Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression

Abstract

BackgroundPulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone.ResultsUsing parallel oligonucleotide array platforms, shared orthologues between species were identified and normalized. The osteosarcoma expression signatures could not distinguish the canine and human diseases by hierarchical clustering. Cross-species target mining identified two genes, interleukin-8 (IL-8) and solute carrier family 1 (glial high affinity glutamate transporter), member 3 (SLC1A3), which were uniformly expressed in dog but not in all pediatric osteosarcoma patient samples. Expression of these genes in an independent population of pediatric osteosarcoma patients was associated with poor outcome (p = 0.020 and p = 0.026, respectively). Validation of IL-8 and SLC1A3 protein expression in pediatric osteosarcoma tissues further supported the potential value of these novel targets. Ongoing evaluation will validate the biological significance of these targets and their associated pathways.ConclusionsCollectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapies.

Screening of diagnostic markers for osteosarcoma

“…The gene expression data GSE16088 were obtained from the Gene Expression Omnibus database (10). A total of 20 samples were examined in the present study, among which 14 patients were diagnosed with osteosarcoma while the 6 normal samples served as negative controls.…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…Breeds considered at high risk of developing canine osteosarcoma tend to be some of larger and giant breeds, including the Rottweiler, Great Pyrenees, mastiff, Dobermann pinscher, Irish wolfhound, Scottish deerhound. Given its frequency in canines, the dog model of naturally occurring osteosarcoma has offered an unparalleled opportunity to understand the genomic origins of osteosarcoma, to learn about the role of metastasis in disease and to pilot new investigational drugs in trials that would otherwise take too long to accrue in humans [12,69]. Several years ago, Scott et al [70] took advantage of the genetic homogeneity in dogs to identify molecular subtypes of osteosarcoma based on genome-wide gene expression profiling in a cohort of high-risk breeds of dogs with osteosarcoma (N ¼ 79).…”

IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells

“…4,5 Despite aggressive treatment including surgery and chemotherapy, little improvement in survival times was achieved in patients with OS over the past 15 years even with significant efforts directed at the incorporation of novel therapeutic approaches. [6][7][8] Although the 5-year survival indeed increased to around 60%, the 5-year survival of OS patients with metastasis was still about 30%. 4,9,10 Thus, OS patients with metastasis presented further worse clinical results, and more effective treatments and/or a more personalized therapy are still needed.…”