Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Abstract

Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

Figure 1

Schematic presentation of estrogen signaling pathways in uterine leiomyoma. ↑ and ↓ denote increased (red) or decreased (blue) level or function, respectively. ER: estrogen receptor; mER: membrane-bound estrogen receptor; PLC: phospholipase C; IP3: inositol triphosphate; IP3R: inositol triphosphate receptor.

Figure 2

Schematic presentation of growth factor signaling pathways in uterine leiomyoma. ↑ and ↓ denote increased (red) or decreased (blue) level or function, respectively. IP3: inositol triphosphate; IP3R: inositol triphosphate receptor.

Figure 3

Schematic presentation of transforming growth factor-β, activin, myostatin and Smad signaling in uterine leiomyoma. ↑ and ↓ denote increased (red) or decreased (blue) level or function, respectively. TGF-β: transforming growth factor-β; TβRI: transforming growth factor-β receptor I; TβRII: transforming growth factor-β receptor II; ALK4: activin-like kinase-4 (activin receptor type-1B); ActRII: activin receptor type II.

Figure 4

Schematic presentation of vitamin D signaling in uterine leiomyoma. ↑ and ↓ denote increased (red) or decreased (blue) level or function, respectively. mVDR: membrane-bound vitamin D receptor; PLC: phospholipase C; AC: adenylate cyclase; IP3: inositol triphosphate; IP3R: inositol triphosphate receptor.