EXTRACELLULAR MATRIX PRODUCTION BY UTERINE FIBROIDS

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Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women. These smooth muscle cell tumors are associated with symptoms that include pelvic pain or pressure, excessive menstrual bleeding, infertility and spontaneous abortion. Leiomyomas appear to be estrogen/progesterone dependent but it is not clear how these ovarian steroids regulate their growth. Despite the fact that these tumors can grow quite rapidly, they display very low rates of mitotic activity. Fibroids are characterized by excessive amounts of extra-cellular matrix. The proposed research focuses on the regulation of extra-cellular matrix production in leiomyomas and normal myometrium by the ovarian steroids and the autocrine growth regulators, transforming growth factor-beta and parathyroid hormone-related peptide. The specific aims of this proposal are: 1. To compare human uterine leiomyoma and myometrial expression of a) the extra-cellular matrix proteins collagen Type I, collagen Type III and fibronectin, and b) the matrix-degrading enzymes stromelysin and collagenase. 2. To determine whether expression of these extra-cellular matrix proteins and matrix-degrading enzymes in leiomyomas and myometrium is regulated by estrogen and/or progesterone. 3. To determine a) whether leiomyomas produce higher amounts of PTHrP and TGF-B than normal myometrium, and b) whether PTHrP and TGF-B regulate the production of extra-cellular matrix proteins or matrix-degrading enzymes. These studies should provide new information on the regulation of extra-cellular matrix production in both normal myometrium and leiomyomas. Overproduction or decreased degradation of certain extra-cellular matrix proteins by fibroids may account for much of their increase in size or "growth". Overexpression of one or more of these matrix proteins by leiomyomas, enhanced responsiveness to the effects of estrogen/progesterone, or increased production of autocrine regulators such as PTHrP or TGF-B may be some of the mechanisms responsible for this excessive accumulation of matrix. The findings may facilitate developments in the clinical management of these common tumors.