Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization

American Journal Of Pathology (Impact Factor: 4.59). 02/2014; 184(4). DOI: 10.1016/j.ajpath.2013.12.025
Source: PubMed


Canine hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these tumors may instead arise from hematopoietic progenitor cells. To clarify this ontogenetic dilemma, we used genome-wide expression profiling of primary hemangiosarcomas and identified three distinct tumor subtypes associated with angiogenesis (group 1), inflammation (group 2), and adipogenesis (group 3). Based on these findings, we hypothesized that a common progenitor may differentiate into the three tumor subtypes observed in our gene profiling experiment. To investigate this possibility, we cultured hemangiosarcoma cell lines under normal and sphere-forming culture conditions to enrich for tumor cell progenitors. Cells from sphere-forming cultures displayed a robust self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the three molecular subtypes seen in primary tumors, including expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and αvβ3 integrin) markers, expression of early hematopoietic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in parallel with increased phagocytic capacity, and acquisition of adipogenic potential. Collectively, these results suggest that canine hemangiosarcomas arise from multipotent progenitors that differentiate into distinct subtypes. Improved understanding of the mechanisms that determine the molecular and phenotypic differentiation of tumor cells in vivo could change paradigms regarding the origin and progression of endothelial sarcomas.

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Available from: Brandi H Gorden, Nov 24, 2015
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    • "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 [6-8]. A similar analogy of progenitor cell origin has been drawn for human angiosarcoma [9]. "
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    No preview · Article · Aug 2014 · Veterinary and Comparative Oncology
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