Canine osteosarcoma is a promising animal model for the study of human osteosarcoma

Al-Khan, S 2018, Canine osteosarcoma is a promising animal model for the study of human osteosarcoma, Doctor of Philosophy (PhD), Health and Biomedical Sciences, RMIT University.


Document type: Thesis
Collection: Theses

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Title Canine osteosarcoma is a promising animal model for the study of human osteosarcoma
Author(s) Al-Khan, S
Year 2018
Abstract Osteosarcoma (OS) is the most common malignant primary bone tumour in dogs and humans. OS is an aggressive malignancy that occurs mostly in the appendicular skeleton of both dogs and humans. OS classification is based on its malignant stroma and formation of extracellular matrix into osteoblastic, chondroblastic or fibroblastic OS. The characterisation of an appropriate natural disease animal model to study human OS is essential to elucidate the pathogenesis of the disease. Several studies have established the vital role of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation and remodeling. In addition, these molecules play a role in the progression and metastasis of several human tumour types. Novel prognostic indicators are crucial to determine a better outcome for cancer patients. The current study aimed to validate canine OS as a model for the human disease by immunohistochemically evaluating the expression of markers known to be important in human OS including vimentin, alkaline phosphatase (ALP), desmin, S100, neuron-specific enolase (NSE), runt-related protein 2 (Runx2) and bone morphogenetic protein 4 (BMP4). In addition, the localisation of PTHR1 and PTHrP in canine OS tissues was investigated and their prognostic values were assessed. The correlation between the three histological subtypes of canine OS and a clinical outcome was determined. The study also examined whether there was any difference in the immunostaining of desmin, S100 and NSE among the three histological subtypes. The validation of canine OS as a model for human OS utilised immunostaining of canine OS samples with antibodies specific for vimentin, ALP, desmin, S100, NSE, Runx2 and BMP4 which were compared with those previously described for human OS. Immunohistochemistry was conducted on formalin-fixed, paraffin-embedded (FFPE) tissue sections from 56 dogs (Bristol-56 group) with confirmed primary OS. Vimentin, ALP, Runx2 and BMP4 were highly expressed by all tumours, while desmin, S100, NSE had variable expressions. Before this study, there was no information about the immunostaining of PTHR1 and PTHrP and their prognostic values in canine OS. FFPE tissue samples from 50 dogs (Australian Specialised Animal Pathology laboratory (ASAP)-50 group) diagnosed with primary OS were immunostained with antibodies specific for PTHR1 and PTHrP. The staining intensity of PTHR1 and PTHrP was correlated with survival time. Both PTHR1 and PTHrP were detected in all OS samples (n= 50). Dogs with strongly stained OS tumours for PTHR1 had remarkably shorter survival times (mean survival time= 61 ± 11 days, n= 21 dogs) when compared with those with OS showing moderate (mean survival time= 227 ± 36 days, n= 27 dogs) or weak staining (mean survival time= 580 ± 122 days, n= 2 dogs) (P= 0.000023, log-rank test). Moreover, univariate (P= 0.002) and multivariate (P= 0.002) Cox regression analyses suggested that the staining intensity of PTHR1 was an independent prognostic indicator for overall survival. However, PTHrP staining intensity did not correlate with survival time (P > 0.05). The association between the three histological subtypes of canine OS and clinical outcomes was investigated and the difference in the localisation of desmin, S100 and NSE among these three histological subtypes was examined. Primary canine OS tissue sections from 106 dogs (Bristol-56 and ASAP-50) comprising osteoblastic (n= 61 dogs), chondroblastic (n= 24 dogs) and fibroblastic (n= 21 dogs) were examined. The survival times correlated with OS subtypes (n= 50 dogs). Dogs with chondroblastic OS showed significantly decreased survival times (mean survival time= 104 ± 22 days, n= 11 dogs) in comparison to those with osteoblastic (mean survival time= 168 ± 33 days, n= 33 dogs) or fibroblastic OS (mean survival time= 463 ± 116 days, n= 6 dogs) (P= 0.037, log-rank test). Furthermore, the current study showed that the histological subtypes of OS were an independent prognostic factor for overall survival (Cox regression: univariate, P= 0.037; multivariate, P= 0.030). The study¿s findings also indicated that there was no significant correlation between the localisation of desmin, NSE or S100 and histological subtypes (n= 56 dogs). In conclusion, this project demonstrated that the localisation of vimentin, ALP, desmin, S100, NSE, Runx2 and BMP4 in canine OS were similar to those described previously for human OS and suggested that canine OS may represent a useful model for the study of the disease in humans. More importantly, it was also showed that increased expression of PTHR1 antigen in canine OS is associated with poor prognosis. This suggests that PTHR1 may be useful as a prognostic indicator in canine OS. Dogs with chondroblastic OS also had a poorer prognosis when compared to dogs with other subtypes. This suggests that the histological subtypes of canine OS have differing behaviours and could be used to categorise patients for risk-based assessment. Finally, the localisation of desmin, S100 and NSE were not correlated with the histological subtypes of canine OS.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health and Biomedical Sciences
Subjects Cancer Diagnosis
Veterinary Pathology
Orthopaedics
Pathology
Keyword(s) Osteosarcoma
Dog
Survival time
Subtype
Parathyroid hormone-related protein (PTHrP)
Parathyroid hormone receptor 1 (PTHR1)
Model
Immunohistochemistry
Prognosis
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