Projects / Programmes
Molecular basis of endometriosis and endometrial cancer - metabolomics approach
| Code |
Science |
Field |
Subfield |
| 3.07.00 |
Medical sciences |
Metabolic and hormonal disorders |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
metabolomics, biomarkers, estrogen metabolites, endometriosis, endometrial cancer
Researchers (15)
Organisations (2)
Abstract
Endometriosis is one of the most common diseases; it is more frequent than cancer or diabetes. Due to invasive surgical diagnosis its exact incidence is not known, but estimates show that 10-15% of women in reproductive age and 35-50% of infertile women are affected. There are three major types of endometriosis: ovarian, peritoneal and deep infiltrating endometriosis. The etiology of endometriosis is multifactorial and includes complex interactions of genetic, immunological, hormonal and environmental factors leading to disturbed cellular processes and thus changed levels of metabolites. Different biomarkers have been tested, but still no reliable non-invasive diagnosis is available. Endometrial cancer (EC) is the most common gynaecological malignancy and the 4th most common cancer in women. There are two types of EC, estrogen dependent type 1 and independent type 2, usually with a poor prognosis. Estrogens act as promoters and initiators of carcinogenesis. As promoters they stimulate proliferation via different mechanisms. In some extrahepatic tissues estrogens can act as initiators. In these tissues catechol estrogen metabolites are formed by phase 1 enzymes and further oxidized to semiquinones and quinones, which form DNA adducts. These reactions also produce reactive oxygen species that damage DNA and proteins. Formation of quinones can be prevented by phase 2 enzymes. In breast cancer estrogens have been shown to act as promoters and initiators, while their role in EC is not clear. With this project we will test the hypothesis that metabolites may serve as biomarkers of endometriosis and EC. Aims: 1) Targeted metabolome analysis of plasma of patients with ovarian endometriosis and control group of healthy women and patients with benign ovarian cysts. We aim to identify metabolites, potential biological markers for non-invasive diagnosis of ovarian endometriosis. 2) Analysis of estrogen metabolites in cancerous tissue, plasma and urine of patients with EC types 1 and 2, and control groups of patients with myoma uteri or prolapsed uterus; and study of estrogen metabolism at the mRNA, protein and activity levels. We will test the applicability of estrogen metabolites as biomarkers for different types of EC or as prognostic markers. The project will be performed in collaboration with Helmholtz Zentrum Munchen, Germany and Center of Excellence in Environmental Toxicology, University of Pennsylvania, Philadelphia, USA. We aim to analyze 163 metabolites, mainly lipids, potent signalling molecules that regulate a multitude of cellular responses and may also be related to etiology of endometriosis. Metabolites will be quantified using the internal stable isotope labelled standards on ESI-MS/MS (Biocrates AbsoluteIDQ™ Kit). Estrogen metabolites will be analyzed using deuterium labelled standards on ECAPCI-MS/MS. To our knowledge, there has been no published report on using metabolomics approach for searching diagnostic biomarkers in endometriosis and EC. Results of the proposed study will contribute to development of non-invasive diagnosis, to a better understanding of pathogenesis of both diseases as well as to identification of novel drug targets. Panel of metabolites in plasma may serve as an assay for diagnosis of ovarian endometriosis, while determination of estrogen metabolites in urine or plasma may be instrumental for separation of both types of EC or as prognostic marker.
Significance for science
Many theories have been proposed, but no single theory can explain all aspects of endometriosis thus the exact pathogenesis still remains elusive. At present endometriosis can only be unequivocally diagnosed invasively, using laparoscopy. There is thus an urgent need for discovery of biomarkers for non-invasive diagnosis. The identified panel of metabolites comprised in our patent application represents foundation for development of novel non-invasive diagnostic method. Our metabolomics study represents a novel approach that has not yet been explored in the search for biomarkers of endometriosis. So far lipids, which regulate different cellular processes, have not been studied as potential biomarkers of endometriosis. We were thus the first to show that lipid metabolites have potential as biomarkers for diagnosis of endometriosis. The metabolomics approach contributed also to a better understanding of lipid signalling and pathophysiology of endometriosis in general as well as to identification of novel drug targets. Although endometrial cancer is considered an estrogen dependent disease, the role of estrogens in development of endometrial cancer has not been elucidated in detail. With this project we clarified biosynthesis and metabolism of estrogens in endometrial cancer and we were the first to show that in cancerous tissue estrogens can be formed mainly via the sulfatase pathway. We successfully employed metabolomics approach also for identification of diagnostic biomarkers of endometrial cancer. Our results thus contribute to a detailed understanding of the role of estrogens and lipid metabolites in this type of cancer, to identification of diagnostic and prognostic markers and novel drug targets.
Significance for the country
Slovenia has one of the lowest birth rates in Europe; therefore diagnosis and treatment of endometriosis, which is diagnosed in 40-50% of infertile patients, is of great relevance for our country. Also incidence of endometrial cancer in Slovenia is very high which supports importance of efficient diagnosis and treatment of this type of cancer. In the framework of the research project novel biomarkers of endometriosis were identified providing a foundation for development of diagnostic assays and also contributing to a better understanding of both gynaecological diseases and to identification of novel drug targets. The results of the project were published in high impact factor journals and led to international patent application. Our findings were presented at several international scientific conferences and at foreign universities, thus contributing to international affirmation and promotion of Slovenia and Slovenian science. The research project enabled research visits to the collaborating institutions, the Helmholtz Zentrum München, Germany and the University of Berne, Switzerland and transfer of the cutting-edge knowledge in biomarker identification to Slovenia. The research project enhanced the quality of research work as well as the quality of teaching at the Faculty of Medicine of the University of Ljubljana. In the framework of this project several undergraduate students and Ph.D. students have been trained and their knowledge and expertise have already been successfully transferred to Slovenian Industry, where they are currently employed. The good results stemming from this project contributed to competitiveness of the collaborating institutions, the Faculty of Medicine and the Medical Center Ljubljana as indicated by involvement of both institutions in recent multinational validation study of biomarkers.
Most important scientific results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
