Die differentielle Expression tumorfördernder und tumorinhibierender Gene im ersten und zweiten Trimester der Schwangerschaft

The invasion of the Extravillous Trophoblast (EVT) in human hemochorial placentation is a crucial step in successful pregnancy. Fetal cells invade decidual tissue (the transformed endometrium) and the first third of the myometrium (interstitial invasion) as well as uterine vessels (endovascular invasion). Trophoblast invasion is important for the anchorage of the placenta and secures the fetal gas exchange and nutrient supply. Invasive growth of these trophoblast cells is greatest in the first trimester of pregnancy and subsides at the beginning of the second trimester. This behavioural change in trophoblast activity appears to be a strictly regulated process. At present, it is not known if this decline in invasivity represents an intrinsic change in the genetic properties of the EVT, or if the maternal organism (in the form of decidual tissue) is involved in the regulatory mechanisms. The goal of this study was to analyse the potential regulatory function of the decidua in trophoblast invasion and to identify decidual factors possibly acting as control variables. A microarray study (von Rango, 2004) that was performed to assay the global gene expression profile in decidual tissue in the first and second trimesters was used as the basis for this study. From its results, eleven differentially expressed genes were chosen for further expression analysis. Only factors with a potential causal link to the change in EVT behaviour were selected. Due to frequently discussed similarities between invasive trophoblast growth and the invasion of malignant cells into surrounding tissues, our focus was placed on markers with a known capacity for promoting or inhibiting tumor invasion. The expression of these factors was analysed on gene and protein levels in a large number of decidual samples to evaluate their activity during the course of pregnancy. In order to assess mRNA activity, RT-PCR, Realtime-PCR with Light Cycler and Northern blotting were employed. If antibodies were available, protein expression was assayed by Western blot and immunohistochemistry. Of the markers analysed, a significant down-regulation could be shown for three (SLPI, SFRP4, CXCL14) and an up-regulation for one (CXCL9) when comparing the first to the second trimester. In addition, one marker’s up-regulation (SLPI) could be further verified on protein level. The results of this study show that genes promoting tumor invasion (like SLPI, SFRP4 and CXCL14) are expressed more strongly in decidual tissue during the first trimester of pregnancy, suggesting a stimulating effect of these genes on trophoblast invasivity. The up-regulation of genes with inhibitory effects on invasive tumor growth like CXCL9 in the second trimester can be viewed as factors limiting excessive trophoblast penetration. These findings support the hypothesis of similarities between tumor and trophoblast invasion. Although in contrast to malignancy, it appears that the maternal organism can exert control over EVT invasion through gene expression