Molecular and Cellular Pathogenesis of Endometriosis

Abstract

Background: A substantial body of studies supports the view that molecular and cellular features of endometriotic lesions differ from those of eutopic endometrium. Apart from that, evidence exists that the eutopic endometrium from pa-tients with endometriosis differs from that of females without endometriosis.

Objective: Aberrant expression profiles include a number of non-steroid signaling pathways that exert their putative influ-ence on the pathogenesis of endometriosis at least in part via crosstalk(s) with estrogen-mediated mechanisms. A rational to focus research on non-steroid signal pathways is that they might be remunerative targets for the development and selection of novel therapeutics to treat endometriosis possibly without affecting estrogen levels.

Results and conclusion: In this article, we describe molecular and cellular features of endometriotic lesions and focus on the canonical WNT/β-signaling pathway, a key regulatory system in biology (including stem cell homeostasis) and often in pathophysiological conditions such as endometriosis. Recently emerged novel biological concepts in signal transduction and gene regulation like exosomes and microRNAs are discussed in their putative role in the pathogenesis of endometriosis.

Keywords: WNT/β-catenin signaling; endometriosis; exosomes; microenvironment; reproductive tract; stem cells.

Fig. (1)

Schematic overview of endometriosis development. Shed menstrual endometrium leaves the cavity mainly antegradely (black arrow) but is also flushed retrograde into the pelvic cavity (red arrow). Endometrial derived exosomes can also be transported retrograde into the pelvic cavity even in the absence of menstruation (grey and blue filled circles). Once in the pelvic cavity, menstrual cells can attach by gravity to the peritoneal surfaces and form temporary lesions. In healthy women, temporary ectopic lesions are removed by the immune system through apoptosis induction. In women developing endometriosis as a disease, these ectopic lesions evade the immunosurveillance and progress in response to e.g. locally present cytokines and/or growth factors (blue arrow). Exosomes derived from endometriotic cells (green filled circles) could act in an autocrine/paracrine manner but could also be transported back through the fallopian tubes into the uterine cavity (green arrow) and modulate signaling events in eutopic endometrium. Albeit the implantation theory is the most likely explanation for the pathophysiological lesion formation, the step-wise development of ectopic lesions could also be explained in part by other proposed theories. For example, the TIAR concept suggests that trauma could cause the displacement of lamina basalis cells (altered uterine contractility) but also the exposure of ectopic attachment sites (injury). This could allow the attachment and invasion of ectopic cells followed by wound closure. It is also conceivable that exosomes could mediate metaplasia of peritoneal cells in other cases.