Endometriosis and Gynaecological Oncology

Research objectives:

  • Pathophysiology of endometriosis and associated pain
  • Pathophysiology of gynaecological cancers

Project description:

Endometriosis is an extremely prevalent condition that is accompanied by chronic pain, reduced fecundity and an increased risk of ovarian cancer later in life all of which can be related to inflammation. The most widely accepted theory of endometriotic lesion development is retrograde menstruation, a process by which viable endometrial cells are refluxed backwards into the peritoneal cavity. These cells attach to the underlying tissue and via a hormonal and inflammatory stimulation continue to grow. As retrograde menstruation has been shown to occur in almost 90% of women additional factors must be involved that support the attachment of the endometrial tissue in those patients who suffer from endometriosis. To date, these factors are still not fully identified. Endometriosis is as such a benign condition but, unfortunately, it is associated with specific ovarian cancer subtypes such as clear cell and endometrioid carcinoma subtypes (also named endometriosis-associated ovarian cancers, EAOC). Direct transformation of endometriotic epithelial cells to a malignant endometrioid, or clear cell ovarian cancer has been documented, although what stimulates this transformation is unclear.

In our studies, we are analysing samples such as endometrial tissues (eutopic and ectopic), body fluids (blood, peritoneal fluid) to better elucidate the biological bases sustaining endometriosis itself but also endometriosis associated pain, fertility loss and oncogenesis. The strength of our research is the large number of samples obtained from the Department of Obstetrics and Gynaecology at the University of Berne and constantly accumulated in our biobank with the great involvement of the physicians and the generous consent of the patients. Through our approach, we hope that these studies ultimately, amongst other scientific benefits, improve the diagnosis and reduce the symptoms for the overall benefit of the patient quality of life.

Highlights:

Progesterone resistance in endometriosis

Dienogest is one of the promising options for the long-term hormonal management of endometriosis. By analyzing the prevalence of somatic mutations, cellular composition, or transcriptomic profile between endometriotic lesions from non-responders, we intend to unveil the mechanism of Dienogest resistance which occurs in several patients. (Nirgianakis K., McKinnon B.)

Endocannabinoids system (ECS) in endometriosis

The cannabinoid receptor CB1 is located on sensory fibers that innervate the ectopic growths suggesting that the ECS modulates pain by acting locally in the peritoneal cavity. We have quantified the levels of endocannabinoids in serums and peritoneal fluids and identified 2-AG as a possible modulator of pain in endometriosis. (Andrieu T., Chicca A.)

Epithelial to mesenchymal transition (EMT) in endometriosis

During the process of EMT, epithelial cells acquire features of mesenchymal cells affecting their proliferation, migration and infiltration rates. The main EMT marker, N-cadherin, has been detected in epithelial cells of a majority of the ectopic tissue. Interestingly, cells that went through this transition were also lacking the progesterone receptor. This result was recapitulated in vitro in endometrial carcinoma cell line. Our study has identified an important link between EMT and progesterone resistance in line with the pathogenesis of endometriosis. (Lijuan M., McKinnon B.)

Endometrial cancer (EmCa) with sentinel lymphnode dissection

In early-stage EmCa sentinel lymph node removal offers a convincing balance between oncological safety and perioperative morbidity. However, lymphovascular space invasion may represent a risk factors for recurrence and therefore prior lymph-node evaluation is crucial. (Imboden S. et al. Eur J Surg Oncol. 2019)

POLE-mutated endometrial cancer (EmCa)

By analyzing molecular markers for EmCa, we could demonstrate that mutations in the exonuclease domain of the DNA polymerase epsilon (POLE) gene is significantly associated with previously unknown clinicopathological characteristics. Especially, when considering hotspot mutations, prognosis for patients with mutation was significantly better in comparison with patients with non-mutated tumours. (Imboden S. et al. PLoS One. 2019)

Central hypersensitivity, immune markers and morphological brain changes in Chronic Pelvic Pain (CPP) in Endometriosis

CPP perceived as a peripheral condition, is in fact associated with significant central changes. An understanding of mechanisms of central hypersensitivity and morphological volumetric brain changes, i.e. functional reorganization of the cortex, may allow an early stratification for treatment of individuals at high risk of persisting CPP. Although central hypersensitivity, immune markers and recently morphological brain changes are recognized as an important pathophysiological mechanisms of pain. The aim of our investigation is to explore the predictive value of hypersensitivity parameters and volumetric brain changes in surgery outcome in endometriosis patients with CPP. (Neziri, AY)

Group Members 11