hrvatski

Metilacija DNA u dijagnostici invazivnosti trofoblasta i tumora

In order for placenta to adequately play its function of meeting the needs of growing embryo and fetus, the trophoblast cells must invade the uterine epithelium and remodel the mother's spiral arteries to create utero-placental circulation. The processes taking place during these events are similar to those during carcinogenesis. Therefore, it is not surprising that placentation and carcinogenesis share many common physiological attributes that can be observed at the genetic and epigenetic levels, and include: expression of common growth factors, cell adhesion molecules, enzymes for extracellular proteins degradation and products of protooncogenes and tumor suppressor genes. The most important difference is that invasive potential of the trophoblast is precisely regulated and spatially and temporally controlled, in order to avoid a shallow invasion, as it occurs during preeclampsia and intrauterine growth failure (IUGR), or invasion that is too deep, as in placenta accreta and percreta. Such similarity on the genetic and epigenetic level cannot be found in any other mammalian tissue, so why not use it and draw parallels, i.e. learn from trophoblasts? Tumor cells do not necessarily reveal new mechanisms compared to those that are operative during embryonal development, they mostly use existing cellular mechanisms to divide and survive in the host. It is currently thought that for facilitation of these proliferative, invasive and migratory properties of both trophoblasts and tumors, the signaling pathways Wnt and Hedgehog are responsible. They are evolutionary conserved pathways that are indispensable for normal embryonal development and placentation and their aberrant activation is associated with the development of many cancers. Our research supports these claims. For example, we found that one of the Wnt signaling inhibitors, the frizzled-related protein (SFRP) is more strongly expressed in IUGR placentas, which is associated with shallow invasion. At the same time, it is less pronounced in choriocarcinomas and serous ovarian carcinomas. Expression of SFRP is in reverse correlation with the degree of DNA methylation, which could potentially be used as a diagnostic and prognostic marker in those pathological entities. From among the components of the Hedgehog signaling pathway, we have so far studied the proteins Patch1, SHH, IHH, GLI1 and GLI3. Our analysis of DNA methylation suggests that methylation is not the main mechanism of control of their expression. SHH and IHH promoters are not methylated in normal ovarian tissue, although there is no protein expression in ovarian epithelial cells. DNA methylation of PTCH1 was observed in 14% of high-grade serous ovarian carcinomas (HGSC). In this presentation we will introduce the Wnt and Hedgehog signaling pathway components, which were investigated in our laboratory, whose expression is regulated by DNA methylation of their genes, and which could potentially be useful in early diagnostics of pathological pregnancies and ovarian cancer. Our aim is to discover new epigenetic biomarkers in circulating serum DNA that would allow for early detection and better monitoring of both pathological pregnancies and serous ovarian cancers.

trofoblast ; karcinomi jajnika ; Hedgehog signalni put ; Wnt signalni put ; DNA metilacija

nije evidentirano

engleski

DNA methylation as a diagnostic target of the trophoblast and tumor invasiveness

In order for placenta to adequately play its function of meeting the needs of growing embryo and fetus, the trophoblast cells must invade the uterine epithelium and remodel the mother's spiral arteries to create utero-placental circulation. The processes taking place during these events are similar to those during carcinogenesis. Therefore, it is not surprising that placentation and carcinogenesis share many common physiological attributes that can be observed at the genetic and epigenetic levels, and include: expression of common growth factors, cell adhesion molecules, enzymes for extracellular proteins degradation and products of protooncogenes and tumor suppressor genes. The most important difference is that invasive potential of the trophoblast is precisely regulated and spatially and temporally controlled, in order to avoid a shallow invasion, as it occurs during preeclampsia and intrauterine growth failure (IUGR), or invasion that is too deep, as in placenta accreta and percreta. Such similarity on the genetic and epigenetic level cannot be found in any other mammalian tissue, so why not use it and draw parallels, i.e. learn from trophoblasts? Tumor cells do not necessarily reveal new mechanisms compared to those that are operative during embryonal development, they mostly use existing cellular mechanisms to divide and survive in the host. It is currently thought that for facilitation of these proliferative, invasive and migratory properties of both trophoblasts and tumors, the signaling pathways Wnt and Hedgehog are responsible. They are evolutionary conserved pathways that are indispensable for normal embryonal development and placentation and their aberrant activation is associated with the development of many cancers. Our research supports these claims. For example, we found that one of the Wnt signaling inhibitors, the frizzled-related protein (SFRP) is more strongly expressed in IUGR placentas, which is associated with shallow invasion. At the same time, it is less pronounced in choriocarcinomas and serous ovarian carcinomas. Expression of SFRP is in reverse correlation with the degree of DNA methylation, which could potentially be used as a diagnostic and prognostic marker in those pathological entities. From among the components of the Hedgehog signaling pathway, we have so far studied the proteins Patch1, SHH, IHH, GLI1 and GLI3. Our analysis of DNA methylation suggests that methylation is not the main mechanism of control of their expression. SHH and IHH promoters are not methylated in normal ovarian tissue, although there is no protein expression in ovarian epithelial cells. DNA methylation of PTCH1 was observed in 14% of high-grade serous ovarian carcinomas (HGSC). In this presentation we will introduce the Wnt and Hedgehog signaling pathway components, which were investigated in our laboratory, whose expression is regulated by DNA methylation of their genes, and which could potentially be useful in early diagnostics of pathological pregnancies and ovarian cancer. Our aim is to discover new epigenetic biomarkers in circulating serum DNA that would allow for early detection and better monitoring of both pathological pregnancies and serous ovarian cancers.

trophoblast ; ovarian carcinomas ; Hedgehog signaling pathway ; Wnt signaling pathway ; DNA methylation

nije evidentirano