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 and molecular mechanisms of disorders affecting the reproductive tract of humans and assessing the role of environmental chemicals/metals, endogenous hormones, and growth factors on the induction of these disorders. In understating the role of environmental impacts on human uterine leiomyoma (fibroid) growth using novel 3D in vitro cultures, we have found that environmental chemicals can play a significant role in the expansion of these tumors, not only through cell proliferation but through the induction of genes and signaling pathways important in extracellular matrix (ECM) production. Our studies show that cell proliferation and ECM production may be the most significant contributors to fibroid expansion, although, mitotic activity of fibroid cells appears to be phasic, it 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 myometrium during the proliferative phase of the menstrual cycle and that many of the RTKs are activated. We have found that upon exposure to chemicals and metals both ECM components and cell proliferation are increased. In addition we have found that metals can induce characteristics of cancer cells and differential expression of genes upregulated in cancer. These studies will help to define some of the basic biological and molecular pathways important in fibroid growth and transformation, which can then be applied to developing alternative noninvasive treatment regimens for fibroids and identifying preventive measures for exposures and exacerbation of the disease. 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 developing 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 2D 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, fibrosis, and malignant transformation. 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 that BPA and some of its analogues/derivatives (BPS, BPAF, TBBPA)can induce extensive fibrosis in our 3D fibroid models, and these exposures may be potential risk factors for women with fibroids. Metals, such as cadmium potentiate the growth of human fibroid cells and continuous exposures result in genomic and morphologic alterations that drive the benign fibroid tumor cell towards a cancer phenotype.