Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma
1 Integrated Department of Immunology, University of Colorado, Denver, School of Medicine (UCD SOM), Denver, CO, USA
2 Department of Medicine, UCD SOM, Aurora, CO, USA
3 University of Colorado Cancer Center, Aurora, CO, USA
4 Department of Veterinary Clinical Sciences, University of Minnesota College of Veterinary Medicine, St. Paul, MN, USA
5 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
6 Department of Pharmacology, UCD SOM, Aurora, CO, USA
7 Department of Veterinary Population Medicine, University of Minnesota College of Veterinary Medicine, St. Paul, MN, USA
8 Department of Biostatistics, University of Alabama, Birmingham, Birmingham, AL, USA
9 IHC Services, Smithville, TX, USA
10 Department of Pediatrics, UCD SOM, Aurora, CO, 80045, USA
11 Array BioPharma, CO 80301, USA
12 Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
BMC Cancer 2010, 10:619 doi:10.1186/1471-2407-10-619Published: 9 November 2010
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.
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.
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).
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.