Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma.
BACKGROUND
The etiology of hemangiosarcoma remains incompletely understood. Its common occurrence in dogs suggests predisposing factors favor its development in this species. These factors could represent a constellation of heritable characteristics that promote transformation events and/or facilitate the establishment of a microenvironment that is conducive for survival of malignant blood vessel-forming cells. The hypothesis for this study was that characteristic molecular features distinguish hemangiosarcoma from non-malignant endothelial cells, and that such features are informative for the etiology of this disease.


METHODS
We first investigated mutations of VHL and Ras family genes that might drive hemangiosarcoma by sequencing tumor DNA and mRNA (cDNA). Protein expression was examined using immunostaining. Next, we evaluated genome-wide gene expression profiling using the Affymetrix Canine 2.0 platform as a global approach to test the hypothesis. Data were evaluated using routine bioinformatics and validation was done using quantitative real time RT-PCR.


RESULTS
Each of 10 tumor and four non-tumor samples analyzed had wild type sequences for these genes. At the genome wide level, hemangiosarcoma cells clustered separately from non-malignant endothelial cells based on a robust signature that included genes involved in inflammation, angiogenesis, adhesion, invasion, metabolism, cell cycle, signaling, and patterning. This signature did not simply reflect a cancer-associated angiogenic phenotype, as it also distinguished hemangiosarcoma from non-endothelial, moderately to highly angiogenic bone marrow-derived tumors (lymphoma, leukemia, osteosarcoma).


CONCLUSIONS
The data show that inflammation and angiogenesis are important processes in the pathogenesis of vascular tumors, but a definitive ontogeny of the cells that give rise to these tumors remains to be established. The data do not yet distinguish whether functional or ontogenetic plasticity creates this phenotype, although they suggest that cells which give rise to hemangiosarcoma modulate their microenvironment to promote tumor growth and survival. We propose that the frequent occurrence of canine hemangiosarcoma in defined dog breeds, as well as its similarity to homologous tumors in humans, offers unique models to solve the dilemma of stem cell plasticity and whether angiogenic endothelial cells and hematopoietic cells originate from a single cell or from distinct progenitor cells.
Integrated Department of Immunology, University of Colorado, Denver, School of Medicine, Denver, CO, USA.
Beth A
BA
Tamburini
Tzu L
TL
Phang
Susan P
SP
Fosmire
Milcah C
MC
Scott
Susan C
SC
Trapp
Megan M
MM
Duckett
Sally R
SR
Robinson
Jill E
JE
Slansky
Leslie C
LC
Sharkey
Gary R
GR
Cutter
John W
JW
Wojcieszyn
Donald
D
Bellgrau
Robert M
RM
Gemmill
Lawrence E
LE
Hunter
Jaime F
JF
Modiano
D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006394:Hemangiosarcoma / Q000378:metabolism* / Q000662:veterinary; D006801:Humans; D007249:Inflammation; D008297:Male; D009154:Mutation; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D051794:Von Hippel-Lindau Tumor Suppressor Protein; D018631:ras Proteins