Abstract
Uterine leiomyomas (ULs) are benign tumors occurring in the majority of reproductive aged women. Despite the high prevalence of these tumors, little is known about their etiology. A hallmark of ULs is the excessive deposition of extracellular matrix (ECM), primarily collagens. Collagens are known to modulate cell behavior and function singularly or through interactions with integrins and growth factor-mediated mitogenic pathways. To better understand the pathogenesis of ULs and the role of ECM collagens in their growth, we investigated the interaction of leiomyoma smooth muscle cells (LSMCs) with two different forms of collagen, non-polymerized collagen (monomeric) and polymerized collagen (fibrillar), in the absence or presence of platelet-derived growth factor (PDGF), an abundant growth factor in ULs. Primary cultures of human LSMCS from symptomatic patients were grown on these two different collagen matrices and their morphology, cytoskeletal organization, cellular proliferation, and signaling pathways were evaluated. Our results showed that LSMCs had distinct morphologies on the different collagen matrices and their basal as well as PDGF-stimulated proliferation varied on these matrices. These differences in proliferation were accompanied by changes in cell cycle progression and p21, an inhibitory cell cycle protein. In addition we found alterations in the phosphorylation of focal adhesion kinase, cytoskeletal reorganization, and activation of the mitogen activated protein kinase (MAPK) signaling pathway. In conclusion, our results demonstrate a direct effect of ECM on the proliferation of LSMCs through interplay between the collagen matrix and the PDGF-stimulated MAPK pathway. In addition, these findings will pave the way for identifying novel therapeutic approaches for ULs that target ECM proteins and their signaling pathways in ULs.
Highlights
Uterine leiomyomas (ULs) are one of the most common pelvic neoplasms in reproductive aged women with a reported prevalence of 25-70% depending on age [1,2,3]
Morphology of leiomyoma smooth muscle cells (LSMCs) on different collagen matrices To understand the interaction of LSMCs with different collagen matrices, we cultured primary LSMCs on plastic, monomeric collagen or fibrillar collagen-coated dishes and examined cell morphology 48 hours later
When the fibrillar coating was removed from one section of the culture dishes by scraping with a sterile, plastic pipette tip the LSMCs returned to their spindle-like morphology and grew to cells on plastic and monomeric collagen matrices (Figure 1D)
Summary
Uterine leiomyomas (ULs) are one of the most common pelvic neoplasms in reproductive aged women with a reported prevalence of 25-70% depending on age [1,2,3] These benign tumors originate from uterine smooth muscle cells (SMCs) and can cause severe symptoms such as abnormal uterine bleeding, pelvic pain and infertility [3]. There is greater remodeling of the ECM in leiomyomas as they express higher levels of specific metalloproteinases (MMPs) including MMP2 and MMP11 [14,15,16] These changes are contributing factors in the altered mechanical homeostasis in ULs leading to changes in cell signaling [17,18]
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