Genetic alterations in uterine fibroids - a new direction for pharmacological intervention?

INTRODUCTION: Though uterine leiomyomas (UL) (syn.: fibroids) are by far the most frequent human symptomatic tumors their pathogenesis still remains to be elucidated. From the detection of microscopically visible alterations of chromosomal structure and molecular cytogenetic analyses, as well as from transcriptome and genome analyses, a picture of a heterogeneous group of benign clonal smooth muscle neoplasms emerges that, for clinical as well as histological reasons, have been summarized under the headline 'UL'. AREAS COVERED: In this review, the authors address the background of genetic alterations identified in UL as well their possible clinical significance. EXPERT OPINION: Of the emerging genetic subgroups of UL those characterized by chromosomal alterations targeting high mobility group protein AT-hook 2 gene (10 - 20%) and those with point mutations of mediator subcomplex 12 (60 - 70%) predominate. Mechanistic models as to how these changes molecularly contribute to tumor development are lagging far behind their identification. Nevertheless, the different sizes of both types of myomas, their different tendency to occur as single or multiple tumors, and even a different probability to undergo malignant transformation suggest that in the future the clinical management of patients with fibroids will benefit from distinguishing between these latter as well as other more rare subgroups.

Uterine fibroids: do we deal with more than one disease?

Uterine fibroids rank among the most frequent symptomatic human tumors at all. Recent data suggest that mutations of the mediator subcomplex 12 gene (MED12) and rearrangements of the gene-encoding high-mobility group protein AT-hook 2 (HMGA2) characterize major genetic subtypes of these tumors, which, for example, differ by their average size. Herein, we have investigated a total of 289 fibroids from 120 patients. Of these fibroids, 256 were fully genetically analyzed. Of the latter group, 20 (7.8%) fibroids had a chromosomal rearrangement of 12q14-15 reflecting a rearranged allele of HMGA2 and 179 (69.9%) fibroids had a mutation of MED12. The remaining tumors had either another genetic abnormality or no detectable abnormality at all. We were able to demonstrate that tumors of both groups also display striking differences of their frequency in individual patients. Whereas 70.0% (14/20) HMGA2-mutated fibroids made their appearance as solitary nodules, 85.5% (153/179) MED12-mutated fibroids occurred as multiple nodules as a rule of independent clonal origin, as reflected by different MED12 mutations. These findings are likely to point to a different pathogenesis of both types of fibroids. In the predominant of these groups so far, an unknown "mutator" may cause independent mutations of MED12, resulting in an independent clonal outgrowth of nodules. Furthermore, the low but existing risk of MED12-mutated fibroids to undergo malignant transformation after a leiomyoma-STUMP (smooth muscle tumors of uncertain malignant potential)-leiomyosarcoma sequence excludes the latter mutation as a suitable stand-alone marker for benign growth.

Permanent activation of HMGA2 in lipomas mimics its temporal physiological activation linked to the gain of adipose tissue.

OBJECTIVE: In this study the activation of HMGA2 and overexpression by FGF1-driven stimulation of adipose tissue derived stem cells (ADSCs) in adipose tissue tumors were analyzed. In addition, the expression of HMGA2 and PPAR-gamma mRNA were quantified in canine subcutaneous abdominal adipose tissue from normal and overweight purebred dogs. DESIGN AND METHODS: ADSCs and adipose tissue explants stimulated with FGF1 followed by gene expression analyses of HMGA2 and p14(Arf) using Western-blot and qRT-PCR. Furthermore, canine subcutaneous white adipose tissue (WAT) were analyzed by qRT-PCR for their expression of HMGA2 and PPAR-gamma. RESULTS: ADSCs and adipose tissue explants are able to execute a HMGA2 response upon FGF1 stimulation. FGF1 enhances proliferation of ADSCs by a HMGA2-dependent mechanism. In lipomas increase of HMGA2 is accompanied by increased expression of p14(Arf) . Furthermore, a significantly elevated level of HMGA2 in overweight dogs and a negative correlation between the expression of HMGA2 and PPAR-gamma in subcutaneous cWAT were noted. CONCLUSIONS: These results suggest that WAT contains cells that as essential part of adipogenesis up-regulate HMGA2 resulting from growth factor stimulation. In subgroups of lipoma, constitutive activation of HMGA2 due to rearrangements replaces the temporal response triggered by growth factors.

Fibroid explants reveal a higher sensitivity against MDM2-inhibitor nutlin-3 than matching myometrium.

BACKGROUND: Spontaneous cessation of growth is a frequent finding in uterine fibroids. Increasing evidence suggests an important role of cellular senescence in this growth control. Deciphering the underlying mechanisms of growth control that can be expected not only to shed light on the biology of the tumors but also to identify novel therapeutic targets. METHODS: We have analyzed uterine leiomyomas and matching normal tissue for the expression of p14Arf and used explants to see if reducing the MDM2 activity using the small-molecule inhibitor nutlin-3 can induce p53 and activate genes involved in senescence and/or apoptosis. For these studies quantitative real-time RT-PCR, Western blots, and immunohistochemistry were used. Statistical analyses were performed using the student's t test. RESULTS: An in depth analysis of 52 fibroids along with matching myometrium from 31 patients revealed in almost all cases a higher expression of p14Arf in the tumors than in the matching normal tissue. In tissue explants, treatment with the MDM2 inhibitor nutlin-3 induced apoptosis as well as senescence as revealed by a dose-dependent increase of the expression of BAX as well as of p21, respectively. Simultaneously, the expression of the proliferation marker Ki-67 drastically decreased. Western-blot analysis identified an increase of the p53 level as the most likely reason for the increased activity of its downstream markers BAX and p21. Because as a rule fibroids express much higher levels of p14Arf, a major negative regulator of MDM2, than matching myometrium it was then analyzed if fibroids are more sensitive against nutlin-3 treatment than matching myometrium. We were able to show that in most fibroids analyzed a higher sensibility than that of matching myometrium was noted with a corresponding increase of the p53 immunopositivity of the fibroid samples compared to those from myometrium. CONCLUSIONS: The results show that uterine fibroids represent a cell population of advanced cellular age compared to matching myometrium. Moreover, the data point to members of the p53-network as to potential novel therapeutic targets for the treatment of uterine fibroids.

Selective visual attention ensures constancy of sensory representations: testing the influence of perceptual load and spatial competition.

We report findings from several variants of a psychophysical experiment using an acceleration detection task in which we tested predictions derived from recent neurophysiological data obtained from monkey area MT. The task was designed as a Posner paradigm and required subjects to detect the speed-up of a moving bar, cued with 75% validity. Displays varied according to number of simultaneously presented objects, spatial distance, and difficulty of the task. All data obtained under different levels of competition with multiple objects were compared to a corresponding condition, in which only a single moving bar was presented in the absence of any interfering distracter object. For attended objects, subjects did not show any difference in their ability to detect accelerations, regardless of the strength of inter-object competition or spatial distance. This finding was consistent in all of the experiments, and was even obtained when the acceleration was made hardly detectable. In contrast, increasing competitive interactions either by enhancing number of objects or spatial proximity resulted in strong reduction of performance for non-attended objects. The findings support current noise reduction models and suggest that attention adjusts neuronal processing to ensure a constant sensory representation of the attended object as if this object was the only one in the scene.