Disease Risks Associated with Spay and Neuter: A Breed-Specific, Gender Specific

Posted on by Janet Boyd

This study extends the investigator’s recently completed AKC Canine Health Foundation-funded project studying 12 dog breeds to identify major differences in the degree to which spay or neuter may be related to an increase in joint disorders (hip dysplasia; cranial cruciate ligament tear) and/or cancers (lymphoma; hemangiosarcoma; and mast cell tumor).

The original breeds studied were: Labrador Retriever, Golden Retriever, German Shepherd Dog, Rottweiler, Boxer, Bulldog, Doberman Pinscher, Dachshund, Corgi (both breeds), Chihuahua, Yorkshire Terrier and Shih Tzu. Findings did not associate an increase in disease association in the small breeds with spaying or neutering, while in larger breeds disease risk was dependent upon gender, and whether the spay or neuter procedure was performed before or after one year of age (Hart, B.L., L.A. Hart, A.P. Thigpen and N. H. Willits. 2014. Long-term health effects of neutering dogs: Comparison of Labrador Retrievers and Golden Retrievers. PLoS ONE 9(7): 10.1371/journal.pone.0102241).

In this second phase, the following breeds have been added to the study: Great Dane, Australian Shepherd, Bernese Mountain Dog, Cocker Spaniel, Border Collie, Beagle, St. Bernard, Irish Wolfhound, Jack Russell Terrier, Pug, Maltese, Pomeranian, Miniature Schnauzer, Boston Terrier, Australian Cattle Dog, Shetland Sheepdog, English Springer Spaniel, Cavalier King Charles Spaniel, and West Highland White Terrier. Upon completion of the study, the major publisher, Wiley, has agreed to place the total data set of all 31 breeds on an open access website as a resource for breeders, dogs owners, researchers and veterinarians.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02275

RESEARCHERS

Dr. Benjamin L Hart, DVM, PhD
University of California, Davis
Amount: $3,000 in 2016 with an additional $2,000 in 2017

A Novel Approach for Prevention of Canine Hemangiosarcoma

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Hemangiosarcoma, an aggressive form of cancer in dogs, is the cause of death for one out of every five Golden Retrievers in the United States. Portuguese Water Dogs and Boxers also have an especially high risk for this disease which is devastating for all dogs. Hemangiosarcoma is incurable partly because the cancer is detected at a very advanced stage when it is resistant to conventional therapies. Thus, an unconventional approach to improve outcomes for hemangiosarcoma patients will involve effective methods for early detection and for disease prevention.

This project will pair two novel technologies consisting of a patented test to detect hemangiosarcoma cells in blood samples, and a treatment that attacks the cells that establish and maintain the disease. Three milestones will be met: first, will be to expand understanding of the performance and utility of the blood test for cancer in dogs with active disease; second will be to confirm the utility of the test to predict disease progression in treated dogs; and third, will be to establish the performance of the test in the “early detection” setting (dogs at high risk without evidence of active cancer), and thus measure hemangiosarcoma prevention through eradication of the tumor initiating cells with the targeted, investigational drug.

This project will create tools to guide further development, licensing and deployment of these paired technologies against cancer, specifically hemangiosarcoma, with an ultimate goal for disease prevention in all dogs.

Co-sponsored through the collaborative efforts and generosity of the Golden Retriever Foundation and American Boxer Charitable Foundation. The AKC Canine Health Foundation supports the funding of this effort, and will oversee administration of funds and scientific progress reporting, Grant Number: 02234‐MOU

For details and logistics of this project, to include eligibility criteria and how to enroll, please visit Dr. Modiano’s page for the Shine On project.

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RESEARCHERS

Jaime F. Modiano, VMD, PhD
University of Minnesota
Amount: $432,000
Administrative Amount: $40,000

Health Implications of Early Spay/Neuter on Canine Health

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Most dogs in the United States are spayed or neutered, and the default recommendation has been to perform these elective surgeries prior to physical maturity. However, recent data suggest that early spay and neuter may adversely impact the health and well-being of dogs.

In preliminary studies funded by CHF, Dr. Ben Hart of the UC Davis College of Veterinary Medicine found that early spay or neuter, prior to 12 months of age, was related to a significant increase in risk in five diseases of concern: hip dysplasia; cranial cruciate ligament tear; lymphosarcoma; hemangiosarcoma; and mast cell tumor.

CHF has now funded the second phase of Dr. Hart’s research in which he will expand his work to consider breed differences in vulnerability to joint disorders and risks of various cancers after early or late spay/neuter. Breeds considered will include: Labrador Retrievers, German Shepherd Dogs, and Dachshunds. Rottweilers, Chihuahuas, Standard Poodles, and Miniature Poodles will be included if resources and patient data are available. The expectation is that by inclusion of multiple breeds in phase II Dr. Hart will be able to develop a generalized understanding of the impact of early spay and neuter on disease risk in dogs. This in turn will enable veterinarians and breeders to make data-driven recommendations regarding timing of spay/neuter procedures to reduce the risk of development of multiple devastating diseases.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 1840

Related News

Long-Term Health Effects of Neutering Dogs: Comparison of Labrador Retrievers with Golden Retrievers

RESEARCHERS

Dr. Benjamin L Hart, DVM, PhD
University of California, Davis

Innovations in Prevention, Diagnosis, and Treatment of Cancer

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Lymphoma and hemangiosarcoma are major health problems in Portuguese Water Dogs. This study collaborates with several top universities and researchers who are utilizing cutting edge technology to identify several regions of the genome that contain genetic, heritable, risk factors for lymphoma and hemangiosarcoma in Golden Retrievers. This information can then be applied to other breeds, including Portuguese Water Dogs. Tumor-specific mutations, when identified, can be clinically applied to reduce the incidence of these cancers, identify cancer earlier, and modify treatment plans to the individual patient.

Research Objective

Lymphoma and hemangiosarcoma are major health problems in Golden Retrievers, causing both suffering and premature death. Through ongoing collaboration, Drs. Jaime Modiano, Matthew Breen, and Kerstin Lindblad-Toh have identified several regions of the genome that contain genetic heritable risk factors for lymphoma and hemangiosarcoma in Golden Retrievers. They have tumor-specific mutations that occur recurrently in both cancers, some of which are linked to duration of remission when treated with standard of care. Their results indicate that a few heritable genetic risk factors account for as much as 50% of the risk for these cancers.

These findings offer the potential to develop tests and strategies for DNA tests that can predict risk for individual dogs, as well as to manage risk across the population as a whole. Indeed, both the inherited risk factors and tumor mutations point to pathways that have been implicated in the pathogenesis of lymphoma and hemangiosarcoma, and thus should inform the development of targeted therapies. In the current study, Drs. Modiano, Breen, and Lindblad-Toh will find the precise mutations for the heritable genetic risk factors and to validate markers (mutations) used to determine risk at the heritable loci in a larger independent population of Golden Retrievers from the United States and from Europe in order to develop robust risk prediction tools and an accompanying DNA test. Further, they will identify and characterize tumor mutations and study their relationship to the heritable risk factors, tumor pathogenetic mechanisms, and disease outcome.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 1889-G

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RESEARCHERS

Dr. Jaime F Modiano, VMD PhD
University of Minnesota

Matthew Breen, PhD, CBiol, FSB
North Carolina State University

Testing Strategies to Treat Drug-Resistant Hemangiosarcomas

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Lysosomal Drug Sequestration by CSF-1R (High) Tumor Cells Contributes to Drug Resistance in Canine Hemangiosarcoma

Summary: Investigators are assessing the potential for a specific tumor-cell population in canine hemangiosarcoma to sequester drugs within their lysosomes as a novel mechanism of drug resistance.

Description: Canine hemangiosarcoma is a common and highly metastatic cancer that affects all breeds of dogs. These tumors are particularly drug resistant, which makes them difficult to treat.

The investigators recently identified a more drug-resistant cell population in hemangiosarcoma. These cells appear to be extremely efficient in isolating cancer drugs and preventing them from reaching their targets. The investigators will use several strategies to try to disrupt this process and they will determine whether any of these approaches improves drug responses and diminishes drug resistance. This could lead to more effective treatment of this difficult cancer.

Co-sponsored with the Morris Animal Foundation, Grant Number: D14CA-047

RESEARCHERS

Dr. Erin B. Dickerson
University of Minnesota

Disrupting the Differentiation of Cancer Stem Cells to Prevent the Spread of Hemangiosarcoma

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Hemangiosarcoma is a rapidly fatal disease. The lifetime risk is alarmingly high for some breeds like Golden Retrievers (~20% will die of this disease) and Portuguese Water Dogs (~15% will die of this disease). The risk of hemangiosarcoma is not limited to just these breeds but is considered a research priority for 40 different breed Parent Clubs and Foundations.

Despite considerable efforts to find effective treatments, the outcome for dogs with hemangiosarcoma has changed very little over the past 30 years. Recent evidence suggests hemangiosarcoma conforms to the “cancer stem cell” model, where a defined subset of cells is responsible for initiating and maintaining the tumor. These cells are resistant to conventional therapies and are very adaptable, being able to survive in a variety of tissues in the body.

For this project, Dr. Modiano proposes to reduce the malignant potential of hemangiosarcoma stem cells by forcing them to terminally differentiate into cells which can no longer self-renew. He further proposes that by disrupting their ability to self-renew he will enhance the sensitivity of these cells to conventional and targeted therapies and improve the outcomes of dogs with this disease.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 01759

RESEARCHERS

Jaime F. Modiano, VMD, PhD
University of Minnesota

Assessing How a Protein Helps Hemangiosarcoma Cells Survive

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Canine hemangiosarcoma is a common and highly fatal cancer in dogs. Recent evidence suggests that populations of cancer stem cells give rise to tumors, promote tumor growth and are the main culprits behind drug resistance and disease recurrence.

This study examines how a protein expressed by stem cells contributes to the maintenance and survival of hemangiosarcoma stem cells.

Co-sponsored with the Morris Animal Foundation, Grant Number: D13CA-062

RESEARCHERS

Dr. Erin B. Dickerson, PhD
University of Minnesota

Searching for Ways to Control Hemangiosarcoma Cancer Cells in Dogs

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Hemangiosarcoma is a highly metastatic and incurable cancer that can affect dogs at any age. It is particularly prevalent in certain breeds such as Golden Retrievers, German Shepherds and Portuguese Water Dogs. Unfortunately, hemangiosarcoma is a disease that is poorly understood and for which there are currently no good treatment options.

One of the main reasons why therapies fail may be due to the existence of cancer stem cells. These cells are responsible for initiating and maintaining the cells within the tumor and they are also highly resistant to most chemotherapy. Researchers at University of Minnesota, funded by Morris Animal Foundation, are examining the role of small molecules that may serve as signals in the regeneration of hemangiosarcoma stem cells. Specifically, investigators are evaluating the potential to control the activity of hemangiosarcoma stem cells by altering these molecular signals in a way that stops stem cell regeneration and enhances sensitivity to chemotherapy.

So far, preliminary data show that one signaling pathway under study has distinct effects on the regeneration of hemangiosarcoma cancer stem cells in the lab. This signaling pathway seems to affect the stem cells’ efficiency in forming a sphere as part of the self-renewal process. If this signal can be altered, it may reduce the stem cells’ ability to renew and maintain the tumor. Further research is needed to confirm the results.

This study is providing valuable insight into the properties of cancer stem cells that could help in the development of tests to predict a patient’s outcome and appropriate therapies to treat canine hemangiosarcoma. Funding for this project is also supporting the training of a promising, new canine cancer researcher.

Co-sponsored with the Morris Animal Foundation, Grant Number: D13CA-400

RESEARCHERS

Jong Hyuk Kim, DVM, PhD
University of Minnesota

Genetic Background and the Angiogenic Phenotype in Cancer

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This project will continue the researchers’ observations on gene appearance profiles in hemangiosarcoma from Golden Retrievers to German Shepherd Dogs and Portuguese Water Dogs, and it also will define how new targeted therapies may effectively control the disease in these and other dog breeds.

Results

Certain dog breeds are prone to develop certain types of cancer; yet, there has been little progress to define genes or other factors that account for this risk. Our recent work on hemangiosarcoma was the first to demonstrate that a dog’s genetic background, defined by “breed,” can influence the profile of genes that are expressed by tumors. Among other important implications, this implies that certain breeds are diagnosed with specific cancers more frequently than others because of the behavior of tumors after they arise, and not simply because they arise more frequently. Specifically, this may apply to the observed predisposition for hemangiosarcoma seen in Golden Retrievers, German Shepherd Dogs, and Portuguese Water Dogs. Here, we continued to test this premise by evaluating genome-wide gene expression profiles in samples from dogs of various breeds.

Our results suggest that, while there are subtle differences that are influenced or modulated differently in tumors from dogs of different breeds, these differences may disappear when tumors are considered in their context as “tissues” that include microenvironment constituents. Rather, there appear to be distinct subtypes of hemangiosarcoma (perhaps with different biological behavior and prognosis?), which might arise from different cells of origin, or more likely, which develop in response to adaptation of the hemangiosarcoma cells to environments that show different patterns of inflammation, angiogenesis, coagulation, and hypoxia, each of which alters not only the predominant or favored differentiation of the tumor cells themselves, but also the way they instruct microenvironment cells to create a favorable niche.

This underscores the importance of looking at these tumors in their context as “new tissues” or “new growths” rather than at the cells in isolation as we work to develop more effective strategies for detection, diagnosis, and therapy. To follow on this premise, we evaluated new therapy approaches that target both tumor and microenvironment compartments. Specifically, one such approach also shows efficacy to kill tumor-initiating cells.

Data funded by this project grant and others allowed us to validate the therapy and move it to the clinic. Angiosarcoma Awareness, Inc. provided the initial funds to support a dose finding and efficacy trial where we will treat ~20 dogs with hemangiosarcoma using a bispecific ligand targeted toxin. We completed production of the molecule under “Good Manufacturing Practices” (i.e., suitable for use in human patients) and enrollment is ongoing. Finally, we identified other potential drugs to treat this disease – or perhaps more likely, the pathways they disrupt as potential targets for development of new therapies.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 01131

RESEARCHERS

Jaime F. Modiano, VMD, PhD
University of Minnesota

Mechanistic Relationship of IL-8 in Cell Proliferation and Survival of Canine Hemangiosarcoma

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Characterize the direct effects of IL-8 on HSA cells.

Results

The hypothesis tested in this project was that interleukin-8 (IL-8) promotes growth and survival of hemangiosarcoma cells. This hypothesis was based on our previous results showing significant enrichment of IL-8 gene expression in hemangiosarcoma cells compared to normal endothelial cells isolated from non-malignant hematomas. Here, we confirmed that IL-8 is constitutively expressed by canine hemangiosarcoma cells in laboratory culture, as well as by primary tumors (fresh frozen samples). However, the levels of IL-8 are moderately variable among tumors.

Hemangiosarcoma cells in culture and primary hemangiosarcoma tumors also express IL-8 receptors (IL-8Rs). The receptors are expressed at comparable levels by virtually all the cultured cells and all the tumors, suggesting changes in expression of the receptor are unlikely to contribute to malignant behavior. We also confirmed that IL-8 binds to IL-8 receptors, and this interaction has functional consequences: IL-8 promotes signal transduction (calcium mobilization) in cultured HSA cells, and when we added IL-8 to cultured cells, they were able to “sense” this IL-8 excess and downregulated the expression of their own IL-8 gene. In contrast, if we blocked the interaction of their own secreted IL-8 with the receptor, they increased the amount of IL-8 gene expression. This is a classic response of compensatory regulation to negative feedback. Expression of a gene whose protein product turns on IL-8 gene expression followed the same pattern. It was downregulated when IL-8 was present in excess and induced when IL-8 was prevented from interacting with its receptor.

Despite its biological activity, IL-8 did not promote growth of hemangiosarcoma cells in culture, and IL-8 blockade did not hinder IL-8 growth in culture. When cells were deprived of nutrients and growth factors, they did not compensate by increasing production of IL-8; instead, IL-8 expression was reduced. And the addition of IL-8 did not prevent these nutrient-deprived cells from dying, and neither did it prevent cells treated with chemotherapeutic drugs from dying. Together, the data suggested that IL-8 did not directly mediate growth or survival of hemangiosarcoma cells in culture, refuting the initial hypothesis.

We then compared the gene expression profiles of cells and tumors that expressed high levels of IL-8 (and thus were adapted to growing in an environment rich in IL-8) with those of cells and tumors that expressed lower levels of IL-8 (adapted to growing in environments with relatively scant IL-8). The data show that cells adapted to high IL-8 environments had gene expression profiles indicative of greater inflammation, coagulation, fibrosis, and angiogenesis. These data suggested that IL-8 could be important to modulate the microenvironment and provide a suitable tumor niche. Experiments from an independent, complementary project funded by the National Canine Cancer Foundation showed that indeed, blocking IL-8 hindered the ability of hemangiosarcoma cells to establish a tumor niche in vivo. Finally, preliminary data suggest that IL-8 also may be necessary to maintain the tumor-initiating populations of canine hemangiosarcoma, by enhancing self-renewal. This hypothesis is under investigation in our newly funded project supported by AKC CHF.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 01429

RESEARCHERS

Jaime F. Modiano, VMD, PhD
University of Minnesota