CSF-1 and c-fms and the Early Endometriotic Lesion

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DESCRIPTION (provided by applicant): Endometriosis is a common gynecologic disease affecting up to 10% of reproductive-age women. Despite this high prevalence and the severe symptoms associated with the disease, little is known about the pathogenesis of endometriosis. One theory, known as Sampson's theory, proposes that fragments of menstrual endometrium pass retrograde through the fallopian tubes into the peritoneal cavity where they attach and grow on peritoneal surfaces. We have developed novel in vitro and in vivo (murine) models of the early endometriotic lesion. Our models demonstrate that endometrial fragments rapidly adhere to intact peritoneal mesothelium then promptly invade into the submesothelial extracellular matrix (ECM). Colony stimulating factor-1 (CSF-1), initially described as a hematopoietic growth factor, has been shown to have important functions in non-hematopoietic cells. CSF-1 interaction with its receptor, c-fms, has been implicated in the growth, invasion, and metastasis of several types of cancer. CSF-1 and c-fms are expressed by endometrial stromal and epithelial cells (ESCs and EECs), and peritoneal mesothelial cells (PMCs). Our preliminary data demonstrate that: (1) co-culture of endometrial cells and PMCs increases expression of CSF-1 and c-fms by endometrial cells and PMCs, (2) CSF-1 interaction with c-fms increases endometrial proliferation and migration, (3) decreased production of CSF-1 by endometrial cells leads to decreased cell proliferation and migration as well as altered transcription of genes implicated in invasion, metastasis, and cell signaling, and (4) pharmacologic agents, targeted against c-fms signaling, lead to a decreased rate of endometriotic lesion formation in an in vitro and in vivo model of endometriosis. Collectively, our preliminary observations lead us to hypothesize that CSF-1/c-fms signaling contributes to the pathogenesis of endometriosis by increasing the rate of: endometrial-PMC attachment, transmesothelial migration by endometrium, and growth of endometrial tissue in the submesothelial ECM. In the proposed studies we will use our in vitro and in vivo models of endometriosis to: (1) evaluate the effect of endometrial- PMC co-culture on the endometrial and PMC expression of CSF-1 and c-fms from patients with and without endometriosis, (2) evaluate the effect of CSF-1 stimulation on endometrial attachment, invasion and growth in the peritoneum, and evaluate the mechanisms involved in CSF-1/c-fms mediated actions that may contribute to endometriosis, (3) demonstrate that interference with CSF-1/c-fms signaling decreases the rate of endometrial attachment, invasion and growth in the peritoneum, and (4) evaluate currently available pharmacologic agents that may decrease c-fms signaling as a potential treatment for endometriosis. The proposed studies are designed to improve our knowledge regarding the pathogenesis of the endometriotic lesion, increase our understanding of the contribution of CSF-1/c-fms signaling in endometriosis, and lead to innovative methods to prevent and treat this disease. Public Health Relevance Statement: Endometriosis is a disease in which there is growth of endometrial cells (i.e. the tissue that lines the uterine cavity) in the abdominal cavity. It is a common gynecologic disease affecting up to 10% of reproductive-age women. Colony stimulating factor-1 (CSF-1), initially described as a growth factor for blood cells, has been shown to have important functions in other cells types including endometrial cells and cells that line the abdominal cavity. The proposed studies are designed to improve our knowledge regarding the pathogenesis of the endometriotic lesion, increase our understanding of the contribution of CSF-1 signaling in endometriosis, and lead to innovative methods to prevent and treat this disease.