Matrix production and remodeling as therapeutic targets for uterine leiomyoma

Abstract

Uterine leiomyoma, commonly known as fibroids, is a benign neoplasm of smooth muscle in women. The incidence of clinically symptomatic fibroids in reproductive-age women is approximately 20 %, with nearly 80 % of black women suffering from this condition. Symptoms include severe pain and hemorrhage; fibroids are also a major cause of infertility or sub-fertility in women. Uterine leiomyoma consist of hyperplastic smooth muscle cells and an excess deposition of extracellular matrix, specifically collagen, fibronectin, and sulfated proteoglycans. Extracellular matrix components interact and signal through integrin-β1 on the surface of uterine leiomyoma smooth muscle cells, provide growth factor storage, and act as co-receptors for growth factor-receptor binding. ECM and growth factor signaling through integrin-β1 and growth factor receptors significantly increases cell proliferation and ECM deposition in uterine leiomyoma. Growth factors TGF-β, IGF, PDGF, FGF and EGF are all shown to promote uterine leiomyoma progression and signal through multiple pathways to increase the expression of genes encoding matrix or matrix-modifying proteins. Decreasing integrin expression, reducing growth factor action and inhibiting ECM action on uterine leiomyoma smooth muscle cells are important opportunities to treat uterine leiomyoma without use of the current surgical procedures. Both natural compounds and chemicals are shown to decrease fibrosis and uterine leiomyoma progression, but further analysis is needed to make inroads in treating this common women's health issue.

Aromatase expression and regulation in breast and endometrial cancer

“…E1 is synthesized in skin and adipose tissues from circulating androstenedione of adrenal origin and is the major form of estrogen produced in postmenopausal women (Shozu et al . 2003, Fujisawa & Castellot 2014). E2 is the most potent estrogen and is the major estrogen product synthesized in the premenopausal ovaries.…”

“…2014). Conjugation of lipophilic estrogens with sulfate is thus a main pathway for estrogen inactivation in estrogen target tissue (Fujisawa & Castellot 2014). …”

A selective serotonin 5-HT 1B receptor inhibition suppresses cells proliferation and induces apoptosis in human uterine leiomyoma cells

“…Benign uterine leiomyomas (UL) (fibroids or myomas) are the most common pelvic tumor in women in the US [1][2][3]. The incidence of uterine myomas has been reported to be about 60% among African-American women by age 35, increasing to >80% by age 50, whereas Caucasian women showed an incidence of 40% by age 35, and almost 70% by age 50 [2,3]. ULs account for more than 200.000 hysterectomies in the USA annually, and are still the most common reason for gynecological surgeries [3].…”

“…The incidence of uterine myomas has been reported to be about 60% among African-American women by age 35, increasing to >80% by age 50, whereas Caucasian women showed an incidence of 40% by age 35, and almost 70% by age 50 [2,3]. ULs account for more than 200.000 hysterectomies in the USA annually, and are still the most common reason for gynecological surgeries [3]. Definitive treatment modality includes only surgical approaches, which cause undesirable side effects and negative impact on women's quality of life, reproductive ability, and a substantial impact on health costs.…”

“…The alterations in the regulatory pathways in cell cycle and proliferation are though one of the main factors causing growth of UL. Overexpression of growth factors, such as epidermal growth factor (EGF), transforming growth factor (TGF)-b, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and their receptors promote UL growth through induction of cell proliferation [3]. While the alterations in these genes or in protein expressions lead to the formation of UL, its progression has been reported to be mainly linked with ovarian steroids [4].…”