Despite standard treatments like doxorubicin chemotherapy—which modestly extends median survival to approximately six months with only 10% of dogs surviving beyond one year—clinical outcomes remain poor. Treatment efficacy is likely hindered by disease heterogeneity, varying genetic profiles, and age-related factors, as hemangiosarcoma predominantly affects older dogs (median onset at 10 years). Comorbidities in aging dogs further complicate treatment tolerance, while younger dogs face long-term risks like doxorubicin-induced cardiotoxicity.
Recent studies indicate that propranolol, a beta-adrenergic receptor antagonist, may enhance chemotherapy efficacy in human angiosarcoma by inhibiting tumor growth and modulating immune responses. Given its role in immune suppression—particularly in myeloid-derived suppressor cell expansion and CD8+ T-cell dysfunction—propranolol was investigated as an adjunct to doxorubicin in canine hemangiosarcoma. However, this study found no survival benefit from propranolol. Instead, it revealed a pronounced age disparity: younger dogs exhibited significantly longer survival with doxorubicin alone, suggesting age at diagnosis as a key prognostic factor.
Gene expression analyses uncovered distinct age-related tumor microenvironments. Tumors from younger dogs showed elevated immune activation markers, while older dogs exhibited up-regulated cell cycle and DNA repair genes, particularly G2/M checkpoint transcripts like E2F1—a regulator linked to poor prognosis in multiple cancers. Older dogs also displayed immunosuppressive TME features, including senescent cells secreting proinflammatory cytokines and expressing immune checkpoints (PD-L1, CTLA-4), which dampen cytotoxic T-cell activity. Immunosenescence in aging dogs, marked by thymic atrophy and exhausted memory T cells, likely exacerbates this dysfunction. Conversely, doxorubicin’s immunogenic effects—promoting CD8+ T-cell activation—may explain younger dogs’ superior responses, as their tumors retained stronger immune signatures. Preclinical evidence supports combining DNA repair inhibitors (e.g., PARP inhibitors) with immune checkpoint blockade to target senescent cells and restore immunity, a strategy that warrants exploration in older dogs.
Propranolol’s limited impact may stem from species-specific pharmacokinetics. Unlike humans, dogs metabolize propranolol’s active S(-) enantiomer faster, reducing its systemic availability. Age-related clearance differences further complicate its use, as younger dogs exhibit faster metabolism of active metabolites. While β-AR blockade has shown immune-enhancing potential in young mice, its effects on aged canine immune cells remain unclear. Future studies should assess β-AR expression across age groups and optimize propranolol dosing for immune modulation.
The study’s key limitation was the small cohort of young dogs and the absence of six-year-old subjects, leaving a gap in age-stratified analysis. Larger trials focusing on dogs under seven are needed to validate doxorubicin’s efficacy in younger patients and explore age-related pharmacokinetic differences. Additionally, while gene expression highlighted immune activation in younger dogs, immunohistochemical analyses of T-cell infiltration were inconclusive, possibly due to tumor heterogeneity. Broader sampling methods may improve detection.
This work is the first to delineate age-driven disparities in canine hemangiosarcoma, linking DNA damage responses and immune decline to poorer outcomes in older dogs. It underscores the need for age-tailored therapies: doxorubicin may suffice for younger dogs, while older patients could benefit from combinations targeting DNA repair and immune checkpoints. These findings not only refine hemangiosarcoma management but also advance its utility as a model for studying age-related cancer biology.
