Extracellular Matrix Collagen Alters Cell Proliferation and Cell Cycle Progression of Human Uterine Leiomyoma Smooth Muscle Cells

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.

Repair of dense connective tissues via biomaterial-mediated matrix reprogramming of the wound interface

“…For instance, collagen fragments can act as biochemical signals for cell proliferation [28] and migration [29]. Likewise, exposing cells to the underlying collagen network via depletion of PGs may stimulate matrix deposition [30].…”

Integrated analysis of long noncoding RNAs and mRNAs reveals their potential roles in the pathogenesis of uterine leiomyomas

“…These benign tumors originate from uterine myometrial cells and can cause uterine bleeding, pelvic pain and infertility[1]. The molecular mechanism underlying uterine leiomyoma tumorigenesis and development is not fully understood.…”

Notch3 Overexpression Promotes Anoikis Resistance in Epithelial Ovarian Cancer via Upregulation of COL4A2

“…Our results indicate that Notch3 promotes cross-talk between the ECM and cytosolic proteins, playing a significant role in disease progression. Not only can the ECM provide pro-survival signals but also the collagen matrix can alter the cell cycle and induce proliferation changes 25 , which may account for some of the cell cycle alterations observed in previous studies. The ECM and collagen are increasingly understood to be important mediators of EOC progression.…”