The Role of Fibroblast Activation in Uterine Fibroid

Uterine fibroids (UFs), also called uterine leiomyomas or myomas, are steroid hormone-responsive, benign tumors of the smooth muscle compartment (myometrium) of the uterus. They are the most common neoplasm affecting women in their reproductive age. It is estimated that up to 77% of women develop UF in their life. UFs are one of the leading causes of hospitalisations for gynaecological disorders and are the most frequent reason for hysterectomy. According to relevant literature, 40%-60% of all the hysterectomies performed are due to the presence of UFs.

* Uterine fibroids (UFs) are steroid hormone-responsive, benign tumors of the smooth muscle compartment (myometrium) of the uterus .They are the most common neoplasm affecting women in their reproductive age. UFs are mainly composed of fibroid cells and a significant ECM component which principally consists of fibroblasts. Previous studies on the pathogenesis of uterine UF have mainly focused on the differentiation and proliferation of fibroid cells. However, the histologic features of fibroid tissue suggest that fibroblasts may play an important role in the generation of UF. * Fibroblast activation protein (FAP), fibroblast-specific marker, is a 95 kDa cell surface glycoprotein. It is a type II transmembrane serine protease and a member of proline-specific proteases family. Recent studies showed that the high expression of FAP is closely related to the occurrence of UF .Luo et al 2015 were the first who suggested that estrogen could stimulate fibroblast activation. In addition, they revealed that proliferative activity of fibroblast and the expression of FAP were significantly increased after estrogen stimulation. They also found that estrogen could promote the release of cytokines (TGFβ and IGF-1) and ECM components (collagen I, fibronectin, and laminin) from fibroblasts. Furthermore they found that silencing of FAP expression significantly decreased promotion effects of estrogen on TAF suggesting that FAP plays an important role in estrogen-mediated fibroblast activation. * Autophag (eating of self) is a collection of processes that enables the cells to digest and recycle their cytoplasmic contents, such as toxic protein aggregates, disused organelles and invading microorganisms. Dysregulation in autophagy process have been recently described in many neoplasms. However the role of autophagy in the pathogenesis of UFs is still unclear and further understanding of its regulation and significance will be needed. * The PI3K/AKT/mTOR signalling pathway is considered the main pathway involved in the initiation and regulation of autophagy. Previous studies found that reduced FAP significantly decreased the expression of phosphorylated AKT suggesting that FAP is an upstream factor modulating the PI3K/AkT. This study will be the first to study the link between fibroblast activation and autophagy in pathogenesis of UF through PI3K/AKT signaling pathway. Although several types of drugs (mostly antiproliferative agents) are available for UF treatment, none of them were introduced specifically as antifibrotic agents. Targeting such novel signaling pathway may be considered useful for future non surgical treatment of UF affecting both proliferative and fibrotic changes.