[Endometriosis--a stem cell disease?]. / Endometriose--eine Stammzellerkrankung?

Endometriosis is an estrogen-dependent and chronic disease with an unknown etiology and pathogenesis. It is however likely and well accepted that retrograde menstruation of endometrial cells into the pelvic cavity is the origin of this disease in many cases. Here we discuss a model in which retrogradely menstruated endometrial cells have different inherent developmental properties because they represent in fact a mixture of different developmental cell stages. These stages can be distinguished in part by the expression of marker proteins such as cytokeratin (intermediate filament protein of epithelial cells) or E-cadherin (intercellular adhesion protein of epithelial cells and metastasis suppressor molecule). Cytokeratin-positive E-cadherin negative cells, for example, would be less differentiated epithelial cells than cytokeratin-positive E-cadherin positive cells. In analogy to findings in other cell systems we assume that the cells which are undifferentiated or not fully differentiated still have the potential to give rise to differentiated daughter cells and, on the other hand, could be maintained as a pool of rather undifferentiated cells and capable of self renewal. This feature would be similar to stem cells (SC) and cells with plasticity. Interestingly we find epithelial cells of different developmental stages in deep infiltrating (e. g. of colon) or peritoneal endometriotic lesions. Therefore we conclude that less differentiated cells in retrogradely menstruated endometrial cell populations possibly representing SC features or plasticity might be the cellular source of primary endometriotic lesions and those present in lesions may contribute to the persistence of the disease by detaching and forming secondary lesions.

Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model.

Studies of molecular, cellular, and pathophysiological parameters in endometriosis are primarily hampered by a lack of in vitro model systems, such as endometriotic cell lines. To overcome this we successfully established cell lines from peritoneal endometriotic biopsies and characterized them at the molecular and cellular level. Two types of cells could be transformed: one exhibiting stromal cell features (cytokeratin/E-cadherin-negative), the other epithelial-like (cytokeratin-positive/E-cadherin-negative, invasive in vitro). Using a Matrigel assay the epithelial-like cell lines proved as invasive as metastatic carcinoma cells, possibly through the influence of N-cadherin implicated as a path-finding cadherin allowing cellular invasion and migration in both normal and pathophysiological processes. Our results support the idea that endometriosis, although not neoplastic, shares features with malignant cells and that metastasis in endometriosis may include mechanisms proposed for micrometastasis in cancer. Thus our cell lines will not only be useful tools for analyzing molecular and cellular events relating to endometriosis, but may also represent a paradigm for invasion and metastasis in general.

In search of pathogenic mechanisms in endometriosis: the challenge for molecular cell biology.

Endometriosis, defined histologically as the presence of endometrium-like glands and stroma outside the uterus, is a chronic, invasive and metastasising disease. It shares features with malignant tumours (invasion and metastasis) but is not neoplastic. Despite the fact that endometriosis is one of the most frequent gynaecological diseases, it is under researched, puzzling and highly debated. The aetiology and pathogenesis is little understood although it is agreed that implantation, at least in many cases, is responsible for endometriosis. This theory advocates retrograde menstruation as the underlying phenomenon, where cells of the menstrual efflux provide the cellular source for endometriotic lesion formation. Causative therapy and non-invasive diagnostics of endometriosis do not exist. Thus, there is a substantial but unmet need for molecular and cellular research to unravel the pathogenic mechanisms of endometriosis as a basis for developing novel diagnostic and therapeutic concepts. In this review, we specifically focus on the cellular basis of lesion formation, the possible modulation of this by cytokines and other factors and the characteristics of endometriotic cells in terms of invasion and metastasis. Considering available experimental information, we concentrate on arguments and ideas in favour of an endometriotic founder cell population exhibiting substantial plasticity for differentiation and self-renewal. Perhaps present in the menstrual efflux or arising by metaplasia (a complementary theory to implantation), this cell type might respond to stimuli present in the ectopic host environment and establish the endometriotic phenotype.

Tracing cellular and molecular mechanisms involved in endometriosis.

The aetiology and pathogenesis of endometriosis, defined as the presence of endometrium-like tissue outside the uterine cavity, is largely unknown. In this paper we present and discuss possibilities to study the putative pathogenic properties of endometriotic cells in vitro. The current focus of our investigations is on the invasive phenotype of the disease, assuming that this might contribute to the pathogenesis of endometriosis. So far, we have shown that: (i) cytokeratin-positive and E-cadherin-negative endometriotic cells have an invasive phenotype in a collagen invasion assay in vitro similar to metastatic carcinoma cells; (ii) the invasiveness of endometriotic but not of eutopic endometrial cells can be stimulated by a heat-stable protein present in peritoneal fluid; and (iii) the endometriotic cell line EEC145T, which we established, may be a useful tool for the identification of gene products which are, positively or negatively, invasion-related. Finally, our studies suggest that the invasive phenotype in endometriosis shares aspects with tumour metastasis, but might also have unique mechanisms.

The kinetics of simian virus 40-induced progression of quiescent cells into S phase depend on four independent functions of large T antigen.

Microinjection of purified simian virus 40 large-T-antigen protein or DNA encoding T antigen into serum-starved cells stimulates them to re-enter the cell cycle and progress through G1 into the S phase. Genetic analysis of T antigen indicated that neither its Rb/p107-binding activity nor its p53-binding activity is essential to induce DNA synthesis in CV1P cells. However, T antigens bearing missense mutations that inactivate either activity induced slower progression of the cells into the S phase than did wild-type T antigen. Inactivation of both activities resulted in a T antigen essentially unable to induce DNA synthesis. Missense mutations in either the DNA-binding region of the N terminus also impaired the ability of full-length T antigen to stimulate DNA synthesis in CV1P cells. The wild-type kinetics of cell cycle progression were restored by genetic complementation after coinjection of plasmid DNAs encoding different mutant T antigens or coinjection of purified mutant T-antigen proteins, suggesting that the four mitogenic functions of T antigen are independent. The maximal rate of induction of DNA synthesis in secondary primate cells and established rodent cell lines required the same four functions of T antigen. A model to explain how four independent activities could cooperate to stimulate cell cycle progression is presented.