Abstract
Because uterine endometrial carcinoma is the most common malignancy of the female genital tract and 1 of every 5 patients dies of this disease, understanding the mechanisms of carcinogenesis and progression of endometrial carcinoma is important. In general, this thesis can be summarized as a study of the role of
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cell-cycle proteins and the HIF-1a pathway in progression from normal endometrium to endometrioid endometrial carcinoma. Hypoxia-inducible factor 1a (HIF-1a) plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. HIF-1a and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1a in endometrial carcinogenesis. Besides hypoxia induced perinecrotic expression, HIF-1a may be regulated by several other factors leading to a more diffuse expression pattern that is often seen in endometrial carcinomas. We evaluated several proteins for their putative role in diffuse HIF-1a expression in endometrial carcinoma. Loss of expression of prolyl hydroxylases may be related to diffuse, non-hypoxia related expression of HIF-1a in endometrial cancer. In previous studies a C1772>T transition leading to Pro582>Ser substitution in the oxygen-dependent degradation domain (ODDD) of HIF-1a, has been associated with unfavourable clinicopathological features in different types of cancer. The aim of one of the studies was to search for mutations in the ODDD of the HIF-1a gene in endometrioid endometrial cancer, and to associate these with clinicopathologic characteristics. In summary, the P582>S genotype variation in the ODDD of HIF-1a occurs at relatively normal frequency in our study and can occur as a de novo somatically acquired mutation in endometrial cancer. The P582>S genotype does not increase risk for endometrioid endometrial cancer, however, this genotype is significantly associated with a higher MVD and AKT activity. Derailments of the control mechanisms of the cell cycle can initiate carcinogenesis, and play a role in progression to cancer. During (endometrioid) endometrial carcinogenesis, there is increasing proliferation paralleled by progressive derailment of cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, and cdk2, indicating the importance of these cell cycle regulators in endometrial carcinogenesis. Furthermore, we explored whether expression of proliferation and hypoxia-related proteins differs in the central parts and the invasive front in endometrial carcinomas. Endometrial carcinomas clearly show an invasive front that is characterized by higher proliferation and progressive derailment of the cell cycle regulators cyclin E, p16 and cdk2, but not by an increased hypoxic response. Cell cycle proteins and HIF-1a with downstream factors are often aberrantly expressed in (pre)neoplastic tissue. As p16 is consistently expressed in TM, less and only patchy expressed in the nomal Fallopian tube, is paralleled by aberrant expression of cell cycle proteins, HIF-1a, CAIX and Glut-1 and resembles the pattern of p16 expression frequently seen in endometrial carcinomas, we propose endometrial TM to be a potential premalignant endometrial lesion. The last study belonging to this thesis describes a link between the hypoxia-response and cell cycle regulation. As there were contradictory results concerning the role of HIF-1a in hypoxia-induced expression of p27kip1, we analysed their relationship in vitro and in vivo in endometrial cancer. We conclude that in endometrioid endometrial carcinoma, p27 re-expression by hypoxia is HIF-1a dependent and leads to cell cycle arrest. This may contribute to survival of cancer cells in hypoxic parts of the tumor.
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