Canine hemangiosarcoma is a rapidly progressive disease that is poorly responsive to conventional chemotherapy. Despite numerous attempts to advance treatment options and improve outcomes, drug resistance remains a hurdle to successful therapy. To address this problem, we used recently characterized progenitor cell populations derived from canine hemangiosarcoma cell lines and grown as non-adherent spheres to identify potential drug resistance mechanisms as well as drug-resistant cell populations. Cells from sphere-forming cultures displayed enhanced resistance to chemotherapy drugs, expansion of dye-excluding side populations and altered ATP-binding cassette (ABC) transporter expression. Invasion studies demonstrated variability between cell lines as well as between sphere and monolayer cell populations. Collectively, our results suggest that sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs. Our approach represents a new tool for the study of drug resistance in hemangiosarcoma, which could alter approaches for treating this disease.
Bibliographical noteFunding Information:
This work was partially supported by the Office of the Vice President for Research, University of Minnesota, award #21873 (E. B. D.), a Comparative Medicine Signature Program Pilot Grant through the University of Minnesota College of Veterinary Medicine (E. B. D.), and Morris Animal Foundation D13CA-0062 (E. B. D.). A. M. F. was supported by the DVM/PhD combined degree program of the College of Veterinary Medicine, University of Minnesota, by Morris Animal Foundation pre-doctoral fellowship D09CA-405, in part by funds from the Animal Cancer Care and Research Program, University of Minnesota, and by a doctoral dissertation fellowship from the Graduate School, University of Minnesota. This work also was supported in part by NIH P30 CA77598 utilizing the University Flow Cytometry Resource. Thanks to Jaime F. Modiano and Leslie C. Sharkey for the critical reading of this manuscript.
- ABC transporter
- drug resistance
- side population