,
a new emphasis has developed to learn more about genetic and
environmental factors that influence cellular and molecular
changes in canine cancer.
Dogs and people are susceptible to many of the same types
of cancer and the natural history of many cancer types appear to
in both species. The
shorter life span of dogs (both in terms of life-years and
generations) and the availability of extended pedigrees with
detailed family histories, provide a unique opportunity to address
causative issues of cancer that will be important for both dogs
is a "genetic" disease.
The term cancer refers to a large number of diseases whose
common feature is uncontrolled cell growth and proliferation
loss of cell growth control results from an accumulation of
mutations (errors introduced into the DNA code) in genes that
control cell division and cell survival.
The most common mechanism that introduces mutations into
the DNA of somatic cells (non-reproductive cells) is the
inherent error that occurs during normal cell division.
In mammalian cells, there is an error rate of about 1 in
1,000,000 to 1 in 10,000,000 bases during each round of
genome consists of many millions of base pairs, so each daughter
cell is likely to carry at least a few mutations in its DNA.
Most of these mutations are silent; that is, they do not
present any problems to the cellís ability to function.
However, others can disable tumor suppressor genes
or activate oncogenes that respectively inhibit or promote
cell division and survival. A
cell that accumulates sufficient mutations which eliminate steps
necessary to restrain proliferation and maintain genetic integrity
can give rise to a tumor.
Because of the mutations, this cell and its progeny acquire
a "selective growth advantage" within their environment.
This is essentially the same phenomenon that we call "natural
selection", albeit in a microscopic scale.
Given the fact that cell division is responsible for most
mutations, it is not surprising that the most common cancers arise
from cells that divide frequently in the performance of their
function. The origin
of these cancers, then, is "genetic" because it lies in
the malfunction of genes that control growth and survival, but
these cancers are considered to be "sporadic" (that is,
they are largely independent of heritable risk factors).
risk can be inherited.
Mutations that contribute to cancer can also be inherited. An inherited mutation in a single gene that is important in
cell growth control will increase the risk of that individual to
develop cancer. This
can be due to reducing the overall number of acquired mutations
that must accumulate before a cell becomes cancerous, or it can be
due to disabling a critical safeguard gene that normally prevents
cells from becoming tumors. In
humans, it is estimated that approximately 5% of cancers are occur
in people who have known heritable risk factors.
In dogs, there appears to be a predisposition among certain
breeds or families to develop specific types of cancer, suggesting
that a hereditary component may be important in the development or
progression of the disease. However,
the existence of heritable cancer syndromes in dogs remains to be
is cancer kept at bay? Although both
heritable factors and behavioral factors are known that increase
the risk of cancer in people, similar information for dogs is
limited. We know, for
example, that neutering has a protective effect on hormone related
cancers (mammary cancer and prostate cancer) and this information
has been used extensively to reduce the prevalence of these tumors
in the non-breeding population of pet dogs.
But little is known regarding specific factors that
influence the risks for other cancers. Nevertheless, it is fortunate that dogs (like other higher
vertebrates) have developed many built-in safeguards which mandate
that abnormal cells be destroyed.
For that reason, before cancer can take hold, a malignant
cell must eliminate or evade these safeguards.
Despite the alarming incidence of cancer in older dogs, the
reliability of these systems is evident in the fact that many of
our pets do not develop cancer until they reach an advanced age if
(cancer of the lymph glands) and osteosarcoma (bone cancer) are
among the tumors that are commonly seen in dogs.
Lymphoma accounts for approximately 20% of all canine
tumors, and >80% of cancers originating from blood cells.
Most of the time, lymphoma appears as "swollen
glands" (lymph Nodes) that can be seen or felt under the
neck, in front of the shoulders, or behind the knee.
Occasionally, lymphoma can affect lymph nodes that are not
visible or palpable from outside the body, such as those inside
the chest or in the abdomen.
In these cases, dogs may accumulate fluid in the chest that
makes breathing difficult, or they may have digestive problems
(diarrhea, vomiting, or painful abdomen).
If left untreated, dogs with lymphoma will generally
succumb to the disease within 3 to 4 weeks.
Treatment with prednisone (a corticosteroid) alone
generally can induce rapid, but short-lived remissions (usually
less than 6 to 8 weeks), and frequently renders the disease
resistant to further treatment.
Durable remissions are achievable in lymphoma, so the
disease is generally considered to be 'treatable.'
Multi-agent chemotherapy, which is the standard of care for
this disease, will induce remissions of 12 to 18 months in many
cases. However, there
are various subtypes of lymphoma that exhibit different behaviors,
and some of the more aggressive types are unresponsive to any
available treatment. For
example, the median survival for dogs with lymphoma originating
from B cells treated with multi-agent chemotherapy is
approximately 14 months, whereas the median survival for dogs with
lymphoma originating from T cells treated with multi-agent
chemotherapy is approximately 6 months.
However, there remains a lot of variability in the
responses seen even when tumors are classified into these
accounts for 85% of skeletal cancers.
Large and giant breed dogs are at highest risk for
developing osteosarcoma, possibly due to the fact that bone cells
at the growth plates must divide many times to create the very
long bones that are characteristic in these breeds.
However, there probably are additional risk factors, which
have yet to be defined. Osteosarcomas
generally occur in the limbs, however, these tumors can arise
anywhere in the long bones, as well as in flat bones (ribs, skull,
and spine). Osteosarcoma
is always a life-threatening disease because it is highly
metastatic, making treatment of this type of cancer especially
standard of care for osteosarcoma of the limbs includes amputation
or limb-sparing surgery, followed by adjuvant chemotherapy.
The median survival for dogs with osteosarcoma treated with
surgery alone is approximately 100 days.
The addition of chemotherapy (usually doxorubicin or a
"platinum" drug) to the treatment regimen increases the
median survival to >300 days.
Various factors can be used to predict response to therapy,
including the anatomic location and size of the tumor and serum
alkaline phosphatase concentrations.
However, there are no truly robust predictors of response,
and the survival of dogs with osteosarcoma treated with standard
of care can range from weeks to years.
can we do to prevent and treat cancer?
several breed clubs and animal health organizations, including the
AKC Canine Health Foundation and the Rottweiler Health Foundation
that are supporting research projects that will help define cancer
risk factors for dogs, and also to develop rational new treatment
strategies to improve the outcome of cancer patients.
The AKC Canine Health Foundation recently launched a "Cancer
Initiative" to raise almost one million dollars to support
cancer research projects. These
projects seek to define markers of heritable cancer risk, identify
markers that improve the ability of veterinarians to predict
responses to standard, available treatments, and develop new
strategies for therapy based on known genetic anomalies peculiar
to tumors. The
research project "Heritable
and Sporadic Genetic Lesions in Canine Lymphoma and
Osteosarcoma" (AKC CHF Grant 2254), which is supported in
part by the Rottweiler Health Foundation, is a collaborative
effort between Dr. Jaime Modiano at the AMC Cancer Research Center
in Denver, CO and Dr. Matthew Breen at North Carolina State
University in Raleigh, NC that seeks to determine how genes
impact the development of cancer in dogs.
Specifically, the researchers will study abnormalities in
genes and chromosomes in lymphoma and osteosarcoma
to determine if these abnormalities are inherited, and to assess
their clinical significance (that is, if they are predictive
regarding response to treatment and prognosis).
In the short term (few years), this study may help identify
"genetic pawprints" in tumors that can be used to
predict if they are likely to respond to conventional therapy,
allowing owners of affected dogs to make more informed decisions
regarding treatment for their pets.
In the long term, we anticipate that this and other studies
may define specific gene markers that define cancer risk for
individuals and their progeny that can be used for judicious
breeding decisions to reduce the incidence of cancer in dogs.
assistance is essential to the success of these projects.
Your generous donations to the Rottweiler Health Foundation
and to the AKC Canine Health Foundation will help support
worthwhile research projects that will help us understand,
prevent, and treat cancer in our dogs.
As important, we urge to you look at the accompanying
solicitation for participants, and if you know of a dog that
is eligible to participate (or a dog that were unfortunate enough
to become eligible), we request that you contact the Rottweiler Health Foundation
or the investigators for additional information.
to learn more
about this study and its requirements for eligible participants,
please click here.
your help, we will improve the health and well-being of our dogs!