Gene expression studies in leiomyomas: New directions for research
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, and Uniformed Services University of the Health Sciences, Bethesda, Maryland 20862, USA. Seminars in Reproductive Medicine
(Impact Factor: 2.35).
06/2004; 22(2):83-90. DOI: 10.1055/s-2004-828614
Uterine leiomyomata (fibroids) are a leading women's health problem, resulting in significant morbidity and surgical intervention. As benign clonal tumors, leiomyomata also represent a target well suited to molecular analysis. Familial studies and genetic syndromes featuring leiomyomata provide compelling evidence that genetic alterations may cause fibroid development, but the specific genes involved in leiomyoma development have not been identified. Microarrays permit simultaneous comparison of the relative expression of thousands of genes, thereby highlighting specific genes that may play a role in the development of leiomyomata. Microarray studies conducted by several laboratories have identified candidate genes. However, few gene products have been confirmed with alternative experimental approaches. The objective of this article is to focus on the insights provided by microarray studies investigating leiomyoma development. Such studies suggest that although hormonal control of leiomyoma growth is observed, there are other critical pathways involved in development of the leiomyoma cell phenotype that warrant investigation. In particular, expression of extracellular matrix genes in leiomyomata is deranged and such genes represent potential novel targets for therapy.
Available from: PubMed Central
- "The underlying biological mechanism of infection-related oncogenesis proposed is that injury caused by infection or inflammation proceeds through several possible pathways, leading to increased extracellular matrix, cell proliferation, and decreased apoptosis, apropos of abnormal tissue repair.19–22 The upregulation of extracellular matrix proteins that is consistently seen in gene profiling studies of fibroids compared with normal myometrium23 is consistent with such a mechanism. As luteinizing hormone (LH) shares a receptor with human chorionic gonadotropin, the hormone that stimulates uterine growth during early pregnancy, it is hypothesized that peri-menopausal increases in LH would stimulate fibroid growth.24 "
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ABSTRACT: Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.
Available from: Beverley Vollenhoven
- "Most studies that have examined differences between myometrium and fibroids using microarrays produced lists of approximately 100 genes that were differentially expressed between the two tissue types. An earlier review of five fibroid microarray studies (Catherino et al., 2004) reported only eight genes that were common in at least three out of five studies reviewed, with one study having no overlapping genes. A more recent review (Arslan et al., 2005) compared results of nine studies. "
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ABSTRACT: Cultured myometrial (M) and fibroid (F) smooth muscle cells (SMCs) have been widely used as a model for the study of F growth. The aim of this study was to compare gene expression profiles using microarrays between six paired M and F tissues from hysterectomy specimens, as well as cells isolated from the same tissues and cultured for up to three passages. A total of 2055 genes were differentially expressed by ANOVA between all experimental groups. Among them, 128 genes were found to be statistically different between M and F tissues. More than 1100 genes were significantly changed between tissues and cultured cells, with 648 genes common between both M and F cells at P0 and P3. Expression profiles of six genes including estrogen receptor-alpha (ERalpha) and progesterone receptor (PR) were also validated using real-time PCR. These data demonstrate that large changes occur in SMC gene expression in culture, reducing differences between M and F cells. They also show that ERalpha and PR levels are reduced in cells compared with whole tissue. These results indicate that although M and F cell cultures provide an important tool to study these tumours, in vitro studies must be carefully planned and evaluated to provide meaningful results.
Available from: Dennis P Orgill
- "COL4A5 was highest positive. It is reported in uterine leiomyomas by Catherino (10), and in esophageal leiomyomas by Aszodi (11). LAMB2 is another gene with altered expression in ECM diseases (11). "
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ABSTRACT: The Gene Set Enrichment Analysis (GSEA) identifies sets of genes that are differentially regulated in one direction. Many
homeostatic systems will include one limb that is upregulated in response to a downregulation of another limb and vice versa.
Such patterns are poorly captured by the standard formulation of GSEA. We describe a technique to identify groups of genes
(which sometimes can be pathways) that include both up- and down-regulated components. This approach lends insights into the
feedback mechanisms that may operate, especially when integrated with protein interaction databases.
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