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Published on: November 18, 2016
Identification of drug-resistant subpopulations in canine hemangiosarcoma
A Khammanivong1, B H Gorden1, A M Frantz1
1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.
Abstract:
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.
Insights
Canine hemangiosarcoma exhibits drug resistance due to unique cell populations identified in sphere cultures. These cells show enhanced chemotherapy resistance and altered transporter expression, offering new therapeutic targets.
Area of Science:
- Veterinary Oncology
- Cancer Cell Biology
- Drug Resistance Mechanisms
Background:
- Canine hemangiosarcoma is aggressive and poorly responsive to chemotherapy.
- Drug resistance is a significant obstacle in treating this canine cancer.
- Novel strategies are needed to overcome therapeutic limitations.
Purpose of the Study:
- To investigate drug resistance mechanisms in canine hemangiosarcoma.
- To identify drug-resistant cell populations using progenitor cell-derived spheres.
- To explore the role of ATP-binding cassette (ABC) transporters in resistance.
Main Methods:
- Utilized progenitor cell populations from canine hemangiosarcoma cell lines.
- Cultured cells as non-adherent spheres to mimic tumor microenvironment.
- Assessed chemotherapy drug resistance, side population expansion, and ABC transporter expression.
- Conducted invasion studies on sphere and monolayer cell populations.
Main Results:
- Sphere-forming cells demonstrated enhanced resistance to chemotherapy drugs.
- Increased populations of dye-excluding side cells were observed in spheres.
- Altered expression of ATP-binding cassette (ABC) transporters was noted.
- Invasion capabilities varied between cell lines and culture types.
Conclusions:
- Sphere cell populations harbor distinct drug-resistant subpopulations.
- Multiple mechanisms, including ABC transporter alterations, contribute to drug evasion.
- This sphere culture model provides a novel tool for studying hemangiosarcoma drug resistance.
- Findings may inform new therapeutic approaches for canine hemangiosarcoma.
