title: Lysosomal drug sequestration as a mechanism of drug resistance in vascular sarcoma cells marked by high CSF-1R expression.
abstract: BACKGROUND
  Human angiosarcoma and canine hemangiosarcoma are thought to arise from vascular tissue or vascular forming cells based upon their histological appearance. However, recent evidence indicates a hematopoietic or angioblastic cell of origin for these tumors. In support of this idea, we previously identified an endothelial-myeloid progenitor cell population with high expression of endothelial cell markers and the myeloid cell marker, colony stimulating factor 1 receptor (CSF-1R). Here, we further characterized these cells to better understand how their cellular characteristics may impact current therapeutic applications.
  
  
  METHODS
  We performed cell enrichment studies from canine hemangiosarcoma and human angiosarcoma cell lines to generate cell populations with high or low CSF-1R expression. We then utilized flow cytometry, side population and cell viability assays, and fluorescence based approaches to elucidate drug resistance mechanisms and to determine the expression of hematopoietic and endothelial progenitor cell markers.
  
  
  RESULTS
  We demonstrated that cells with high CSF-1R expression enriched from hemangiosarcoma and angiosarcoma cell lines are more drug resistant than cells with little or no CSF-1R expression. We determined that the increased drug resistance may be due to increased ABC transporter expression in hemangiosarcoma and increased drug sequestration within cellular lysosomes in both hemangiosarcoma and angiosarcoma.
  
  
  CONCLUSIONS
  We identified drug sequestration within cellular lysosomes as a shared drug resistance mechanism in human and canine vascular sarcomas marked by high CSF-1R expression. Taken together, our results demonstrate that studies in highly prevalent canine hemangiosarcoma may be especially relevant to understanding and addressing drug resistance mechanisms in both the canine and human forms of this disease.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Avenue, Saint Paul, MN 55108, USA.
authors.forename: Brandi H
authors.initials: BH
authors.lastname: Gorden
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Avenue, Saint Paul, MN 55108, USA.
authors.forename: Jhuma
authors.initials: J
authors.lastname: Saha
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Avenue, Saint Paul, MN 55108, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Khammanivong
authors.affiliation: Laboratory of New Drug Development, Department of Medicine, Columbia University Medical Center, New York, NY, USA ; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Avenue, Saint Paul, MN 55108, USA ; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Dickerson
keywords: Angiosarcoma; CSF-1R; Chemoresistance; Endothelial; Hemangiosarcoma; Lysosome; Myeloid