During a woman's reproductive years, myometrial smooth-muscle cells undergo multiple cycles of growth followed by involution under the influence of ovarian hormones or the hormones of pregnancy. These cycles make stem cells vulnerable to the development of mutations. A point mutation affecting the function of MED12, a chromosomal rearrangement increasing the expression of HMGA2, or some other gene defect in a somatic stem cell in the myometrium may be the initiating event of tumorigenesis. This original, single genetic hit may alter key signaling pathways such as those involving β-catenin and TGF-β, which regulate cell proliferation, survival, and senescence and the formation of extracellular matrix, leading to clonal expansion of the stem cells within the genetically normal myometrium. The majority of the cells in this expanding clone will differentiate and develop a phenotype similar to that of myometrial smooth-muscle cells but will also maintain the original mutation or chromosomal rearrangement and an abnormal epigenetic signature favoring further growth. In this context, the inherent capability of myometrial tissue to respond to estrogen and progesterone for physiologic expansion during the luteal phase of the ovulatory cycle or pregnancy may work to the advantage of fibroid-tumor growth. Such growth may be mediated by high levels of estrogen and progesterone receptors in normal myometrial cells or by the differentiated population of fibroid cells that send paracrine signals to the receptor-deficient fibroid stem cells for self-renewal. For unknown reasons, most uterine fibroids do not acquire further critical genetic hits and therefore remain benign. Many diverse molecular and cellular abnormalities may give rise to a uterine fibroid, an extraordinarily common phenotype. Thus, depending on their genetic and epigenetic makeup and the nature of the surrounding molecular and endocrine environment, these tumors vary in their potential for massive further growth, dormancy, and regression. The diverse mechanisms that favor tumorigenesis and the growth of uterine fibroids also provide the basis for their heterogeneous response to medical therapy. A class of antiprogestins currently represents the most specific medical approach to targeting a defined mechanism in fibroids (Fig. 4).69-72 In fact, antiprogestins induce amenorrhea and reduce tumor size in the majority of treated patients.71,72 Targeting of pathways involving fibroid stem cells that primarily control tumor growth should lead to the development of new treatments.
ASJC Scopus subject areas