Abstract
BackgroundHuman 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.
Highlights
Human angiosarcoma and canine hemangiosarcoma are aggressive malignancies of vascular tissue or vascular forming cells [1,2], and their morphology and pathological progression are virtually indistinct
In a more recent analysis, we identified and characterized a myeloid subpopulation from hemangiosarcoma cell lines that showed the expression of markers associated with bone marrow-derived myeloid progenitors (CD14 and CD115 or the colony stimulating factor 1 receptor, CSF-1R) co-expressed with surface markers associated with endothelial progenitor (CD34 and CD133) and endothelial cell differentiation (CD105, CD146, and αvβ3) [8]
Flow cytometry analysis showed that a small percentage of cells expressed high levels of CSF-1R in each cell line whereas the majority of the cells showed little to no expression (Figure 1)
Summary
Human angiosarcoma and canine hemangiosarcoma are aggressive malignancies of vascular tissue or vascular forming cells [1,2], and their morphology and pathological progression are virtually indistinct. Canine hemangiosarcoma and human angiosarcoma have been classified historically as tumors of malignant endothelium due to their histology and the expression of endothelial cell surface markers [2,5]. Based on the expression of early hematopoietic and endothelial progenitor markers, other studies have challenged this idea, suggesting instead that hemangiosarcomas might arise from bone marrow-derived angioblastic progenitors [6,7,8]. Human angiosarcoma and canine hemangiosarcoma are thought to arise from vascular tissue or vascular forming cells based upon their histological appearance. 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). We further characterized these cells to better understand how their cellular characteristics may impact current therapeutic applications
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