Pathobiology Of Uterine Leiomyomas (fibroids)

National Institute Of Environmental Health Sciences

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Abstract

The Molecular Pathogenesis Group has focused much of its research on defining the pathogenesis of disorders affecting the reproductive tract of humans and rodents and assessing the role of environmental and endogenous hormones, and growth factors on the growth and induction of these disorders. In understating the role of proliferation in human uterine leiomyoma (fibroid) growth, we have found that both positive and negative regulators of apoptosis are not differentially expressed in fibroids compared to normal myometria, and that altered apoptosis does not appear to play a significant role in the expansion of these tumors. Our studies show that cell proliferation and extracellular matrix production may be the most significant contributors to fibroid expansion, although, mitotic activity of fibroid cells appears to be phasic, does not correlate with tumor size, and is autonomous for each tumor within a uterus. In studies addressing the role of growth factors in the pathogenesis of fibroids, we have found that Receptor Tyrosine Kinases (RTKs) and their ligands are overexpressed in fibroids compared to normal myometria during the proliferative phase of the menstrual cycle and that many of the RTKs are activated. These studies will help to define some of the basic biological and molecular pathways important in fibroid growth, which can then be applied to developing alternative noninvasive treatment regimens for fibroids. We have also found that nonclassical estrogen receptors (ER), such as ERalpha36 and G protein-coupled ER (GPER) are important in fibroid cell growth and are responsive to environmental estrogen mimics. In vitro model systems for studying fibroids are limited in that human derived leiomyoma cells grow poorly in culture. We have overcome this obstacle by development of hTERT (human telomerase) immortalized uterine leiomyoma and myometrial cell lines. We have also developed 3D culture models of fibroid and myometrial cells to further mimic the in vivo microenvironment. These cells and 3D cultures are being used to study leiomyoma tumorigenesis in a prospective manner and to determine the impact of environmental exposures on fibroid cell growth and fibrosis. In determining the role of environmental agents in fibroid development and growth we have found that the phytoestrogen, genistein, can be stimulatory or inhibitory to uterine leiomyoma cell growth depending on its concentration. We have also found that Bisphenol A (BPA), can induce cell proliferation in uterine leiomyoma through a membrane-associated ER, ERalpha36, and may be potential risk factor for fibroids. Metals, such as Cadmium potentiate growth of human fibroid cells and continuous exposure results in genomic and morphologic alterations that drive the benign fibroid tumor cell towards a cancer phenotype.