Role of Transforming Growth Factor β in Uterine Fibroid Biology

Abstract

Uterine fibroids (UFs) are benign tumors of the female genital tract made of the smooth muscle of the uterus. UF growth depends mostly on the influence of the steroid hormones and selected growth factors. Transforming growth factor β (TGF-βs) is a polypeptide that consists of three isoforms: TGF-β1, TGF-β2, and TGF-β3. At present, TGF-β is considered to be one of the key factors in the pathophysiology of UFs. It plays a major role in cellular migration within the tumor, stimulates tumor growth, and enhances tumor metabolism. As a consequence of various dependencies, the synthesis and release of TGF-β in a UF tumor is increased, which results in excessive extracellular matrix production and storage. High concentrations or overexpression of TGF-β mediators may be responsible for clinically symptomatic UFs. The aim of this review was to check the available evidence for the influence of the TGF-β family on UF biology. We conducted their search in PubMed of the National Library of Medicine with the use of the following selected keywords: "uterine fibroid", "leiomyoma", and "transforming growth factor β". After reviewing the titles and abstracts, more than 115 full articles were evaluated. We focused on the TGF-β-related molecular aspects and their influence on the most common symptoms that are associated with UFs. Also, we described how the available data might implicate the current medical management of UFs.

Keywords: leiomyoma; pathophysiology; therapy; transforming growth factor β; uterine fibroid.

Figure 1

TGF-β isoforms, TGF-β receptors; TGF-β intracellular signaling pathways. TGF-β: transforming growth factor β; FAK: focal adhesion kinase; TAK: TGF-β-activated kinase; MKK: Mitogen-activated protein kinase kinase; JNK: c-Jun N-terminal kinase; p38: p38 mitogen-activated protein kinases; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: mechanistic target of rapamycin; Ras: Ras protein; Raf: Raf protein; MEK: MAPK/ERK kinase; ERK: Extracellular signal-regulated kinases; Smad: Smad protein.

Figure 2

Increased secretion of Wnt ligands under the influence of estrogen and progesterone (Figure 3) from smooth muscle cells, which are placed around uterine fibroid stem cells. This pathway leads to excessive production of the transforming growth factor β and extracellular matrix, as well asenhanced proliferation of uterine fibroid stem cells.

Figure 3

Estrogen and progesterone—two main hormones influencing the metabolism and proliferation of uterine smooth muscle cells or uterine fibroid cells. Wnt signaling is one of the most important pathways in uterine fibroid pathophysiology. Excessive production of transforming growth factor β depends greatly on Wnt signals. The drugs influencing the hormonal pathways and their potential site of effect are presented. ER: Estrogen receptor; PR: Progesterone receptor.