Pathobiology Of Uterine Leiomyomas (fibroids)

子宫平滑肌瘤（肌瘤）的病理学

基本信息

批准号：
10924932
负责人：
DARLENE DIXON
金额：
$ 110.58万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10924932
关键词：
Address Affect Apoptosis Apoptosis Regulation Gene Archives Benign Biological Biological Models Cadmium Cell Line Cell Proliferation Cells Clinical Clinical Treatment Data Development Disease Environmental Estrogen Environmental Exposure Environmental Impact Environmental Risk Factor Estrogen Receptor alpha Estrogen Receptors Extracellular Matrix Fibroid Tumor Fibrosis GPER gene Genistein Genomics Goals Growth Growth Factor Growth and Development function Hormones Human Human Cell Line Knowledge Leiomyoma Ligands Malignant Neoplasms Membrane Metals Mission Mitotic Activity Modeling Molecular Morphology Mus Myometrial Pathogenesis Pathway interactions Patients Phase Phenotype Phytoestrogens Play Premenopause Prevention strategy Production Proliferating Public Health Receptor Protein-Tyrosine Kinases Research Risk Factors Rodent Role Sampling Signal Pathway Telomerase Therapeutic Intervention Tissue Sample Tissues Treatment Protocols Tumor Expansion Uterine Fibroids Uterus Woman bisphenol A carcinogenesis cell growth disorder prevention environmental agent improved in vitro Model in vivo neoplastic cell overexpression proliferative phase Menstrual cycle prospective receptor reproductive tract three dimensional cell culture tumor tumor growth tumorigenesis

项目摘要

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.

分子发病机组的大部分研究集中在定义影响人类和啮齿动物生殖道的疾病的发病机理上，并评估环境和内源激素的作用，以及生长因子对这些疾病的生长和诱导的作用。在低估了增殖在人子宫平滑肌瘤（肌瘤）生长中的作用时，我们发现与正常肌分立相比，凋亡的阳性和阴性调节剂在肌瘤中均未差异表达，并且凋亡的改变似乎在这些肿瘤扩张中没有重要作用。我们的研究表明，细胞增殖和细胞外基质产生可能是肌瘤膨胀的最重要因素，尽管肌瘤细胞的有丝分裂活性似乎是阶段性的，与肿瘤的大小无关，并且对于子宫内的每个肿瘤都是自主的。在解决生长因子在肌瘤发病机理中的作用的研究中，我们发现受体酪氨酸激酶（RTK）及其配体在男性循环的增殖阶段与正常肌谱相比，在肌瘤中过表达肌瘤，并且许多RTK被激活。这些研究将有助于定义一些在肌瘤生长中重要的基本生物学和分子途径，然后将其应用于开发肌瘤的替代性非侵入性治疗方案。我们还发现，非经典雌激素受体（ER），例如Eralpha36和G蛋白偶联ER（GPER）在肌瘤细胞的生长中很重要，并且对环境雌激素模拟物有反应。用于研究肌瘤的体外模型系统受到限制，因为人类衍生的平滑肌瘤细胞在培养中生长较差。我们通过发展HTERT（人端粒酶）永生的子宫平滑肌瘤和肌层细胞系来克服这一障碍。我们还开发了肌瘤和肌层细胞的3D培养模型，以进一步模拟体内微环境。这些细胞和3D培养物用于前瞻性研究平滑肌瘤肿瘤发生，并确定环境暴露对肌瘤细胞生长和纤维化的影响。在确定环境药物在肌瘤发育和生长中的作用时，我们发现植物雌激素，染料黄酮可以刺激性或抑制性子宫平滑肌瘤细胞的生长，具体取决于其浓度。我们还发现，双酚A（BPA）可以通过膜相关的ER，ERALPHA36诱导子宫平滑肌瘤的细胞增殖，并且可能是肌瘤的潜在危险因素。金属，例如镉增强人肌瘤细胞的生长和连续暴露会导致基因组和形态学改变，从而将良性肌瘤细胞推向癌症表型。

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NTP/NIEHS Global Contributions to Toxicologic Pathology.

NTP/NIEHS 对毒理学病理学的全球贡献。

DOI：
10.1177/0192623317740326
发表时间：
2017
期刊：
Toxicologic pathology
影响因子：
1.5
作者：
Sills,Robert;Brix,Amy;Cesta,Mark;Churchill,ShebaR;Cora,MichelleC;Dixon,Darlene;Dykstra,Michael;Flake,Gordon;Herbert,Ron;Kovi,Ramesh;Janardhan,Kyathanahalli;King-Herbert,Angela;Malarkey,David;Pandiri,Arun;Travlos,Greg;Willso
通讯作者：
Willso

Recommendations from the INHAND Apoptosis/Necrosis Working Group.

DOI：
10.1177/0192623315625859
发表时间：
2016-02
期刊：
Toxicologic pathology
影响因子：
1.5
作者：
Elmore SA;Dixon D;Hailey JR;Harada T;Herbert RA;Maronpot RR;Nolte T;Rehg JE;Rittinghausen S;Rosol TJ;Satoh H;Vidal JD;Willard-Mack CL;Creasy DM
通讯作者：
Creasy DM

An endocrine-disrupting chemical, fenvalerate, induces cell cycle progression and collagen type I expression in human uterine leiomyoma and myometrial cells.

DOI：
10.1016/j.toxlet.2010.03.004
发表时间：
2010-07-15
期刊：
TOXICOLOGY LETTERS
影响因子：
3.5
作者：
Gao, Xiaohua;Yu, Linda;Castro, Lysandra;Moore, Alicia B.;Hermon, Tonia;Bortner, Carl;Sifre, Maria;Dixon, Darlene
通讯作者：
Dixon, Darlene

Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming.