Abstract
Uterine fibroids are the most common type of benign, gynecologic neoplasm and are the primary indication for performance of a hysterectomy, accounting for >200,000 hysterectomies annually in the USA. At present, females are younger and exhibit larger leiomyomas at the time of diagnosis. Cancer-associated fibroblasts in tumor microenvironments have emerged as an important target for cancer therapy. Repeated stimulation by infectious or non-infectious agents in the uterine tissues, including inflammation, mechanical forces or hypoxia, stimulate the resident fibroblasts to undergo specific activation and, thus, are significant in tumorigenesis. Furthermore, complex signaling pathways regulate the mechanisms of fibroblastic activation. The current review focuses on the molecular mechanisms of fibroblastic activation and the potential association with uterine leiomyoma pathogenesis, enabling an integrated pathogenic analysis for review of the therapeutic options.
Highlights
Uterine fibroids are the most common type of benign, gynecologic neoplasm and are the primary indication for performance of a hysterectomy, accounting for >200,000 hysterectomies annually in the USA
These findings indicate the importance of the interactions between fibroid tumor cells and ECM fibroblasts in vivo, as well as the role of growth factors and ECM proteins in the pathogenesis of uterine fibroids
The present review focuses on the fibroblast activation pathway
Summary
TGF‐β is a multifunctional cytokine, which is important in embryonic development, and the regulation of repair and regeneration processes following tissue injury [15] This large superfamily of soluble factors includes three isoforms, TGF‐β1, ‐β2 and ‐β3, which are encoded by three separate genes, but bind to the same high affinity receptor [16,17]. ED‐A is the binding site for cell membranes and for other matrix molecules It has been shown, in skin granulation tissue and hepatic models, that the fibronectin ED‐A domain is necessary for TGF‐β to trigger α‐SMA expression and collagen secretion in the stellate transformation of myofibroblasts [18](Fig. 1). As a result of Smad signals that promote the expression α‐SMA, the fibroblasts are activated and differentiated
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