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Background <p>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.</p> Results <p>In the retrospective case-control analysis of 105 dogs with malignant tumors, we evaluated potential risk factors for distant metastasis, including pre-existing CVD and relevant clinical covariates. Pre-existing CVD was significantly associated with distant metastasis (OR = 3.719, 95% CI = 1.66–8.35, <i>P</i> = 0.001), and this association remained significant after adjustment for body condition score (adjusted OR = 3.595, 95% CI = 1.50–8.62, <i>P</i> = 0.004). In vitro, assays applying serum from myxomatous mitral valve disease model dogs and direct ESM-1 overexpression in three canine tumor cell lines were used to evaluate metastasis- and proliferation-related mRNA expression and cell viability. MMVD-derived serum produced heterogeneous effects on cancer cell viability and mRNA expression, whereas 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.</p> Conclusions <p>Our experimental and clinical findings support the emerging concept that pre-existing CVD may potentiate tumor progression, providing initial evidence of reverse cardio-oncology in dogs. Although the heterogeneous responses in the serum-treatment model suggest that circulating factors are multifactorial and insufficient to confirm ESM-1 as the sole key mediator of this relationship, its direct overexpression consistently upregulated MMP-2, suggesting its intrinsic potential to facilicate 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.</p>

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Evaluation of endothelial cell-specific molecule-1 in cardiovascular disease-associated tumor progression in dogs

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Seongsoo Lim,
  • Kyeong-Hyeon Eom,
  • Soo-Young Yum,
  • Cheyoun Kim,
  • Beomkwan Namgoong,
  • Seunghun Heo,
  • Jihwan Kang,
  • Hayoung Shin,
  • Goo Jang,
  • Min-Su Kim

摘要

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 case-control analysis of 105 dogs with malignant tumors, we evaluated potential risk factors for distant metastasis, including pre-existing CVD and relevant clinical covariates. Pre-existing CVD was significantly associated with distant metastasis (OR = 3.719, 95% CI = 1.66–8.35, P = 0.001), and this association remained significant after adjustment for body condition score (adjusted OR = 3.595, 95% CI = 1.50–8.62, P = 0.004). In vitro, assays applying serum from myxomatous mitral valve disease model dogs and direct ESM-1 overexpression in three canine tumor cell lines were used to evaluate metastasis- and proliferation-related mRNA expression and cell viability. MMVD-derived serum produced heterogeneous effects on cancer cell viability and mRNA expression, whereas 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 initial evidence of reverse cardio-oncology in dogs. Although the heterogeneous responses in the serum-treatment model suggest that circulating factors are multifactorial and insufficient to confirm ESM-1 as the sole key mediator of this relationship, its direct overexpression consistently upregulated MMP-2, suggesting its intrinsic potential to facilicate 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.