Advances Noted in Research of Hemangiosarcoma and CCL Disorders

Advances in research of hemangio­sarcoma in Golden Retrievers are helping to identify risk factors for the extremely aggressive and highly malignant canine cancer. The findings may one day be used to identify risk factors in other breeds. Additionally, studies looking at the biochemical pathways that control the cancer may shed light on ways to genetically alter these pathways and eliminate the risk of death from the cancer.

Likewise, research of cranial cruciate ligament (CCL) disorders promises early diagnosis in dogs that are not yet lame as well as novel treatment options. Using a biomarker panel, the researchers are able to measure proteins contained in joint fluid that indicate the presence of CCL even before clinical signs occur.

Here is a review of the recent research and treatment advances.

Hemangiosarcoma Susceptibility

Hemangiosarcoma is one of the most baffling cancers for scientists and owners to understand. It usually has metastasized by the time it is discovered. Known as a silent killer, hemangiosarcoma seldom is detected before the tumor ruptures, causing a life-threatening condition.

A recently completed study in Golden Retrievers focused on the relationship between inherited traits and dogs' susceptibility to hemangiosarcoma and lymphoma. The collaborators wanted to learn if there is a link between the two cancers that are common in the breed.

The MADGiC: Making Advanced Discoveries in Golden Cancers study aimed to find genetic makers that predispose dogs to cancer. "Ultimately, our goal was to provide breeders with information to help reduce disease incidence while retaining the positive phenotypes of their breed," says Jaime Modiano, V.M.D., Ph.D., the Perlman Endowed Chair in Animal Oncology at the University of Minnesota College of Veterinary Medicine.

The research team included Modiano, Matthew Breen, Ph.D., C.Biol., FSB, professor of genomics at North Carolina State University College of Veterinary Medicine, and Kerstin Lindblad-Toh, Ph.D., director of vertebrate genome biology at the Broad Institute of MIT and Harvard and professor at Uppsala University in Sweden.

Though the data is being prepared for publication in a scientific journal, the results have been exciting, Breen says. "We found things we didn't realize we would find. This study is testimony to the power of an integrated collaborative approach. While these early data are focused on Goldens, identifying the risk factors in one breed makes it much easier to assess the role of those risk factors in other breeds."

In a new hemangiosarcoma investigation, Modiano is exploring the nature of stem cells, or tumor-initiating cells. Due to stem cells' adaptability to various environments and their resistance to conventional therapies, Modiano believes they are the true instigators of cancers like hemangiosarcoma.

The hope is that these cells can be genetically altered along specific pathways to foil their transformative abilities, he says. "The intent is to use the potential of these cells to become different cell and tissue types and force them down a path that would eliminate the danger of metastasizing or hemorrhaging, which ultimately is the cause of death for most dogs with this cancer."

The biochemical pathways that control hemangiosarcoma also are the focus of research under way in several breeds of dog at the Van Andel Institute in Grand Rapids, Mich. A nonprofit medical research facility, Van Andel studies diseases in dogs that could illuminate human health issues with a goal of developing effective personalized medicine. The hemangio­sarcoma research in dogs may help them learn more about a similar, but rare, cancer in humans, angiosarcoma.

The first results of the research are expected to be published soon. "We look at the biochemical pathways that get turned on in canine tumors so we can better understand how tumors work," explains Nick Duesbery, Ph.D., head of the Laboratory of Cancer and Developmental Cell Biology. "To do this, we collect tumor samples, break them apart in their component cells, grow them in cultures and analyze the pathways that are turned on or off when they are treated with different drugs."

Enlisting Support from Owners & Breeders

Barbara Axel of Pisgah Forest, N.C., has lost two Dachshunds to hemangiosarcoma. She is passionate about helping to advance understanding of the cancer in the breed, which is not listed among those considered at high risk. As the parent club's liaison to the cancer research laboratory of Breen at North Carolina State University, Axel is working to encourage owners and breeders to submit DNA samples from dogs diagnosed with hemangiosarcoma to help advance the research.

In 2010, her red longhaired Standard Dachshund, CH Camp Guthrie Mountain Mist L, TDI, a granddaughter of her first Dachshund that died from hemangio­sarcoma woke up one morning with pale gums and listless behavior. Sensing that something was terribly wrong, Axel took "Mischief" to the emergency veterinary clinic. A radio­graph did not show abnormalities, but blood work indicated internal bleeding. Having experienced the cancer in Mischief's granddam, Axel recognized the signs of hemangiosarcoma.

A biopsy of Mischief's spleen was taken to learn whether the Dachshund had a benign hemangioma or malignant hemangiosarcoma. The veterinarian could not stabilize the dog, and she died in the emergency room. An autopsy showed hemangiosarcoma in the spleen and liver.

"This is how it happens," Axel says. "One day, your dog seems fine, and the next day, it dies. This is what makes hemangiosarcoma so frustrating and tragic."

Though any breed could potentially develop hemangiosarcoma, at-risk breeds include Bernese Mountain Dogs, Boxers, Flat-Coated Retrievers, German Shepherd Dogs, Golden Retrievers, Portuguese Water Dogs, and Sky Terriers. Golden Retrievers are highly affected, with about 20 percent dying from the cancer. Experts estimate about 100 Dachshunds are diagnosed with the cancer each year.

Comprising 5 to 7 percent of all canine cancers, hemangiosarcoma typically originates in the endothelial cells, the thin layer of cells that line the interior surface of blood vessels. The rich blood supply of the blood vessels contributes to the cancer's metastasis throughout the body.

As the cancer cells circulate through the bloodstream, they eventually attach to a primary tumor site. About 50 percent of cases develop in the spleen. Other primary sites are the heart, liver, skin, kidneys, mouth, muscle, bone, brain, and bladder.

"Most cases we see — about 85 percent — are the visceral form of hemangiosarcoma with spleen, liver or heart involvement," Breen says. "Cutaneous and subcutaneous forms that develop on or under the skin make up the other 15 percent."

As the cancer grows, angiogenesis, a normal process in which new blood vessels are generated from existing blood vessels, feeds the cancer through a tortuous network of blood vessels that cause clotting and hemorrhaging. Mini-hemorrhages heal quickly with few signs, but hemorrhaging of a large tumor can be fatal.

When a tumor in the spleen or heart ruptures and bleeds into the abdominal cavity or the pericardial sac, it results in acute weakness, collapse and shock. Dogs often have pale gums. These signs, similar to what Axel noticed in her Dachshund Mischief, are dramatic and usually prompt owners to seek emergency veterinary care. They often are the first obvious sign of a problem.

"We have seen dogs with tumors of several pounds cause no clinical problems, which makes early detection difficult," Breen explains. "It also is a highly metastatic cancer, so by the time a large mass is detected, metastasized tumors are present with devastating consequences."

Without treatment, survival is short, especially if the cancer is in the spleen or other internal organs and the dog has collapsed due to internal hemorrhage. Despite the best standard treatment — surgery and chemotherapy — most dogs do not live more than six months. Surgery is not a cure because the cancer almost always has metastasized by diagnosis. The cancer also resists chemotherapy and spreads quickly and invasively into vital organs.

Since signs of hemangiosarcoma are not apparent until the cancer is in its advanced stages, it is nearly impossible to detect early. The cancer adapts to its microenvironment and mimics the tissues to which it attaches. It does not show up in blood tests until hemorrhaging occurs, and ultrasounds fail to detect fast-growing tumors.

As Modiano says, "As we learn more about this cancer, we realize the more we learn, the less we know."

The Most Common Orthopedic Problem

Active sporting dogs, even well-conditioned ones, are at risk for injuries. The most common orthopedic injury seen by veterinarians are CCL disorders.

One of the main supportive structures of the stifle (knee) joint in a dog's hind limbs, the CCL plays a key role in stabilizing the femur (thighbone) on the tibia (shinbone). Without the normal CCL stabilization, a dog's movement is compromised and painful osteoarthritis develops.

Reluctance to bear weight on the leg, decreased performance and/or signs of pain in the stile are often the first things an owner notices in a dog with a CCL problem. Swelling of the joint, clicking when walking, stiffness after exercise, sitting with the leg extended to the side, and holding the leg up also are common.

"While these signs may be noticed acutely after an incident or injury, they almost always are the result of a slow breakdown of the CCL and thus some degree of arthritis is invariably already present in the joint," explains James L. Cook, D.V.M., Ph.D., DACVS, DACVSMR, director of the Comparative Orthopedic Laboratory at the University of Missouri College of Veterinary Medicine. "Owners who recognize these signs should take their dog to the veterinarian for a complete diagnostic evaluation.

"In the vast majority of dogs, CCL tearing occurs as a developmental disorder, rather than a single injury, and is related to the structure of a dog's stifle joint as well as degenerative changes noted in the CCL during aging. For these reasons, we prefer to refer to this condition as CCL disease rather than a CCL tear or CCL rupture. Unfortunately, at least 60 percent of dogs that develop CCL disease in one hind leg will develop the same problem in their other hind leg within two years."

The high prevalence of bilateral (both stifles) CCL disease in dogs led Cook and his research team to study methods for early diagnosis of CCL disease in dogs that are not yet lame, as well as novel treatment options designed to improve the safety and efficacy of therapeutic interventions. They are completing a clinical trial using a biomarker panel they developed and patented that shows promise for determining which dogs are likely to have CCL disease in the future.

"Using just a few drops of joint fluid from the stifle, we can measure the levels of seven proteins that can indicate the presence of CCL disease prior to clinical signs," Cook explains.

Currently, to diagnose CCL disease, a veterinarian evaluates the way a dog sits and walks, and palpates the stifle for joint instability, known as a cranial drawer test. Radiographs are performed to help verify the diagnosis, assess the severity of arthritis, determine treatment options, and make sure there are no other problems.

Though there is no cure for CCL disease, nonsurgical treatment involving rest, pain-relieving medications and physical rehabilitation can be effective for some dogs. How­ever, surgery to stabilize the stifle results in more consistent functional outcomes, particularly in performance dogs.

Surgical stabilization procedures include TightRope (TR) CCL, lateral suture (LS), tibial plateau leveling osteotomy (TPLO), and tibial tuberosity advancement (TTA). TR and LS are extracapsular stabilization procedures in which a synthetic material is placed attaching the femur to the tibia to mimic the function of the CCL and allow fibrous tissue to form for long-term stability. TPLO and TTA are osteotomy (bone-cutting) procedures designed to alter the anatomy of the stifle so stability is achieved through reorientation of muscle forces.

Each procedure has advantages and disadvantages, and an owner should carefully research which one is best for his or her dog. Costs range widely, from $600 to $6,000, based on the procedure and type of veterinary practice and location. The choice of treatment should be individualized to the dog.

Breeders and Owners Can Contribute to Hemangiosarcoma Research

Breeders and owners whose dogs have been diagnosed with hemangiosarcoma are encouraged to have their veterinarian submit blood and tissue samples to help advance research of this cancer.

Samples can be sent to the laboratory of Matthew Breen, Ph.D., C.Biol., FSB, professor of genomics at North Carolina State University College of Veterinary Medicine, who is coordinating the collection and sharing of DNA samples with other cancer researchers. To learn about the Breen laboratory and research of hemangiosar­coma, go to www.breenlab.org/recruitment.html. Owners should contact the Breen laboratory prior to sending samples via email at info@BreenLab.org.

Hemangiosarcoma samples also can be shipped directly to the Van Andel Institute to support ongoing research. Visit www.vai.org/helpingdogs for instructions for veteri­narians on sample collection and information and consent forms for owners.

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