Macrophages inhibit and enhance endometriosis depending on their origin.

Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduces peritoneal macrophage populations and increases the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM are replaced by monocyte-derived LpM decreases the number of lesions that develop. We propose a putative model whereby endometrial macrophages are "proendometriosis" while newly recruited monocyte-derived macrophages, possibly in LpM form, are "antiendometriosis." These observations highlight the importance of monocyte-derived macrophages in limiting disease progression.

Endometriosis-Associated Pain - Do Preclinical Rodent Models Provide a Good Platform for Translation?

Pelvic pain is a common symptom of endometriosis. Our understanding of its etiology remains incomplete and medical management is limited by poor translation from preclinical models to clinical trials. In this review, we briefly consider the evidence, or lack thereof, that different subtypes of lesion, extra-uterine bleeding, and neuropathic pathways add to the complex and heterogeneous pain experience of women with the condition. We summarize the studies in rodent models of endometriosis that have used behavioral endpoints (evoked and non-evoked) to explore mechanisms of endometriosis-associated pain. Lesion innervation, activation of nerves by pronociceptive molecules released by immune cells, and a role for estrogen in modulating hyperalgesia are key endometriosis-associated pain mechanisms replicated in preclinical rodent models. The presence of ectopic (full thickness uterus or endometrial) tissue may be associated with changes in the spinal cord and brain, which appear to model changes reported in patients. While preclinical models using rats and mice have yielded insights that appear relevant to mechanisms responsible for the development of endometriosis-associated pain, they are limited in scope. Specifically, most studies are based on models that only resulted in the formation of superficial lesions and use induced (evoked) behavioral 'pain' tests. We suggest that translation for patient benefit will be improved by new approaches including models of ovarian and deep infiltrating disease and measurement of spontaneous pain behaviors. Future studies must also capitalize on new advances in the wider field of pain medicine to identify more effective treatments for endometriosis-associated pain.

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors.

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5-1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.