Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times.
BACKGROUND
Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS.


RESULTS
The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans.


CONCLUSIONS
A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression.
Selvarajah
Gayathri T
GT
Department of Clinical Sciences of Companion Animals, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands. G.T.Selvarajah@uu.nl.
Kirpensteijn
Jolle
J
van Wolferen
Monique E
ME
Rao
Nagesha A S
NA
Fieten
Hille
H
Mol
Jan A
JA
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors