Canine
hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these
tumors may arise instead 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.