Learn about cancer from pet dogs

Research on pet dogs with cancer may help fight the disease in humans and at the same time benefit man's best friend.

By David G. Waters and Kathleen Wildsin

Imagine a 60-year-old man recovering at home after prostate cancer surgery, with an elderly golden retriever by his side. He may know that a few years ago the director of the American Cancer Institute issued a challenge to cancer researchers, urging them to find ways to "eradicate by 2015 the suffering and death that cancer brings." But the man does not know, obviously, that the pet by his side may play an important role in this task.

To achieve the ambitious goal by 2015, researchers will need every possible research tool, including openness to new ideas. Despite the unprecedented progress in understanding the capabilities of cancer cells, the translation of this knowledge into saving lives is unacceptably slow. Researchers have discovered many drugs that cure artificially induced cancers in rodents, but in humans these substances usually have difficulty passing the tests. Using rodents to simulate human cancer simply does not meet the requirements. If we want to eradicate cancer, we must pave a new way to move forward.

Now, consider these facts: More than a third of households in the United States have dogs, and scientists estimate that about four million of them will be diagnosed with cancer this year. Pet dogs and humans are the only two species that naturally develop fatal prostate cancer. Breast cancer that affects pet dogs spreads mainly to the bones, just like in women. And the most common bone cancer in pet dogs, osteosarcoma, is the same cancer that affects teenagers.

Researchers specializing in the new field of comparative oncology believe that these parallels open the door to a new approach to fighting the cancer problem. These scientists compare types of cancer that develop naturally in animals and humans, and study both the similarities and differences between them.

Today, comparative oncologists are recruiting dogs to solve the problems that are delaying the eradication of cancer by 2015. They are trying, among other things, to discover better treatments, to decide what the most effective drug doses are, to identify environmental factors that cause cancer to develop, to understand why some people are resistant to cancerous tumors and find ways to prevent cancer. As the "2015 cancer clock" continues to tick, comparative oncologists ask why not turn the topic of cancer in dogs from a source of sadness today into a national resource tomorrow, to help both other pets and people?

Why Rexy?

For decades, scientists tested the toxicity of new cancer drugs on lab beagle dogs before the substances were tested on humans. Comparative oncologists have good reason to think that pet dogs with cancer may serve as a good model for testing the efficacy of promising anticancer drugs.

 One of the reasons for this is the way human tests are conducted. It is necessary to ensure that the potential benefit of the drug outweighs the risks involved in taking it. Because of this, researchers are trying to evaluate its effectiveness against all odds and defeat large tumors in an advanced state, which did not respond to other drugs in previous treatments. In contrast, comparative oncologists can afford to test new treatment ideas already in the initial stages of the disease and give the drugs exactly the same way they would give them to humans. When experimental drugs are found to be effective in pets, it helps researchers decide which drugs might help human patients. Comparative oncologists believe that the findings in dogs will be more predictive than studies in rodents and will help quickly discover which substances should be tested in large-scale clinical trials in humans and which should not.

Pet dogs can teach us much more about human cancer, in part because they tend to get the same types of cancer as us, and there are many examples of this. The most common lymphoma in dogs is similar to the type called "non-Hodgkin's B-cell lymphoma" in humans, of medium and high grade. Osteosarcoma, the most common bone cancer of large dog breeds, is most similar to juvenile osteosarcoma in terms of location and aggressiveness. Through the microscope, it is impossible to distinguish between cancer cells taken from teenagers with osteosarcoma and cells taken from cancer cells in the bones of a golden retriever. Bladder cancer, melanoma (a type of skin cancer) and oral cancer are other examples of cancers that attack both dogs and their owners. A different kind of similarity manifests itself in that female dogs spayed before reaching sexual maturity are less prone to breast cancer than dogs that have not been spayed. Similarly, women who had surgery to remove the ovaries, got their first period at a late age, or stopped menstruating at a young age have a lower risk of developing breast cancer.

Another characteristic of cancer in dogs that is similar to that in humans is metastasis - the life-threatening spread of cancer cells to different areas throughout the body. How cancer cells spread to certain organs remains one of the most burning mysteries in cancer research. When certain types of cancer cells spread to distant organs, they tend to reach certain tissues and not others, for reasons that are not entirely clear. Since metastases are the cause of most cancer deaths, researchers are interested in better understanding what affects them. Studies in pet dogs suffering from prostate cancer or breast cancer may prove to be particularly useful in this context, because these types of cancer often spread in dogs as in humans - to the bones of the skeleton. Indeed, research in pet dogs is already trying to understand the connections between cancer cells and bones that make the skeleton a favorite site for metastases.

There are also more fundamental reasons for believing that dogs are a good model system for human cancer. Evolutionists point out that dogs and humans are built like race cars, with successful reproduction being the equivalent of the finish line. We are built to win the race, but afterwards it doesn't matter if we fall apart. This design makes it difficult for us to repair the accumulated genetic damage in our body. Eventually, the damage can turn healthy cells into cancer cells. In the distant past, our ancestors did not live long enough and therefore did not get age-related cancers. But modern hygiene and medical conditions have made both longevity and cancer in old age common. These considerations are mostly true for our pets as well. We protect them from predators and diseases, so the life expectancy of the pet dogs is higher than that of their wild ancestors and they are more exposed to cancer in their later years. That is, when it comes to a high risk of getting cancer during life, pets and humans are in the same boat.

Apart from suffering from cancers similar to those in humans, pet dogs are a valuable source of information for additional reasons. Compared to humans, they have a short lifespan, so scientists can determine more quickly whether a new prevention method or treatment might improve the chances of survival in humans. Finally, although veterinarians today are better equipped than ever to treat cancer, the standard treatment for cancer in dogs remains ineffective. Since most cancers diagnosed in dogs end in death, dog owners are often eager to involve their dogs in clinical trials that may save their lives. These tests may also provide the evidence needed to begin human clinical trials of a promising new drug.

promote cancer treatment

Several studies that rely on treating cancer in dogs have already been conducted or are currently being conducted. Some of the earliest research focused on saving the limbs of teenagers with bone cancer. 25 years ago, a diagnosis of osteosarcoma (bone cancer) in teenagers led to amputation of the affected leg or arm, ineffective chemotherapy (drugs injected into the bloodstream to attack cancerous tumors anywhere in the body), and almost certain death. Today it is possible to avoid amputation by removing the damaged bone tissue and replacing it with a bone and metal graft, a process previously tried on dogs by Stephen Withrow and his colleagues at the University of Colorado. Withrow's group developed technological innovations that reduced the risk of complications, such as placing bone cement in the bone marrow cavity of the implant. The researchers also showed that administering chemotherapy directly to the artery, before surgery, may turn an inoperable tumor into a surgically resectable tumor. The work of the research group has significantly increased the proportion of young people who are currently being cured of osteosarcoma.

Although the local impact of a tumor can often be controlled with surgery or radiation, metastases are more difficult to combat. For this, drug treatment is necessary. New drugs currently in development are supposed to damage important cellular processes that control the survival of cancer metastases and their proliferation as well as their sensitivity to anti-cancer drugs. One experimental drug, ATN-161, which inhibits the formation of new blood vessels that feed the tumor and metastases, is currently being tested in large dogs with bone cancer that has spread to the lungs. ATN-161's ability to enhance the effect of existing drugs is also being tested. If these tests are completed successfully, they can pave the way for clinical tests in humans.

Cancer researchers are also interested in more familiar drugs, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Some NSAIDs have considerable anticancer activity against some types of cancer in dogs. For example, in studies on pet dogs with bladder cancer, the NSAID drug piroxicam had a very impressive anti-cancer activity that led to the conduct of clinical trials in humans to test whether this treatment could prevent the precancerous cells in the bladder from degenerating into a life-threatening tumor.

Developing new methods to treat cancer does not only involve finding new drugs, but also improving the way the drug is administered to the patient. Should you give the medicine intravenously or by inhalation? This is the kind of information that scientists who are testing new agents to treat lung cancer need. Care must be taken to ensure that the correct amount of the drug reaches the tumor, otherwise even substances that have effectively destroyed cancer cells in culture will not be successful in humans. More than that, sending the medicine directly to the target, what is known as regional treatment, has another advantage and is avoiding the poisoning associated with systemic treatment.

Researchers used pet dogs to study administering a cytokine known as interleukin-2 (IL-2), a small molecule that belongs to the immune system, to treat lung cancer. The drug was given by inhalation through the nose. Positive results in these experiments led to tests of the feasibility of IL-2 inhalation in humans with cancer metastases in the lungs, and these experiments in turn led to tests with another cytokine, G-CSF. Pets can also help researchers find the most effective doses and routes of administration for drugs already in human clinical trials.

Another challenge is determining the degree of spread of the cancer, that is, the stage in which the tumor is located. Pet dogs can also be used here. Accurate determination of the stage of the tumor is essential for planning the most effective treatment, which, if possible, does not involve exposure to toxic substances, which are unlikely to be able to help at a given stage of the disease. For example, a boy or girl's chance of being cured of osteosarcoma increases when there is accurate detection (and surgical removal) of lung metastases.

Doctors usually determine the presence and level of spread of such metastases with the help of non-invasive imaging methods, such as computed tomography (CT). To determine how accurate this method is, one of us (Waters), in collaboration with researchers at the Indiana University School of Medicine, collected CT scans of lungs from pet dogs that had bone cancer and developed metastases, and then examined the tissue at postmortems to make sure that what was considered a "tumor" "In the scan there was indeed a tumor. The results showed that advanced CT imaging, the same type used to determine the growth stage of bone cancer in teenagers, significantly underestimates the number of metastases in the lungs. This is an example of how pet dogs demonstrate the limited accuracy of conventional and experimental methods, helping to improve next-generation methods of cancer detection and diagnosis.

Cancer prevention

Cancer researchers are not content with improving cancer diagnosis and treatment. They also seek to prevent the disease. Surprisingly, prevention is a relatively new concept among cancer researchers. Cardiologists have long known that millions of people could be saved by preventing heart disease, but this view is just beginning to gain traction in cancer. The term "chemical prevention" was coined 30 years ago regarding the administration of chemical compounds to prevent cancer, but it was not until October 2002 that scientists from all over the United States gathered for the first time to discuss in depth the current knowledge on the subject.

Today, the subject is being dealt with at an increasing rate and researchers are testing a wide variety of substances that may prevent cancer. But it has always been a challenge to find the right dose of any promising substance. Indeed, failure to find the right dose of prophylactic agent was disastrous in some of the early human clinical trials. For example, in two large tests for the prevention of lung cancer, there was actually an increase in the incidence of cancer in the group of people who received a high dose of the antioxidant beta-carotene compared to people who received a dummy drug (placebo).

Can dogs speed up progress in cancer prevention research? Recently, studies in dogs have helped define the dose of selenium, an element needed by the body in tiny amounts and considered an antioxidant. Selenium minimizes cancer-causing genetic damage in the aging prostate gland. The lesson learned from the dogs is that when you take food supplements like selenium to reduce the risk of getting cancer, anything that increases them is not necessarily good. In elderly dogs that received a moderate dose of selenium, less DNA damage was found in the cells of the prostate gland than in dogs that received a lower or higher dose. Comparative oncologists believe that studies on dogs conducted before large-scale prevention trials in humans may streamline the process of finding the optimal dose of cancer-preventing agents and allow oncologists to throw a well-aimed hand grenade at the cancerous enemy.

Pet dogs can help prevent cancer in humans in another way. For years, dogs used in laboratory research have increased knowledge about the immediate and long-term effects of high doses of cancer-causing substances. But pet dogs can be used as a means

Monitoring, simply by how they live their lives, and provide us with information about carcinogens in the home and yard. If something is cancerous, the disease will appear in the short-lived pets, long before it appears in humans.

Take asbestos for example. Most human cases of mesothelioma (cancer of the tissues lining the chest and abdomen) result from exposure to asbestos. Symptoms can appear even 30 years after the fatal exposure. Researchers recently discovered that even in pet dogs, mesothelioma is mainly associated with exposure to asbestos, probably because the dogs accompanied their owners when they were exposed to the substance during work or as a hobby. Since in dogs the time between exposure and diagnosis is relatively short, less than eight years, the appearance of cancer in them may alert people to look for and eliminate asbestos sources that still remain. Also, careful monitoring of people who were exposed, and were located thanks to their dogs, may lead to an earlier diagnosis of mesothelioma and allow the cancer to be cured.

Pet dogs may help identify additional environmental hazards. There are some well-documented "hotspots" where there is a high incidence of certain types of cancer. For example, women living in Marin County in California had the highest incidence of breast cancer in the country. Scientists usually try to locate the carcinogens in these foci by comparing the genetics and lifestyle of people who have developed cancer with healthy people. To help in these efforts, comparative oncologists are now establishing pet dog databases in these areas. If both the dogs and the people living in a certain community are prone to cancer, this would strengthen the suspicion that these malignant diseases were caused by an environmental factor.

Canine tissue testing can even help identify the risk factor. Many toxic chemicals, such as pesticides, concentrate in the fatty tissues of the body. So it makes sense to take tissue samples from dogs while they are undergoing some kind of surgery anyway (e.g. neutering) or during a postmortem. Then, if a higher-than-usual number of people in an area develop a certain type of cancer, researchers can test the levels of different chemicals in the samples to see if any stand out and could be considered a possible carcinogen.

Why didn't Uncle Bill get cancer

Because cancer in pet dogs is so common, the animals may be able to help solve an ancient mystery. Almost everyone has some Uncle Bill who smoked two packs a day and never got lung cancer. Which factors therefore affect resistance to cancer? One way to find the answer is to find populations resistant to cancer and carefully study their genetics, diet and lifestyle.

Such a population was indeed found - people aged a hundred years or older. It turns out that most people who live to be 100 years old die of other causes than cancer. But it's nearly impossible to gather reliable information from a 102-year-old woman about her diet and exercise habits when she was a teenager or in her 40s. Because of this, one of us (Waters) asked a simple question: Does this phenomenon of cancer resistance in the extremely elderly also exist in pet dogs? The answer is yes. Comparative oncologists can now interview the owners of elderly dogs and chart accurate life histories of dogs that have reached extreme old age. Combine this ability with the ability to collect biological samples (such as blood for genetic analysis and for activity tests of various organs) from especially old dogs and their offspring for several generations, and you have a unique field laboratory for the analysis of the genetic and environmental factors that confer resistance to cancer.

You can try to solve the mystery of cancer resistance in another way, by comparing the tendency to develop cancer in dogs and in humans. In humans, obesity and consumption of animal fat are known risk factors for colon cancer. In contrast, colon cancer in dogs is not common, even though many pet dogs are obese and eat high-fat foods. Scientists are now considering using dogs as a "negative model" for colon cancer in hopes of identifying factors capable of conferring resistance to cancer in people whose lifestyle encourages the development of the disease. Identifying resistance factors may lead to the development of new ways of treating people who are not resistant to cancer.
Expanding efforts

In the past, research in mammary oncology was conducted in university hospitals and laboratories where veterinary oncologists specialize. But other organizations have begun to recognize the ability of this type of research to contribute to better human care, and these institutes are now conducting studies in comparative oncology.

In 2001, the Gerald P. Murphy Cancer Foundation began to accelerate the discovery of improved methods for the prevention and treatment of prostate and bone cancer in both humans and dogs. The Animal Cancer Foundation of New York has funded research in comparative oncology and recently established a database of biological samples from healthy and diseased animals so that researchers can identify biomarkers that indicate cancer risk. In 2003, the American Cancer Institute developed the Comparative Oncology Program, which designs studies conducted on dogs with naturally occurring cancer and also provides researchers with high-quality canine research chemicals to study the molecular biology, biochemistry and genetics of canine tumors.

Moreover, the sequencing of the dog genome is complete. Researchers will now be able to test whether a gene that is found to be involved in some type of cancer in dogs is also involved in tumors in humans. Scottish Terriers with bladder cancer, Rottweilers with bone cancer and Golden Retrievers with lymphoma, each breed could help in understanding the deadly combination of genes and environment that led to cancer.

Of course, there are limitations to using animals to model human cancer, whether we're talking about rodents, dogs, or other species. There is no single ideal animal model for cancer research. The best science is done by asking good questions and using the most effective research tools to get meaningful answers. Sometimes, this means resorting to dogs to obtain this elusive knowledge.

The intriguing similarity between human and pet canine cancers, once a curiosity, is now helping to turn cancer from a killer to a liveable nuisance. Comparative oncologists do not give dogs cancer, but treat pet dogs suffering from the same deadly cancers that develop naturally in humans and their best friend. They use our canine companions to track down the killer in a way that can save both pets and humans.
 Overview / Cancer in dogs 
Millions of dogs will be diagnosed with cancer this year. In many of them, the tumor will look and behave similarly to human tumors. It will spread, for example, to those organs.

Studying these tumors can help researchers better understand the biology of cancer in humans. Also, experimental treatments in dogs can dictate the most appropriate treatments for follow-up studies in dogs and humans. These treatments can also teach about the dosages and the most effective ways of administering the drugs.

Such studies are expected to improve cancer prevention and treatment in both humans and their canine companions.

 

The ideal model animal: a misconception
Some experts claim that cancer drug discovery has progressed at an infuriatingly slow pace because there are no suitable animal models for human cancer. But the problem may not be with the animals themselves but with the way we use them and what we force them to reveal to us.

The dictionary defines a model as "imitation". Therefore, by definition, an animal model for cancer is not the same as a person with cancer. Rodent models are often produced by injecting cancer cells into the animal or by bombarding it with carcinogens in doses higher than those a human would be exposed to in a lifetime. It is doubtful whether tumors created in this way will accurately simulate the complex process that develops in humans over 20 or 30 years. Naturally occurring cancerous tumors, such as those in pet dogs, provide the opportunity to explore this complexity in a less artificial way. 

But no single animal model is capable of answering all the important questions related to the prevention or treatment of one type of human cancer. Researchers would do well to spend time formulating specific questions and let the questions dictate the choice of the model system. For some of the questions, cell cultures or studies in rodents will be suitable. To answer other questions, researchers will need to study humans. In this sense, clinical trials on humans are a type of animal model research. That is, a defined collection of people is used to represent the human population as a whole.

 

About the authors

David G. Waters
(Waters) and Kathleen Wildasin (Wildasin) are interested in stimulating original thinking about cancer. Waters is a professor of comparative oncology at Purdue University, associate director of the Purdue Center on Aging and the Life Course, and executive director of the Gerald P. Murphy Cancer Foundation in West Lafayette, Indiana. He completed a bachelor's degree and a degree in veterinary medicine at Cornell University, and a doctorate in veterinary surgery at the University of Minnesota. Wildsin is a science and medical reporter in Kentucky.

 

Cancer resistance: lessons from the extreme elderly
The risk of getting most types of cancer, both in dogs and in people, increases significantly with age. Because of this, the belief that cancer is the result of a time-dependent accumulation of genetic damage has taken root. But recent studies of people living to the age of 70 reveal an intriguing paradox: the extremely elderly are much less likely to die of cancer than people who die in their 80s or 10s. Do even extremely elderly dogs show resistance to dying from cancer? To answer this question, my colleagues and I interviewed veterinarians and dog owners to collect the medical history of a large group of Rottweilers living in North America. We found that the probability of dying from cancer within two years increased with age during the adult years, until the dogs reached about 13 years of age, but then the probability decreased. What's more, extremely old dogs (over XNUMX years old) had a much lower chance of dying from cancer compared to dogs with normal lifespans, even though the risk of dying from other causes rose steadily.
These findings raise the fascinating possibility that studies comparing extremely elderly dogs with normal dogs may discover genes that control cancer resistance. After that, it will be possible to see if changes in the gene sequence (polymorphisms) that confer cancer resistance and extreme longevity in dogs also exist in humans who live to extreme old age. If so, scientists will be able to try and understand how the molecular processes controlled by these genes change the resistance to cancer at the tissue level.

The exact nature of cancer resistance in the extremely elderly is still not well defined. Post-mortems of elderly dogs are now being conducted to investigate the issue. These studies are supposed to determine whether resistance to cancer reflects a complete inhibition of biological events that cause cancer, for example by increased DNA repair, or if tumors do form - but they are non-life-threatening types. With a better understanding of the genetic and pathological basis of cancer resistance in the very elderly, scientists will be better able to develop effective treatment methods that will reduce the average person's risk of developing cancer.

 

And more on the subject

Exceptional Longevity in Pet Dogs Is Accompanied by Cancer Resistance and Delayed Onset of Major Diseases. DM Cooley, DL Schlittler, LT Glickman, M. Hayek and DJ Waters in Journal of Gerontology, Vol. 58, no. 12, pages B1078–B1084; 2003.
Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies. CA London et al. in Clinical Cancer Research, Vol. 9, pages 2755–2768; 2003.

Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies. CA London et al. in Clinical Cancer Research, Vol. 9, pages 2755–2768; 2003.

 

Spontaneous and Genetically Engineered Animal Models: Use in Preclinical Cancer Drug Development. K. Hansen and C. Khanna in European Journal of Cancer, Vol. 40, pages 858–880; 2004.

 

The American Cancer Institute's Comparative Oncology Program (including information on canine clinical trials):

http://ccr.cancer.gov/
resources/cop/