UNTERSUCHUNGEN ZUR ONKOGEN-INDUZIERTEN SENESZENZ UND ZUR WACHSTUMSREGULATION VON STAMMZELLPOPULATIONEN AUS NORMALEN SOMATISCHEN GEWEBEN UND TUMOREN

Abstract

Uterine leiomyomas (syn: fibroids ) are the most common tumors of the female genital tract. Up to 77 % of women of reproductive age have leiomyomas (Cramer and Patel, 1990). Regardless of their benign character, leiomyomas are responsible for severe clinical symptoms including infertility and pregnancy loss (Greenberg and Kazamel, 1995). As a consequence leiomyomas are the major cause for hysterectomy in the United States accounting for over 200,000 hysterectomies annually (Walker and Stewart, 2005). Despite their high prevalence there has been little innovation in therapies for leiomyomas over the past years and the treatment options besides surgical removal are still limited. Also, relatively little is known about the pathogenesis of fibroids and the causes of tumor-development are still unknown. The aim of the present thesis was to investigate the mechanisms contributing to the spontaneous growth arrest frequently observed in uterine leiomyomas. The results identify p14Arf and therefore the p53-dependent senescence as a major player in the growth control of fibroids. HMGA2 plays a major role in the development of benign mesenchymal tumors and is associated with self-renewal capacity of stem-cells. In order to understand the HMGA2-p14Arf relationship in the genesis of fibroids a series of experiments on mesenchymal stem cells, the proposed cells of origin of leiomyomas, was performed. Contrary to the expectation that HMGA2 represses p14Arf the results show an activation of p14Arf by HMGA2 that ensures genomic stability in case of oncogenic stress whereas in turn p14Arf can repress HMGA2 via the stabilization of p53 which in turn is able to upregulate several micro RNAs of the let-7 family. The results of the present thesis are in line with the idea that uterine fibroids develop from mesenchymal stem-cells resinding in the myometrium. Due to HMGA2-rearrangements a dormant stem-cell is activated resulting in continuous self-renewal leading to the development of the fibroid. Simultaneously, HMGA2 behaves like a classical oncogene and induces OIS via activation of the p14Arf-MDM2-TP53-pathway ensuring the genomic stability of the fibroid. This pathway keeps fibroids in a delicate balance between growth and senescence. In cell cultures of leiomyomas this balance could be disturbed by MDM2 inhibitors resulting in senescence and apoptosis. Analysis of 52 leiomyomas and 31 matching myometrium samples revealed a significantly higher expression of p14Arf in the tumors than in the matching myometrial tissues. In line with these findings it was possible to show that tissue explants taken from leiomyomas display a higher sensitivity against MDM2-inhibition than those taken from matching myometrium. In summary, the results of the present thesis show that senescence and apoptosis play an important role in the growth control of uterine leiomyomas and offer new opportunities for the treatment of these frequent tumors.