Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization

Brandi H. Gorden, Jong Hyuk Kim, Aaron L. Sarver, Aric M. Frantz, Matthew Breen, Kerstin Lindblad-Toh, Timothy D. O'Brien, Leslie C. Sharkey, Jaime F. Modiano, Erin B. Dickerson

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Abstract

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 α v β 3 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.

Original languageEnglish (US)
Pages (from-to)985-995
Number of pages11
JournalAmerican Journal of Pathology
Volume184
Issue number4
DOIs
StatePublished - Jan 1 2014

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Hemangiosarcoma
Gene Expression Profiling
Canidae
Stem Cells
Neoplasms
Adipogenesis
Differentiation Antigens
Hematopoietic Stem Cells
Integrins
Sarcoma
Cell Differentiation
Cultured Cells
Endothelial Cells
Genome
Inflammation
Cell Line
Genes

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Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization. / Gorden, Brandi H.; Kim, Jong Hyuk; Sarver, Aaron L.; Frantz, Aric M.; Breen, Matthew; Lindblad-Toh, Kerstin; O'Brien, Timothy D.; Sharkey, Leslie C.; Modiano, Jaime F.; Dickerson, Erin B.

In: American Journal of Pathology, Vol. 184, No. 4, 01.01.2014, p. 985-995.

Research output: Contribution to journalArticle

Gorden, Brandi H. ; Kim, Jong Hyuk ; Sarver, Aaron L. ; Frantz, Aric M. ; Breen, Matthew ; Lindblad-Toh, Kerstin ; O'Brien, Timothy D. ; Sharkey, Leslie C. ; Modiano, Jaime F. ; Dickerson, Erin B. / Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization. In: American Journal of Pathology. 2014 ; Vol. 184, No. 4. pp. 985-995.
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