Characterization and cell of origin of prostate carcinoma in the dog

Chen-Li Lai

    Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

    Abstract

    Human and dogs share several similarities in their prostate disorders. The dog has therefore been proposed as a suitable animal model for the study of human prostate diseases. The aim of this thesis was to evaluate the dog as a suitable animal model for human prostate cancer (hPC) by obtaining basic information of spontaneous canine prostate cancers (cPC), validating the cellular origin of canine prostate cancer and comparing the results with the current knowledge of human prostate cancer development. In humans, the transiently proliferating/amplifying (TP/A) type cells of the prostatic acini have been postulated as the cellular origin of PC. In dogs however, the prostatic ductal cells have been hypothesized as the cellular origin of PC. To clarify this issue, we first investigated and described the canine hierarchical system of cell differentiation of the normal prostate epithelium. We then classified the different growth patterns of cPC and characterized the differentiation status of the cPC cells with various differentiation markers by immunohistochemistry. The histopathological classification shows that canine prostate cancer appears to be more aggressive and of a less differentiated type than most common hPC. From the immunohistochemical results we concluded that cPC most likely originates from the basal cells of the collecting ducts. In humans, DNA sequence mutations, expression and regulation changes of the androgen receptor (AR) are among the causes of androgen unresponsiveness. In addition, men with a decreased size of a CAG repeat within the AR gene are more prone to developing PC than others. We therefore investigated the contribution of the androgen receptor to the development of cPC by evaluating AR expression and AR sequence analysis in cPC specimens. We also investigated the influence of a similar canine AR CAG repeat on the incidence of cPC. A predominant cytoplasmic AR staining was found in prostate cancer of both castrated and intact dogs. The cytoplasmic localization was not related to mutations in the DNA binding domain of the AR, which suggests that mechanisms that lead to an impaired androgen –AR signaling or a basal/stem cell like origin may explain the low cytoplasmic AR staining in cPC. Moreover, our study about the CAG repeats of AR gene suggest that short CAG-1 repeats are associated with an increased risk of developing PC in the dog. Many studies report the importance of chronic inflammation as the cause of PC initiation and progression and the expression of the inflammatory mediator COX-2 has been documented in both human and canine prostate cancer. We evaluated whether COX-2 expression in cPC is related to the tumor histology and to the presence of inflammation. Although COX-2 expression was demonstrated in cPC, a potential role for inflammation in the carcinogenesis of cPC could not be proven due to an inverse correlation between inflammation and COX-2 expression. Our results indicate that spontaneous cPC resembles human late stage PC in several, histological and molecular, aspects. Hence, further research using spontaneous canine prostate as a model for its human counterpart may generate beneficial results for both humans and dogs.
    Original languageUndefined/Unknown
    QualificationDoctor of Philosophy
    Awarding Institution
    • Utrecht University
    Supervisors/Advisors
    • van Dijk, J.E., Primary supervisor
    • Teske, Erik, Co-supervisor
    • van den Ham, R., Co-supervisor, External person
    Award date12 Feb 2009
    Publisher
    Print ISBNs978-90-393-5001-0
    Publication statusPublished - 12 Feb 2009

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