|
Hemangiosarcoma
Jaime F. Modiano, VMD, PhD
Perlman Professor of Oncology/Comparative Medicine
University of Minnesota College of Veterinary Medicine and Cancer Center
http://www.modianolab.org
|
|
Canine hemangiosarcoma is an
incurable tumor of cells that line blood vessels (endothelial cells). Based
on current estimates of the lifetime risk of cancer in dogs and the prevalence
of hemangiosarcoma, we predict that of 65 million pet dogs living in the
United States today, as many as two million may get this cancer and die from
it. Although dogs of any age and breed are susceptible to hemangiosarcoma,
it occurs more commonly in dogs beyond middle age, and in breeds such as
Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, and Skye
Terriers, among others. Hemangiosarcoma is extremely indolent – that is,
it develops slowly and is essentially painless – so clinical signs are usually
not evident until the advanced stages when the tumors are resistant to most
treatments. Less than 50% of dogs treated with standard-of-care of care for
this tumor (surgery and intensive chemotherapy) survive more than six months.
Many dogs die from severe internal bleeding before there is an opportunity
to institute treatment. For this reason, our lab is working to develop a
test for early detection, which will allow us to diagnose the disease before
it is clinically evident. Similarly, a number of novel approaches using targeted
therapies and tumor vaccines to treat canine hemangiosarcoma are in preclinical
development or in the early stages of clinical testing.
The following article was first published in The Courier (official magazine
of the Portuguese Water Dog Club of America) and the German Shepherd Review
(official magazine of the German Shepherd Dog Club of America). It is included
here with permission.
Canine Hemangiosarcoma -
the Road from Despair to Hope
Jaime F. Modiano, VMD, PhD, Michelle G. Ritt, DVM, DACVIM,
Matthew Breen, PhD, CBiol, MIBiol, and Tessa Breen, BSc (Hons), Dip GD, CMM
University of Colorado Health Sciences Center, Denver,
CO (JFM), Animal Hospital Center, Highlands Ranch, CO (MGR), and North Carolina
State University (MB, TB)
In following article, we describe
the current state of knowledge for canine hemangiosarcoma, including what
it is, why it may happen, and how it can be managed. In addition, we present
recent findings from our programs that promise to help us improve our ability
to diagnose, treat, and prevent this disease.
The Natural History of Canine
Hemangiosarcoma
Canine hemangiosarcoma is among
the most challenging and mysterious diseases encountered in veterinary practice.
It is an incurable tumor of cells that line blood vessels, called vascular
endothelial cells. Hemangiosarcoma is relatively common in dogs; it is estimated
that this type of cancer accounts for 5-7% of all tumors seen in dogs. Considering
the lifetime risk of cancer for dogs is between 1 in 2 and 1 in 3, we can
calculate that 1.5 to 2.5 million of the ~72 million pet dogs in the United
States today will get hemangiosarcoma and succumb from it. Although dogs
of any age and breed are susceptible to hemangiosarcoma, it occurs more commonly
in dogs beyond middle age (older than 6 years), and in breeds such as Golden
Retrievers, German Shepherd Dogs, Portuguese Water Dogs, Bernese Mountain
Dogs, Flat Coated Retrievers, Boxers and Skye Terriers, among others. According
to the Golden Retriever Health Study published in 2000, the estimated lifetime
risk of hemangiosarcoma in this breed is 1 in 5, illustrating the magnitude
of this problem.
Unlike other cancers, hemangiosarcoma is almost an exclusive disease of
dogs. In people, a similar type of tumor (angiosarcoma) occurs only rarely
in association with workplace exposure to vinyl chloride and polychlorinated
biphenyls (PCBs), such as is found in rubber and tire plants. An even smaller
fraction of women who receive high dose radiation therapy for cancer (usually
breast cancer) can develop angiosarcoma of the skin. Yet, angiosarcomas
account for much less than 1% of all tumors seen in people. Certain mutations
are known to predispose laboratory mice to hemangiosarcoma, but whether
these mutations contribute to the disease in dogs is not known. Benign tumors
of vascular endothelial cells, called hemangiomas, arise in the skin of
people and dogs that have extended exposure to sunlight. These tumors are
distinct from hemangiosarcomas and angiosarcomas, and they are not life
threatening.
In dogs, the common primary sites for hemangiosarcoma are the spleen,
the right atrium of the heart, and the subcutis, which is the tissue beneath
the skin. The pattern of growth for these tumors involves infiltration into
normal tissues surrounding the tumor as well as distant spread (metastasis).
The disease is indolent; in other words, it does not cause pain and the rate
of growth in the early stages is relatively slow. Dogs harboring even large
hemangiosarcomas may show no clinical signs or evidence that they have a life
threatening disease. Generally, the tumor cells retain some normal aspects
of behavior, so they try to make blood vessels. But these vessels are tortuous
and malformed, and blood cells tend to pool in them and clot. The clots then
prevent blood and nutrients from reaching tumor cells, in turn causing them
to die. This creates small ruptures in the tumor through which blood may escape
into the abdomen, heart sac, chest, or subcutaneous space. Depending on the
amount of blood lost, affected dogs may show non-specific (constitutional)
signs such as lethargy and weakness, but these are transient and resolve as
dogs reabsorb the blood components and make new blood cells. The clinical
signs are recurrent, but they also are subtle enough to go unnoticed for some
time. Since hemangiosarcoma tends to metastasize aggressively to lungs, liver,
intestines, and mesentery (the membranous connective tissue that supports
the intestines), distant spread (either microscopic or macroscopic) has inevitably
occurred once the disease is finally diagnosed. The eventual outcome for
patients with this disease often follows the rupture of a large or rapidly
growing tumor, which results in acute, severe hemorrhage, collapse, shock,
and death.
What Causes Hemangiosarcoma
We do not precisely know what causes canine hemangiosarcoma. The observations
that the disease occurs more commonly in dogs than in other animals, and
that some breeds are at higher risk than others tell us that heritable factors
must contribute to risk. Ultimately, the interactions of these heritable
risk factors with the environment probably lead to the spectrum of mutations
that give rise to the tumor. As a matter of brief review, it is important
to understand that “cancer is a genetic disease, although it is not always
heritable.” Tumors arise when cells accumulate mutations that eliminate normal
constraints of growth and genetic integrity. These mutations provide cells
a selective growth advantage within their environment, essentially the same
evolutionary phenomenon that we call natural selection, albeit on a microscopic
scale. Most mutations arise because the enzymes that control cell division
are not foolproof. About 1 mutation occurs for each one to ten million bases
that are replicated when time a cell divides (genomic DNA in dogs consists
of about 2.5 billion base pairs; in other words, when a cell divides, it must
copy 2.5 billion bases and the inherent error rate of the DNA replication
machinery will introduce between ~250 and 2,500 errors, or mutations, to
the DNA of each daughter cell). Since some cells in the body divide continuously
to replace others that die or are damaged (for example, blood cells, skin
cells, and gut cells), mutations are pretty much introduced constantly into
cells in the body. For this reason, we say the greatest risk factor for cancer
is “being alive”. As mentioned above in the example of humans that are at
risk to develop angiosarcoma, mutations also can occur from exposure to
environmental toxicants. Fortunately, most of these mutations are silent
(they neither help nor hurt the cell or the organism), and the body has mechanisms
to eliminate most cells that acquire deleterious mutations. A relatively
new concept about how cancer happens invokes the theory that only “stem cells”
can give rise to tumors, making the acquisition of mutations in somatic cells
(any cell that is not a sperm or an egg) a lesser concern. This will be
discussed in detail later in the article. For now, it is important to understand
that simply carrying a mutation does not necessarily mean an individual will
get cancer - it only means that his or her risk is elevated. The practical
implication of this statement is that we will probably never eliminate cancer
completely from our population (human or canine), but we can achieve a significant
reduction in the number of cases as we learn more about how the disease happens
and we work to diminish risk factors or detect the disease early enough
to treat it before it becomes a life-threatening condition.
The news is not all bad. We have identified some of the fundamental properties
of canine hemangiosarcoma, and it is possible one or more of these may prove
to be an “Achilles heel” for the tumor. For example, most of these tumors
make growth factors that they need to survive, or they “coerce” cells in
their environment to do this for them. One of these growth factors is vascular
endothelial growth factor-A or VEGF, which acts by binding specific receptors
on the hemangiosarcoma cells. New drugs under development by various pharmaceutical
companies are designed specifically to interfere with the signals transmitted
by these receptors. The reliance of hemangiosarcoma cells on VEGF signals
to survive should make them more sensitive than normal cells to these drugs.
Several groups are working to bring these drugs into the clinic, but the
process is slow because testing must be done in a careful, deliberate way
to ensure the compounds are safe and effective. The rules for participation
in clinical trials are stringent, but if you have a dog that is diagnosed
with terminal hemangiosarcoma, your veterinarian may have information about
trials for which he or she may be eligible. As we will detail below, our work
and that of others continues to illuminate new avenues that we may be able
to use to more effectively prevent, control, and treat this disease.
Treatment for Canine Hemangiosarcoma
Regrettably, the standard-of-care for this disease has not seen significant
advancement over the past 20 or 30 years. There is presently no readily available,
effective test for early diagnosis of hemangiosarcoma. Careful analysis
of blood samples by experienced pathologists may hint at the presence of
chronic hemorrhage and blood vessel abnormalities that are suggestive of
hemangiosarcoma. However, this method is neither sensitive nor specific to
confirm the diagnosis. Non-invasive imaging methods are useful aids to diagnose
the disease. In particular, ultrasound is moderately specific, but it is
not sensitive, and the tumor must be large enough to be grossly visible. In
addition, biopsies are required for confirmation of imaging results. Repeated
biopsies of tissues where the tumors may arise (without other evidence for
the presence of a tumor) are of little use to provide early diagnosis, and
considering the fact that there is some risk to these procedures, such an
approach is practically and ethically unacceptable.
The options for therapy of canine hemangiosarcoma are limited, largely
because the disease is not diagnosed until the late stages. The standard
consists of surgery to shrink or remove the primary tumor, when possible,
followed by intensive chemotherapy. In some cases, surgery is not feasible,
or it can be impractical or inappropriate (for example, if there is evidence
of extensive metastatic spread to sites beyond the primary tumor). Median
survival for dogs treated with surgery alone is approximately 90 days, and
that is extended to approximately 180 days by the addition of chemotherapy
using one of several protocols available. Because the goal for chemotherapy
in pet dogs is to extend life with good quality, toxicity is generally not
a major issue of concern, and when it occurs it is most often managed without
much difficulty.
There is no other therapy that has been proven to be effective to manage
or control hemangiosarcoma. As we will mention below, the cells that give
rise to this disease originate in the bone marrow. We do not yet know when
(or why) they localize to the organ where the disease will arise, but this
means that prophylactic splenectomy (removing the spleen to prevent the development
of the disease) is unlikely to have any benefit, since in the absence of
a spleen, the transformed cell (or cells) can simply go to another organ.
Also, the spleen is not simply a “window dressing” organ, and even though
dogs can function without a spleen, they will have reduced ability to adapt
or respond to a variety of conditions.
Several alternative and complementary approaches (diet, herbs, mystical
energy, etc.) have recently become popular as people try to find treatments
for canine hemangiosarcoma. This usually follows extensive publicity (such
as from Internet chat groups) after a dog receives these treatments and
survives longer than anticipated, leading proponents to advertise this as
success and evidence that their approach is curative for hemangiosarcoma.
The danger of attributing curative power to treatment approaches after an
anecdotal response cannot be overstated. There is no reported case where
one of these therapies has been consistently successful (or even as good
as the standard of care) after it has been tested without bias to try to
replicate the anecdotal response. In fact, sometimes such treatments can
actually interfere with - or increase the toxicity of chemotherapy drugs.
We know that when some tumors are caught early enough, surgery alone, surgery
plus chemotherapy, and in some cases no treatment at all can lead to extended
survival. In rare instances, the behavior of the tumor itself is such that
disease progression is extremely slow and dogs can survive for an extended
period regardless of the therapy used. This means that a small proportion
of dogs diagnosed with hemangiosarcoma will live 2, 3, 4 years and longer
even without aggressive management. Therefore, it is essential for families
who have dogs that are diagnosed with cancer to recognize two things. One
is that veterinarians would not willingly hold back effective therapies for
any disease. Our job and our responsibility are to improve the health and
well being of dogs and their families, and all of us would welcome an effective
and non-toxic cure for this disease. The other is that there is no shortage
of predators on the Internet and elsewhere who benefit from the desperation
people feel when they know a beloved family member will probably die from
a serious, incurable disease (please visit http://www.quackwatch.org/00AboutQuackwatch/altseek.html
if you want to read more about “miracle cures” for cancer advertised in the
lay press and on the Internet).
Hope for the Future
The unwavering support of the dog-loving community has already made a
difference in our understanding of canine hemangiosarcoma. To end this article,
we will highlight new information that makes us optimistic about our chances
to win the battle against this disease. Here, we wish to note our gratitude
for the support that our group and our collaborators have collectively received
from dog clubs and owners alike, both financial and by making samples available
for ongoing studies.
Development of a Test for Early Detection. As we mentioned above, one
way to improve our success treating hemangiosarcoma is by detecting the
disease early. Previous work from our group showed there are unique patterns
of protein expression that can help distinguish hemangiosarcoma cells from
normal blood vessel lining cells, even within the tumor. We also knew that
most tumors shed some cells into the circulation. We reasoned, then, that
we could take advantage of this to develop a test to look for tumor cells
in the circulation, providing a minimally invasive, accurate diagnostic test
for hemangiosarcoma. In many ways, this is similar to the proverbial search
for a needle in a haystack. The tumor cells are so infrequent that they cannot
be detected in routine blood tests, nor are they easy to enrich. To accomplish
our goal, we needed to use a robust technology called flow cytometry. For
this, cells are “tagged” with fluorescent molecules that identify their lineage
of origin and then cells are run through an instrument (the flow cytometer)
that combines sophisticated optics, fluidics and software that make it capable
of analyzing tens of thousands or hundreds of thousands of cells in a matter
of minutes. With financial support from the Portuguese Water Dog Foundation,
Inc., the Portuguese Water Dog Club of America, and Idexx Laboratories, we
were able to show proof of principle for this test. The work was published
in the July 2006 issue of the journal Experimental Hematology. Idexx Laboratories
has licensed the technology from the University of Colorado. As of the writing
of this article, the test is in the final stages of optimization and transfer
to Idexx for final testing. Several questions remain to be answered before
the test can be offered commercially, not the least of which are cost analysis
and market research to ensure that the final product is not only diagnostically
useful, but also affordable for veterinarians and pet owners.
A planned future use for this test is its application to detect the presence
of hemangiosarcoma in dogs at risk before the tumor poses a clinical hazard.
As is true for other tumors, early detection is likely to offer the highest
probability of successful treatment outcomes. There is, however, an important
caveat. The presence of hemangiosarcoma cells in the circulation does not
tell us where in the body the tumor is likely to develop, as tumors in the
spleen, liver, heart, and skin all produce positive results in this test.
Therefore, we have initiated several studies with support from the AKC Canine
Health Foundation, the National Canine Cancer Foundation, and others, to
develop novel treatment strategies for hemangiosarcoma that are independent
of the site of origin (these are still in the earliest stages of laboratory
development). Only then will we be able to ethically and judiciously use early
detection to improve outcomes for dogs affected with this disease.
Is Hemangiosarcoma a Disease of Stem Cells? A lot of attention has been
focused recently on stem cells and their potential use to cure a wide variety
of diseases. The “dark side” of stem cells is that these may be the only
cells that can give rise to tumors. It is very important to note here that
this is not a reason to avoid or abandon research on the therapeutic promise
of stem cells, as there is no practical, documented evidence that the possibility
to develop cancer is any higher in laboratory animals or patients that receive
stem cell transplants.
Until recently, the dominant theory for the origin of cancer assumed that
all cells possess an equal capacity for self-renewal; that is, the capacity
to make a new identical cell that retains all the properties of the mother
cell, and that proliferation of cancer cells was a random process driven
entirely by selection of mutations that increased the fitness of a cell in
a particular environment. A competing theory now exists whose main concept
is that self-renewal is limited to a small population of “cancer stem cells.”
These cells possess the two features that define “stemness”: (1) self-renewal
and (2) multipotency (the capacity to make new cells that can differentiate
into more than one type or lineage). In other words, a very small number of
self-renewing cells in a tumor generate large numbers of progeny that make
up the bulk of the tumor (or tumors). The existence of “cancer stem cells”
is now well documented; they have unique properties of gene and protein expression,
and the initial transformation seems to involve a relatively small number
of mutations. The accumulation of additional mutations determines the extent
to which the progeny from these cells will differentiate, variably resulting
in distinct clinical entities such as high-grade, aggressive tumors and low-grade,
indolent tumors.
This model of cancer explains why multicellular animals like a dog, with
trillions of cells in their bodies, can survive to reproductive age without
developing cancer, as the capacity for tumor formation is limited to perhaps
a few hundred “stem cells”, dramatically reducing the probability that any
cell with cancer-causing potential will accumulate the set of mutations needed
to develop the disease. Still, the high incidence of cancer among older
individuals reinforces the notion that even with a limited number of susceptible
stem cells, the probability to develop cancer over a long life is quite
high. With regard to canine hemangiosarcoma, recent data from our lab support
the idea that this is a disease of stem cells, the first such evidence for
a canine tumor. Current work is focused on characterizing these stem cells,
as their unique properties may provide opportunities to develop highly targeted,
non-toxic therapies to effectively treat this disease.
What Are the Breed-Specific Risk Factors for Canine Hemangiosarcoma? We
mentioned previously that hemangiosarcoma is a rather common cancer in certain
breeds, including Golden Retrievers, German Shepherd Dogs, and Portuguese
Water Dogs. This tells us that heritability contributes to risk, and so
it may be possible to reduce the incidence by eliminating the highest risk
alleles from the population. Moreover, if risk factors responsible for the
disease are unique among breeds, we might have to consider the possibility
that various new therapy approaches will have to be developed to effectively
treat this disease in different breeds of dogs. To date, we have taken several
approaches to identify how heritable factors influence hemangiosarcoma risk.
One approach, developed largely in collaboration with Dr. Elaine Ostrander
at the National Human Genome Research Institute of the National Institutes
of Health and Dr. Kerstin Lindblad-Toh at the Broad Institute of MIT and
Harvard, seeks to map risk alleles in Portuguese Water Dogs, Golden Retrievers,
and German Shepherds using resources made available by the recent completion
of the Canine Genome Project. We continue to collect samples for these projects,
and we would be extremely grateful to owners who wished to participate by
contributing blood and pedigree information from healthy (aged) dogs and from
affected dogs. Information for participation is available at http://www.modianolab.org/studyInfo/studyInfo_index.shtml.
A second approach, developed largely in collaboration with Dr. Matthew Breen,
seeks to determine breed specific abnormalities that are detectable in tumors
obtained from dogs of different breeds. We have made significant progress
on this project, and have new data showing that, indeed, tumors from dogs
of one specific breed are functionally and genetically more similar to each
other than they are to tumors from dogs of other breeds. We are extremely
excited about this information, as it will, for the first time, provide tangible
evidence that heritable risk factors are a contributor to the development
of canine cancer. More importantly, these results are the first step in our
long-term goal to develop strategies for prevention and treatment that address
specific causes underlying the biology of canine hemangiosarcoma.
In conclusion, hemangiosarcoma remains a devastating, untreatable disease
of dogs. However, ongoing work in our laboratories and elsewhere is rapidly
increasing our understanding of this disease, providing hope that we will
achieve our goals to reduce its incidence and control its impact on dogs
and their human families within our lifetime.
Jaime F. Modiano, Ph.D
Is the lab principal investigator. He hails from Mexico City, where
he graduated from the baccalaureate program at Colegio Columbia. He did undergraduate
work in Biomedical Sciences at Texas A&M University in College Station,
TX for three years before moving on to veterinary school at the University
of Pennsylvania in Philadelphia. He completed his veterinary training and
PhD in Immunology at Penn, followed by a residency in Veterinary Clinical
Pathology at Colorado State University in Fort Collins, CO, and a post-doctoral
fellowship at the National Jewish Center for Immunology and Respiratory Medicine
in Denver, CO. He was appointed to the faculty in the Department of Veterinary
Pathobiology at Texas A&M University as Assistant Professor between 1995
and 1999. Dr. Modiano returned to Denver from 1999 to 2007; there, he held
Scientist and Senior Scientist appointments at the AMC Cancer Research Center
and he was Associate Professor of Immunology and Full Member of the Cancer
Center at the School of Medicine of the University of Colorado Health Sciences
Center. In July of 2007, Dr. Modiano joined the College of Veterinary Medicine
and the Comprehensive Cancer Center at the University of Minnesota, where
he continues his research program as Professor of Comparative Oncology holding
the Al and June Perlman Endowed Chair.
Between 2001 and 2003, Dr. Modiano served as Director of Cancer Immunology
and Immunotherapy for the Donald Monk Cancer Research Foundation; he also
is a partner at Veterinary Research Associates, LLP, a company focused on
development and implementation of diagnostics for veterinary medicine and
a founder/scientist at ApopLogic Pharmaceuticals, LLC, a biotechnology company
focused on development of cancer therapeutics. His research program has had
uninterrupted support from federal and private sources for 13 years, leading
to co-authorship of more than 50 peer-reviewed scientific manuscripts, and
~200 abstracts, presentations, and book chapters focused on various aspects
of immunology, cancer cell biology, the genetic basis of cancer and applications
of gene therapy.
Dr. Modiano is married to Dr. Michelle Ritt, a board certified specialist
and Clinical Associate Professor of Medicine at the University of Minnesota.
They share their home with Logan, a champion agility Gordon setter and Quetzal,
a German Shepherd Dog.
The above information is simply informational. It's intent is not
to replace the advice of a veterinarian nor to assist you in making a diagnosis
of your pet. Please consult with your own veterinarian for confirmation of
any diagnosis. Your pets life may depend on it.