Vergleichende Tumorgenetik: Der Hund (Canis familiaris) als Modelltier für die humane Tumorgenese

Abstract

Animal models have been used in cancer research for a long time. Due to the similari-ties of human and canine cancer the dog has gained importance as the animal of choice for therapeutic and preclinical studies. Dogs and humans are exposed to comparable life- and environmental conditions. Tumours in dogs occur spontaneously and show similar biological behaviour and pathohistological findings. However, by using the the dog as an animal model it is easier to observe large quantities of tumours in less time, because of the faster progression of the tumours and the larger numbers of descendants compared to their human counterparts. Even cancer progression as well as effectiveness of the therapy of choice can be more easily observed.This thesis is addressed to different aspects of canine tumour development and is divided into five sections: Cytogenetic investigations in canine neoplasias, physical mapping of different tumour-associated genes in the canine genome, establishment of a tissue bank, HMGA2 expression in different canine prostatic tissues and cell culture, as well as the development of new therapeutic approaches using adeno-associated viruses.Cytogenetic investigation of canine neoplasias showed clonal aberrations like trisomies or centric fusions of canine chromosomes. The latter is rarely seen in man, while it is a frequent event in canine tumourigenesis. The frequent appearance of ab-errations (numeric as well as structural) affecting the canine chromosome 13 is of no-table interest, as CFA13, which shares homology with human chromosome 8, seems to contain important genes associated with the development of cancer. Knowledge about localisation and structure of several tumour-associated genes is precondition for better understanding of the function of these genes. This again is ba-sic requirement for the development of new therapeutic approaches. Herein a subset of six selected tumour associated genes have been physically mapped by fluores-cence in situ hybridization. By using tissue samples of the newly established tissue bank for tumours and non neoplastic tissues, some of these genes were further inves-tigated with respect to cDNA-structure, partial DNA-structure and protein-expression.Special attention was called on HMGA2 Expression in canine prostatic tissues. To elucidate the question if HMGA2 proteins are overexpressed in canine prostate carci-nomas, four non-neoplastic tissues of the canine prostate, three prostatic cysts, three canine prostatic hyperplasias and six canine carcinomas of the prostate as well as cells of the newly established prostate carcinoma cell-line were examined by quantita-tive real time PCR in respect to HMGA2 expression. Those investigations clearly showed a correlation between pathohistological findings and HMGA2 expression. Furthermore, adeno-associated viruses were generated, carrying HMGA1 and HMGA2 in antisense orientation. The infection of cells of the spontaneously immortal-ized cell-line CT1258 with those viruses lead to a statistically significant reduction of cell growth and viabilitiy, whereas the infection of cells with viruses carrying LacZ or no insert at all did not show any statistically significant reduction of cell growth. This antisense strategy for suppression of HMGA2 expression seems to be an effective target for the treatment of both, canine and human prostate carcinoma as well as any other tumour showing overexpression of HMGA2. Due to the fact of the very low or even absent expression of HMGA2 in adult organisms, very little side effects are to be expected.