Mechanical signaling through the cytoskeleton regulates cell proliferation by coordinated focal adhesion and Rho GTPase signaling

Abstract

SummaryThe notion that cell shape and spreading can regulate cell proliferation has evolved over several years, but only recently has this been linked to forces from within and upon the cell. This emerging area of mechanical signaling is proving to be wide-spread and important for all cell types. The microenvironment that surrounds cells provides a complex spectrum of different, simultaneously active, biochemical, structural and mechanical stimuli. In this milieu, cells probe the stiffness of their microenvironment by pulling on the extracellular matrix (ECM) and/or adjacent cells. This process is dependent on transcellular cell-ECM or cell-cell adhesions, as well as cell contractility mediated by Rho GTPases, to provide a functional linkage through which forces are transmitted through the cytoskeleton by intracellular force-generating proteins. This Commentary covers recent advances in the underlying mechanisms that control cell proliferation by mechanical signaling, with an emphasis on the role of 3D microenvironments and in vivo extracellular matrices. Moreover, as there is much recent interest in the tumor-stromal interaction, we will pay particular attention to exciting new data describing the role of mechanical signaling in the progression of breast cancer. Journal of Cell Sciencephysiological conditions, a dynamic force balance -termed tensional homeostasis -occurs between the cell and the microenvironment, and the cell will proliferate at normal levels (Klein et al., 2009). By contrast, if matrix stiffness is uncharacteristically elevated, an abnormally elevated tensional homeostasis arises that can result in aberrant cellular behaviors. For example, increased matrix stiffness associated with the increased deposition, altered composition and alignment of the collagenous stroma that accompanies breast tumor progression can promote disruption of epithelial architecture (Paszek et al., 2005;Provenzano et al., 2008a;Wozniak et al., 2003). Cells in this environment hyperactivate a mechanically regulated signaling loop that results in increased expression of a conserved set of carcinomaassociated proliferation genes, such as genes that encode cyclins, aurora kinases, cell division cycle regulators and E2F transcription factors, which are important for cell proliferation (Provenzano et al., 2009). Hence, in addition to the cellular microenvironment being an intricate system that includes a complex chemical milieu surrounding the cell, it is now clear that the stiffness of the ECM and the corresponding mechanical response of the cell have a role in regulating fundamental processes -including cell proliferation.In this Commentary, we will cover recent advances in our understanding of the regulation of cell proliferation by mechanical signaling. The emphasis is on the role of mechanical signal transduction in the context of 3D microenvironments, which include cell culture models of defined ECM composition and concentration, such as collagen matrices that contain individual cells or cell communities, models of com...

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…53,54 Cells, in turn, are able to sense changes in the mechanical properties of the local environment and respond to them in ways that deviate from behaviors under normal tissue homeostasis. 55,56 Therapeutic targeting of lysyl oxidase in mouse models has shown promise in reducing collagen cross-linking and tumor stiffness, and ultimately in reversing the malignant phenotypes of cells. 57 Likewise, ablating mechanically interacting aligned collagen tracks between cancer cells results in a similar phenotype reversal.…”

Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics

“…The mechanism by which stiffness influences junctional integrity remains unclear; however, the localization of VE-cadherin is changed in a stiffness-dependent manner, with more VEcadherin being present in the cytoplasm on more flexible substrates. One possible mechanism of control might involve the small GTPases, Rho and Rac, because ECM stiffness 44 and mechanical forces 45,46 control their activities, and Rho and Rac have been shown to regulate VE-cadherin localization and cell-cell junctional integrity 47 .…”

A mathematical model of HiF-1-mediated response to hypoxia on the G1/S transition

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