Fibroids and Fibroid Biology – Technical Article

 

Fibroids have a single cell origin.

Uterine fibroids are benign (non-malignant) tumours of the myometrium of the uterus that are made up of a widely varying amount of extracellular fibrous material and smooth muscle. The vast majority of fibroids occur randomly amongst the female population, whilst a small number of fibroids grow and develop as part of the rare hereditary leiomyomatosis and renal cell cancer syndrome. Fibroids occur much more frequently in the body of the uterus (womb) than in the cervix.

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Each fibroid is known to grow from a single cell in the myometrium of the uterus. This fact was determined by studies of women who had developed multiple fibroids, who were also heterozygous for the glucose-6-phosphate dehydrogenase (G6PD) gene on the X chromosome. In women, each somatic (body) cell contains 2 X chromosomes, whilst each male body cell carries only one X chromosome. One female X chromosome can be made silent by packaging it in repressive heterochromatin. Which X chromosome is inactivated is randomly determined, and once a cell’s X chromosome has been inactivated, it remains inactive throughout the life of that cell. In the women who were studied, all cells in any given fibroid were either G6PD variant A or variant B, and not a mixture of the two. From this observation it was concluded by the medical researchers, Linder, Gartler and by Townsend et al. that each fibroid arises from one cell alone, in the myometrium. In addition X chromosome inactivation patterns studied in DNA methylation, in monoclonal androgen receptor DNA, and in enzyme phosphoglycerokinase have also shown that each uterine fibroid grows from a single cell in the myometrium of the uterus.

Therefore, we can conclude that multiple fibroids in the same uterus are not related clonally. In other words, each fibroid arises independently. Since many types of uterine fibroids contain considerable amounts of fibrous tissue, which is assumed to be generated by fibroblasts, this medical evidence suggests that in addition to myometrial cells within fibroids, growing from a single cell, fibroblasts within fibroids are derived from the same cell line. This further suggests that the progenitor cells from which fibroids originate are pluripotential and able to generate at least fibroblast and myometrium cell types. In addition, the frequent incidence of fibroids within the general population, suggests that the origin of fibroids is related to a frequently occurring cellular event. Menstruation is a very frequently occurring event in modern women, and the positive correlation of the risk of fibroids with age (which is a correlate for the number of menstrual cycles) suggests that excessive menstrual cycles may be causally related to fibroids.

Fibroids and genetics

Gynaecologists believe that susceptibility to fibroids has a genetic component. This is because there is a familial predisposition to fibroids, there is a higher incidence of fibroids in black women when compared with white women, and there is a higher risk of fibroids in monozygotic twins when compared with dizygotic twins.

It has been widely assumed by doctors, but never conclusively demonstrated, that fibroids develop from mutations in myometrial cells. Actually proving this assumption is thought to be very difficult. Single nucleotide polymorphisms are known to exist widely in the human genome, generating many alleles for each gene, some of which have no effect at all upon protein expression, and others which produce two different but normally functioning proteins. In those diseases in which hundreds of genes may be undergoing mutation to cause a specific disease, elaborating which single nucleotide substitutions are associated with a specific disease and those which are not is an enormous task. To give an example, only recently has the genome of breast cancer been defined. In an analysis of over 13,000 genes, which is a little more than half of the human genome, the medical researchers, Sjoblom et al. identified 105 mutant genes which were thought to be causally related to breast cancer. A research project of this enormous magnitude will also be required to work out the genetic basis of fibroids.

In addition, it is known that cell proliferation and differentiation may take place without genetic mutation. The fertilised ovum differentiates and proliferates into all of the wide variety of tissue types of a growing foetus’s body through differential activation of the transcriptome. Epigenetic phenomena might be at work in the formation, maintenance and degeneration of uterine fibroids.

The transcriptome is usually defined by complementary DNA gene-array techniques that are able to define the state of mRNA at a given point in time of a cells life. However gene-array technology is in its infancy and is not yet stable and mature. There have been many micro-array studies published which have compared fibroid tissue with adjacent myometrium tissue. In one study, 106 fibroid related genes were identified and in another study 68 separate fibroid related genes were discovered. The vast majority of identified fibroid genes were unique to each study. Only 11 genes were differentially expressed in fibroid tissue and myometrium tissue in both studies. This type of study is still in its infancy. However, one of the themes that has emerged is that many extracellular matrix genes have been found to be not working properly in fibroid tissue when compared to normal myometrium tissue.

Fibroids and abnormal chromosomes

Medical research has shown that chromosomal abnormalities within fibroid cells are not rare. However, the cytogenetic abnormalities that are seen in fibroids are thought to be most likely secondary phenomena, which develop after a fibroid is established and growing rapidly. The cytogenetic abnormalities seen in fibroids are not thought to be causal.

The malignant potential of fibroids

It is extremely rare for fibroids to become malignant. Fibroids are extremely benign tumours and they are very very common. Gynaecologists debate whether leiomyosarcomas arise from fibroids. Leiomyosarcomas are very very rare. If leiomyosarcomas did arise from fibroids, then it would be expected that their incidence would be much more frequent. Some gynaecologists question whether fibroids ever progressed to malignant sarcomas. The medical researchers Packenham et al carried out a chromosomal analysis of 14 cases of uterine fibroids and eight cases of uterine leiomyosarcomas, using genomic hybridisation. They concluded that: “Our results do not provide evidence for the progression from benign leiomyoma (fibroid) to malignant leiomyosarcoma.” This conclusion and evidence is extremely reassuring for women who have fibroids.

Multiple fibroids

Multiple fibroids are common in those women who have fibroids. In a study of 100 consecutive hysterectomy specimens, which were serially sectioned at 2 mm intervals, multiple fibroids were discovered in 84% of the specimens from women who had at least one fibroid. The existence of multiple fibroids suggests that multiple genome or transcriptome changes have taken place at different times throughout a woman’s life. In addition, fibroids developing at different times in a woman’s life suggests that at any point in time, fibroids are at different stages of development. This means that fibroids of different sizes will be present within the same uterus.

Multiple fibroids which are present in the same uterus, with some being small, undetectable and asymptomatic and others being larger, detectable and symptomatic pose a significant problem for treatments that are aimed at selectively or focally removing or treating one fibroid at a time. There are a wide range of medical treatments for treating fibroids. These involve focal, nonexcisional methods of killing fibroids in situ. These treatments involve radiofrequency energy delivered by bipolar needle (with heat) cryoablation probe (with cold) and even the direct injection of 98% ethanol. All these treatments have been shown to kill fibroids. However if a woman has many fibroids which ones should be treated using these medical methods? Do you treat the large fibroids, the small fibroids, a young fibroids or the old fibroids?

Fibroids continue to develop throughout the reproductive lives of some women.

It is known that fibroids tend to recur after treatment. Studies have shown that following treatment with myomectomy or myolysis, fibroids are found again in the uterus in about 50% of cases. There are two possible explanations for the recurrence of fibroids following surgical removal or in situ ablation.

The first explanation is that some of the original fibroid may have survived the surgery or ablation and regrown. If this were the case then the appearance of uterine fibroids following myomectomy or myolysis would truly be a recurrence. Some gynaecologists favour this interpretation. Further growth of ablated fibroids has been described. On the other hand, if all or nearly all of the original fibroids were killed or removed during surgery, the appearance of fibroids at some time interval following myomectomy could simply represent continued growth of small, untreated fibroid tumours. Or alternatively, the interval appearance of new fibroids which were not present when the surgical intervention was carried out. In this case, referring to the appearance of fibroids as “recurrence” is clearly inappropriate. A fibroid seen at some time interval following surgery would not be a recurrence of the original fibroid which had been removed, it would be either the clinical appearance of a small overlooked fibroid or the mechanical appearance of an altogether new fibroid. Most gynaecologists believe that in the vast majority of cases, fibroids seen following myomectomy do not represent regrowth of the treated fibroid. Therefore many gynaecologists prefer the term “appearance of new fibroids” rather than “recurrence”.

Gynaecologists note that women with fibroids can be divided into two groups: those that develop only a few fibroids during their life, and those women who develop many. A gynaecologist researcher, Malone, carried out a study where he divided women with fibroids into two groups. Those who were treated with myomectomy for a single fibroid, and women who were treated with myomectomy for multiple fibroids. He studied 125 women using clinical findings only. He found that the post operative appearance of new fibroids took place in 26% of women with single fibroids and about 59% of women who had multiple fibroids. The appearance of new fibroids following surgery is more common in women who have many fibroids in a uterus, when compared with women who have few. Another study found that women who had more than three fibroids removed, had a new fibroid appearance rate of 90%. A gynaecologist, Nishiyama, has demonstrated high new fibroid appearance rates in Japanese women. Some gynaecologists have attempted to reduce the rate of new fibroid appearance following surgery by giving a gonadotropin releasing hormone analogue either pre-or post-operatively without success.

Fibroid size is thought to be a balance between cell growth and cell death.

Researchers report that fibroid growth is a balance between mitosis, which produces new fibroid sells and necrosis (apoptosis) which kills fibroid cells. Therefore if mitosis increases and necrosis remained static, then the fibroid will grow. If mitosis increases and necrosis decreases, then the fibroid will grow even more. It is known that spontaneous necrosis of fibroids occurs, leading to fibroid degeneration and shrinkage.

 

Fibroids grow from their periphery.

It is known that fibroids grow mainly from their periphery, in what has been compared to the trunk of a tree. A researcher Bourlev et al. demonstrated this process by carefully examining proliferative and apoptotic (necrotic) activity, and the expression of sex steroid receptors in peripheral and central areas of fibroids, throughout the different phases of the menstrual cycle. He obtained paired biopsy samples from the myometrium and from the peripheral and central parts of fibroids in 15 women, who were in the proliferative phase of the menstrual cycle, and eight women who were in the secretory phase of the menstrual cycle. He found that during the secretory phase, mitosis was significantly greater in the periphery than in the central part of the fibroid. During the proliferative phase of the menstrual cycle necrosis, or apoptosis, was significantly greater in the periphery when compared with the central parts of the fibroids. In summary, this data showed that fibroids grow from the periphery and that they grow during the secretory phase of the menstrual cycle.

Another researcher, Wei et al. took tissue biopsies from large (<10 cm diameter), and small (<2 cm diameter) fibroids, from the same uterus, and compared these fibroid tissue samples to adjacent normal tissue samples taken from the myometrium of seven different hysterectomy specimens. He then spatially divided each large fibroid into six zones, with the first zone starting at the outer margin of fibroid and the sixth zone in the centre of the fibroid. The next step was to compare the differential micro-array expression of selected genes in fibroids, to that of adjacent normal myometrium tissue. He found that hypoxia, as measured by HIF-1 expression, was higher throughout large fibroids when compared with normal myometrium or small fibroids. Furthermore, he found that hypoxia increased towards the centre of large fibroids. Cellular proliferation was higher in large and small fibroids when compared with normal myometrium and increased from very high levels in the periphery of large fibroids to lower, but still raised levels in the centre of fibroids. Conversally, hyaline degeneration was absent in normal myometrium and small fibroids and present throughout large fibroids, increasingly so towards the centre of large fibroids. The conclusion was that small fibroids and the periphery of large fibroids are more biologically active than myometrium, and that large fibroids grow from their periphery.

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