Why Leiomyomas Are Called Fibroids: The Central Role of Extracellular Matrix in Symptomatic Women

Abstract

Uterine leiomyomas are highly prevalent and symptomatic tumors of women in their reproductive years. The morbidity caused by these tumors is directly related to increasing size. Leiomyoma cells do not rapidly proliferate; instead, the tumors grow primarily due to excessive production of disorganized extracellular matrix (ECM). The aberrant ECM results from excessive production of collagen subtypes and proteoglycans, increased profibrotic cytokines including transforming growth factors beta1 and beta3, and decreased or disrupted matrix metalloproteinases. These alterations result in the development of an ECM that is exceptionally stable. As a result, therapeutic interventions must redirect leiomyoma cells toward extracellular matrix dissolution, rather than solely inhibiting cell proliferation. Gonadotropin-releasing hormone analogues and selective progesterone receptor modulators with demonstrated clinical efficacy provide such a change in abnormal extracellular matrix formation by leiomyoma cells, inhibiting and reversing the fibrotic process. Novel therapies using pathways distinct from gonadal hormones, including antifibrotics, retinoic acid, peroxisome-proliferator-activated receptor gamma ligands, and curcumin, provide promise for a future with improved therapeutic options for women suffering from uterine leiomyomas.

Leiomyoma Cells in 3-Dimensional Cultures Demonstrate an Attenuated Response to Fasudil, a Rho-Kinase Inhibitor, When Compared to 2-Dimensional Cultures

“…34,36 Collagen 1, fibronectin, and versican are ECM proteins that are known to be increased in the leiomyoma tumor, as compared to normal myometrium, and therefore dysregulation of these genes is a crucial component of tumor formation. 3,9,10,62,63 In present study, we examined the changes in expression of these genes in response to fasudil treatment of leiomyoma and myometrial cell lines in 2D and 3D culture systems. In 2D cultures of both myometrial and leiomyoma cells, downregulation of transcripts resulted in reduced amount of ECM proteins in response to fasudil treatment.…”

“…4,7,8 It is an accepted fact that leiomyomas are characterized by excessive and disordered extracellular matrix (ECM) which contributes to the total bulk of the tumor. 9,10 Furthermore, the tumor is characterized by increased stiffness as studied in vitro 11,12 or in vivo by magnetic resonance elastography. 13,14 Cells sense the changes in the surrounding stiffness as mechanical cues and translate them into biochemical signals.…”

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…In addition to alterations in composition, the ultrastructure of collagen fibrils in leiomyoma is altered in both structure and orientation compared with normal myometrium (150). In fact, this disordered matrix represents the major part of the tumor (151) and is responsible for most of the symptoms (152).…”

Comparative systems genetics view of endometriosis and uterine leiomyoma: Two sides of the same coin?

“…Decisive changes potentiating UL growth occur in extracellular matrix (ECM). Pathogenesis of fibroids seems to involve a positive feedback loop between extracellular matrix production and cell proliferation and vitamin D. Extracellular matrix components mainly consisting of collagen subtypes, fibronectin, and proteoglycans, a series of collagen subtypes, such as COL1A1, 4A2, 6A1, 6A2, 7A1, and 16A1 have been recently found expressed to a greater extent in UL cells compared to normal myometrial cells [Malik et al 2010].…”