Golden Labrador Retriever opened mouth on green grass (Photo by Orlando Tapia on Unsplash)
In a nutshell
- Researchers discovered how a specific genetic mutation (PIK3CA) changes the way blood vessel cancers grow and evade the immune system in both dogs and humans, potentially leading to new treatment approaches for both species.
- The study found that cancer cells with this mutation can hijack nearby healthy cells to build blood vessels that feed tumors, while also reprogramming how the cancer cells use energy — insights that could help develop more effective targeted therapies.
- By studying this cancer in dogs, where it occurs much more frequently (50,000 cases annually vs. 1,000 in humans), scientists gained valuable insights that may accelerate the development of treatments for both canine hemangiosarcoma and human angiosarcoma.
GAINESVILLE, Fla. — Scientists studying an aggressive cancer that affects thousands of dogs annually have uncovered a genetic signature that could hold the key to treating an extremely rare human cancer. Their discovery reveals how a single mutation can transform normal blood vessels into malignant ones, while simultaneously hijacking the body’s immune system. It’s a finding that could lead to more effective treatments for both species.
Published in Cancer Gene Therapy, the study led by University of Florida researchers demonstrates how specific genetic mutations strengthen immune system responses in angiosarcoma, an aggressive cancer that affects blood vessels. By examining both human and canine cases, researchers uncovered crucial mechanisms that could help develop more effective treatments for this rare but devastating disease.
For dogs diagnosed with hemangiosarcoma, the outlook is particularly grim. Only 10% survive beyond one year, and none make it past two years. This aggressive cancer grows silently before suddenly rupturing, often leading to life-threatening emergencies. While any breed can develop hemangiosarcoma, older golden retrievers face an especially high risk.
Scientists from UF’s College of Veterinary Medicine and the UF Health Cancer Center investigated how mutations in a gene called PIK3CA impact the development and progression of angiosarcoma. This rare cancer, which affects approximately 1,000 Americans annually, forms when the cells lining blood vessels become malignant, creating irregular and leaky vessels that often lead to severe bleeding.
Making matters more complex, researchers discovered that hemangiosarcoma doesn’t simply create its own blood vessels, it actively hijacks nearby healthy cells, forcing them to assist in building the blood vessel network that feeds the tumor. Even more significantly, specific mutations in the PIK3CA gene cause cancer cells to emit signals that confuse the body’s immune system.
Using sophisticated genetic engineering techniques, researchers created specialized cell lines carrying specific PIK3CA mutations commonly found in both human and canine patients. These mutations occur in approximately 20% of human cases and 30% of canine cases, making them significant targets for investigation.
“The best four-legged friends of humans help us do high-quality cancer research,” said Jon Kim, D.V.M., Ph.D., an assistant professor at the college and the study’s lead researcher, in a statement. “We learn a lot about human cancer biology from studying cancer in dogs.”
In laboratory experiments, the research team discovered that hemangiosarcoma cells possess a unique ability to stimulate blood cell production. This process could influence the generation of “cancer-friendly” immune cells, effectively confusing the body’s immune system and enabling cancer growth. The team’s work demonstrates that this process can be driven by the mutant PIK3CA gene, suggesting new therapeutic possibilities.
Specifically, cells with mutated PIK3CA genes developed distinct molecular signatures that enhanced immune system signaling. These mutations triggered increased production of several important immune system proteins, including interleukin-6 (IL-6), interleukin-8 (IL-8), and MCP-1. Think of these proteins as cellular “emergency flares” that summon immune system reinforcements.
Moreover, researchers found that these mutations reprogrammed how cancer cells process energy. Some mutated cells became more dependent on glucose for energy (similar to how a car might prefer high-octane fuel), while others developed enhanced mitochondrial respiration (like having a more efficient engine).
While scientists have known about PIK3CA mutations in human cancers for years, they haven’t fully understood how these mutations affect cancer growth and treatment response. “This new research provides us with critical insights that could lead to novel therapies for both canine hemangiosarcoma patients with this mutation and human patients with angiosarcoma,” Kim explained.
Perhaps most importantly, the study identified potential weaknesses in how these mutated cancer cells respond to a specific drug called alpelisib, which targets the PIK3CA protein. While some cancer cells showed sensitivity to the drug, others demonstrated resistance through various molecular mechanisms, particularly through a pathway called MAPK signaling.
Understanding these resistance mechanisms is crucial because alpelisib is already FDA-approved for treating certain types of breast cancer with PIK3CA mutations. This research suggests that combining alpelisib with drugs targeting the MAPK pathway might provide better treatment outcomes for angiosarcoma patients.
While human angiosarcoma’s rarity has historically hindered research efforts, making it difficult to gather enough data for meaningful clinical trials, the high incidence of hemangiosarcoma in dogs provides researchers with an invaluable natural model for study. “We see a lot of dogs with hemangiosarcoma in veterinary clinics,” Kim noted. “We hope our work will be beneficial, not only for sick dogs, but also for human patients with this terrible disease.”
Paper Summary
Methodology
The research team employed CRISPR/Cas9 gene editing technology to create cells with specific PIK3CA mutations. This sophisticated approach allowed them to study exactly how these mutations affect cancer cell behavior. They then analyzed these cells using multiple advanced techniques, including RNA sequencing to examine gene activity, metabolomics profiling to study cellular energy use, and various cellular assays to understand cell behavior. The team also conducted extensive drug treatment experiments to understand how the mutations affected treatment responses.
Results
The study revealed several significant findings. First, mutated cells showed increased production of immune signaling molecules, suggesting they can influence the immune system’s behavior. Second, these cells displayed altered energy metabolism patterns, demonstrating how the mutation changes basic cellular functions. Third, researchers identified specific cell populations that were resistant to drug treatment, providing valuable insights into potential treatment strategies. Perhaps most importantly, they discovered that hemangiosarcoma cells can actually hijack nearby healthy cells to help build blood vessels that feed the tumor.
Limitations
While comprehensive, the study primarily used cell lines and animal models. Additional research in human patients would be needed to confirm these findings’ clinical relevance. The sample size for some experiments was also relatively small. Additionally, while the canine model provides valuable insights, there may be some differences in how the disease behaves in humans versus dogs that require further investigation.
Discussion and Takeaways
This research demonstrates how PIK3CA mutations influence both immune responses and metabolism in angiosarcoma, suggesting potential new combination treatment strategies. The findings may also have implications for other cancers with similar mutations. Most significantly, the discovery of how cancer cells can recruit healthy cells to assist in blood vessel formation opens new avenues for therapeutic intervention. The research team’s innovative approach to studying this rare cancer in dogs as a model for human disease could accelerate the development of effective treatments for both species.
Funding and Disclosures
The research was supported by multiple grants, including funding from the Department of Defense Peer Reviewed Cancer Research Program, the AKC Canine Health Foundation, and the Morris Animal Foundation. No competing interests were declared by the authors.
Publication Information
Published in Cancer Gene Therapy (2024), this study represents one of two pioneering publications from the research team at the University of Florida College of Veterinary Medicine and the UF Health Cancer Center, along with their collaborators at other institutions. The paper is titled “PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers.” This research builds upon previous work by the team and represents a significant step forward in understanding how this aggressive cancer develops and responds to treatment in both species.
