Evaluation of Endothelial Cell-Specific Molecule-1 in Cardiovascular Disease-Associated Tumor Progression in Dogs

Background: Cardiovascular disease (CVD) and cancer are leading causes of mortality in humans and dogs, sharing common risk factors and overlapping pathophysiological mechanisms. Human studies in reverse cardio-oncology suggest that pre-existing CVD may accelerate cancer development and metastasis; however, this relationship remains unexplored in veterinary medicine. Endothelial cell-specific molecule-1 (ESM-1), a circulating proteoglycan associated with endothelial dysfunction in CVD, has been implicated in the growth and metastasis of various human cancers. This study aimed to investigate whether ESM-1 could serve as a potential pathophysiological link between CVD and tumor progression in dogs using in vitro experiments and retrospective clinical analyses. Results: In the retrospective analysis of 105 dogs with malignant tumors, pre-existing CVD was significantly associated with distant metastasis (OR = 3.719, 95% CI = 1.66–8.35, P = 0.001), and underweight body condition also correlated with metastasis. Serum from myxomatous mitral valve disease model dogs produced heterogeneous effects on cancer cell viability and gene expression. Conversely, direct ESM-1 overexpression consistently upregulated the metastatic marker MMP2 across all three canine tumor cell lines and significantly increased the viability of osteosarcoma and kidney sarcoma cells. Conclusions: Our experimental and clinical findings support the emerging concept that pre-existing CVD may potentiate tumor progression, providing the first evidence of reverse cardio-oncology in dogs. Although the current data are insufficient to confirm ESM-1 as a key mediator of this relationship, its overexpression consistently upregulated MMP-2, suggesting a role in metastatic progression. Future prospective studies integrating longitudinal monitoring of serum ESM-1 concentrations and stratification by cancer subtype are warranted to clarify causality and advance understanding of dogs with concurrent CVD and malignancy.