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• W33133512 abstract "Devil facial tumour disease (DFTD) is a transmissible cancer that threatens the survivalof the Tasmanian devil (Sarcophilus harrisii), the world’s largest living carnivorousmarsupial. Despite devils having a competent immune system, there is no evidence ofnatural immunity to the tumours. Affected animals die within months of tumourappearance. The species could face extinction within 25 to 35 years. Cytogenetic andmolecular studies have confirmed that the infectious agent is the cancer cell itself.However, our knowledge about the nature and biology of this tumour is limited.Tumour transcriptome analyses of DFTD tumours and devil tissues revealed that DFTDexpresses a set of genes related to the myelination pathway in the peripheral nervoussystem. This thesis examined the protein expression of peripheral nerve and otherneuronal markers in DFTD to further elucidate the nature of the tumour. It alsoevaluated the utility of neuronal and peripheral nerve proteins as diagnostic markers forthe disease. Immunohistochemistry and flow cytometry confirmed that DFTD tumourcells express a number of proteins found throughout the neuronal system. Notably,DFTD tumour cells expressed structural proteins found in myelinating Schwann cells inthe peripheral nervous system. These included peripheral myelin protein 22 (PMP22),myelin protein zero (MPZ), myelin basic protein (MBP), and the recently describedperiaxin (PRX). Nerve growth factor receptor (NGFR), which is involved in thedifferentiation of Schwann cells, was also detected in DFTD tumour cells. These resultscoupled with the available genetic data confirm that DFTD cells are of Schwann cellorigin.Furthermore, this study showed that periaxin, a specific marker of Schwann cells, isconsistently expressed in DFTD primary tumours, DFTD metastases, DFTD cell linesand murine xenografted DFTD tumours. Therefore, this thesis identified periaxin as asensitive and specific marker for DFTD. This will greatly facilitate the diagnosis of thedisease.How DFTD can be transplanted across major histocompatibility (MHC) barriers is anaspect of DFTD that is not understood. Initially this was attributed to the reduced diversity at the major histocompatibility complex (MHC) loci. However, recent studiesshowed that the limited MHC diversity in devils is sufficient to produce measurablemixed lymphocyte reactions and the rejection of skin allografts. Thus, this thesisinvestigated the expression of MHC to determine if this may explain the lack ofimmune response to DFTD cells.Analysis of the expression of MHC proteins in devils has been hindered by the lack ofcross-reacting reagents. During the course of this study collaborators from theUniversity of Cambridge (UK) developed the first anti-devil MHC class I (MHC-I)antibody. This antibody was used to examine the expression of MHC-I in devil tissuesand DFTD. MHC-I protein expression in primary tumours and metastases was lowerthan normal tissues. Its expression was also variable within a tumour and amongdifferent tumours. These results suggest that alteration of MHC-I expression couldcontribute to the immune escape of DFTD.Immunisation trials with non-viable DFTD cell lines revealed that some Tasmaniandevils can produce antibodies against DFTD cells. This thesis utilised animmunoproteomic approach to identify immunogenic proteins in DFTD. Severalcandidates were identified as DFTD tumour associated antigens. These include heatshock proteins, tubulin, histone H2B, stathmin protein, and proliferating cell nuclearantigen (PCNA). These proteins are excellent targets for the development of earlydiagnostic tools as well as therapeutic approaches.In summary, this thesis provided strong supporting evidence for a Schwann cell originof DFTD and generated a specific diagnostic marker for the disease. Additionally, thisthesis opened new opportunities for the understanding of the mechanisms that allowimmune evasion and the interaction between the tumour cells and the devil’s immunesystem. These results will have direct implications for the future development of avaccine approach." @default.
• W33133512 created "2016-06-24" @default.
• W33133512 creator A5058095833 @default.
• W33133512 date "2012-01-01" @default.
• W33133512 modified "2023-09-27" @default.
• W33133512 title "Insights into the nature and immune escape of a transmissible cancer in Tasmanian devils" @default.
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