Abstract 672: Prognostic significance of urokinase plasminogen activator system in a naturally occurring model of osteosarcoma

Abstract

Abstract Introduction Human pediatric and canine osteosarcoma (OSA) are both highly metastatic primary bone cancers that share molecular and clinical similarities. Urokinase plasminogen activator (uPA) and its receptor uPAR promote invasion, metastasis and angiogenesis in multiple cancer types and have been shown to play critical roles in malignant characteristics of OSA in vitro, yet their clinical significance has not been investigated in OSA patients. Methods Serum samples of dogs with naturally-occurring appendicular OSA (n=26) and clinically healthy dogs (n=6) were analyzed using commercially available canine-specific ELISA and uPA activity kits. Dogs with OSA that presented without metastatic disease at diagnosis and received treatment with amputation plus adjuvant carboplatin chemotherapy were included. Survival data and patient characteristics were obtained from medical records. Differences in serum uPA/uPAR results between the groups was tested by t test or Wilcoxan rank sum test. Kaplan Meier survival curve and log rank test were used for survival analysis in the OSA cohort after subgrouping by X-Tyle software. Well-established prognostic factors and serum uPA/uPAR results were tested for prognostic significance by cox regression analysis in both univariate and multivariate analyses. Results Dogs with OSA had significantly higher serum uPA (p=0.008; 1905.4 vs 1439.5 pg/mL) but not uPAR (p=0.866) levels compared to healthy dogs. OSA-bearing dogs with high serum uPA had significantly shorter progression-free (p=0.003; 94 vs 266 days) and overall survival (p=0.01; 123 vs 338 days) than dogs with low uPA level. Similarly, dogs with high serum uPA activity had significantly shorter progression-free survival (p=0.043; 227 vs 266 days). Serum uPAR was not prognostic in this cohort. Multivariate analysis revealed increased serum uPA level (p=0.024) as a poor prognostic indicator in addition to other established prognostic factors in dogs such as humeral location (p=0.022) and increased monocyte count (p=0.015). Conclusions Circulating uPA quantity and activity are increased in canine OSA patients with more aggressive disease, indicating importance of the uPA system in OSA disease progression. While an OSA-associated increase in circulating uPAR was not evident, this receptor likely contributes to OSA malignancy subsequent to the increased uPA ligand production. Serum uPA may be an attractive prognostic biomarker in OSA and the up-regulated uPA/uPAR axis should be further investigated as a potential therapeutic target for this disease. Citation Format: Arata Matsuyama, Anthony J. Mutsaers. Prognostic significance of urokinase plasminogen activator system in a naturally occurring model of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 672.