Gene Expression Profiling of Histiocytic Sarcomas in a Canine Model: The Predisposed Flatcoated Retriever Dog

Abstract

BackgroundThe determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed.MethodsMicroarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses.ResultsQPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process.ConclusionsThis study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human.

Reduced angiogenic gene expression in morbillivirus‐triggered oncolysis in a translational model for histiocytic sarcoma

“…The biological behaviour of HS and the underlying molecular mechanisms have been subject to detailed research infrequently, and an ideal treatment scheme is still lacking . Resembling the human counterpart in many aspects, the relatively higher prevalence of HS in dogs emphasizes the dog as an interesting translational animal model . Similar to human beings, canine histiocytic sarcoma may occur as a localized and a disseminated form .…”

Genomic and proteomic profiling for cancer diagnosis in dogs

“…As well as distinguishing between different types of soft tissue sarcoma, genomic profiling can assist subclassification within sarcoma types. Microarray analysis of 15 Histiocytic sarcomas in the Flatcoated retriever identified nine genes that separated tumour from normal spleen (five downregulated; four upregulated) (Boerkamp et al, 2013) but also identified further genes that were differentially expressed between the two clinical presentations of the disease: the soft tissue form affecting limb muscles and joints and the visceral form affecting internal organs with widespread dissemination (Boerkamp et al, 2014). qRT-PCR confirmed the differential expression of three genes: C6 upregulated and VLEC12A and CCL5 downregulated in the visceral compared to the soft tissue form.…”

The Two Main Forms of Histiocytic Sarcoma in the Predisposed Flatcoated Retriever Dog Display Variation in Gene Expression

“…Our previous research of HS in Flatcoated retrievers has provided evidence that the expression of nine common genes is altered when comparing both STHS and VHS with normal spleen; indicating a common ground for the general development of HS [15]. As a next step we compared the two forms of HS with one another.…”