The Mechanical Rigidity of the Extracellular Matrix Regulates the Structure, Motility, and Proliferation of Glioma Cells

Abstract

Glioblastoma multiforme (GBM) is a malignant astrocytoma of the central nervous system associated with a median survival time of 15 months, even with aggressive therapy. This rapid progression is due in part to diffuse infiltration of single tumor cells into the brain parenchyma, which is thought to involve aberrant interactions between tumor cells and the extracellular matrix (ECM). Here, we test the hypothesis that mechanical cues from the ECM contribute to key tumor cell properties relevant to invasion. We cultured a series of glioma cell lines (U373-MG, U87-MG, U251-MG, SNB19, C6) on fibronectin-coated polymeric ECM substrates of defined mechanical rigidity and investigated the role of ECM rigidity in regulating tumor cell structure, migration, and proliferation. On highly rigid ECMs, tumor cells spread extensively, form prominent stress fibers and mature focal adhesions, and migrate rapidly. As ECM rigidity is lowered to values comparable with normal brain tissue, tumor cells appear rounded and fail to productively migrate. Remarkably, cell proliferation is also strongly regulated by ECM rigidity, with cells dividing much more rapidly on rigid than on compliant ECMs. Pharmacologic inhibition of nonmuscle myosin II-based contractility blunts this rigidity-sensitivity and rescues cell motility on highly compliant substrates. Collectively, our results provide support for a novel model in which ECM rigidity provides a transformative, microenvironmental cue that acts through actomyosin contractility to regulate the invasive properties of GBM tumor cells. [Cancer Res 2009;69(10):4167-74]

Modeling crawling cell movement on soft engineered substrates

“…This simplication, while useful, is not very realistic: it is known that some parts of cells still adhere while others lose contact. 18,51,59 In other words, inhomogeneously distributed force affects the adhesion and provides a feedback on the overall shape and motion. This is remedied here, in contrast to ref.…”

Numerical modeling of cell differentiation and proliferation in force-induced substrates via encapsulated magnetic nanoparticles

“…Cells may respond to the mechanical properties of their ECM, such as substrate stiffness, by differentiation, proliferation and/or apoptosis [22,23,31,67]. Experiments demonstrate that a specific deformation range sensed by a cell leads to a specific differentiation [10,34,69].…”

“…To avoid such abnormal conditions, cells have to be particularized in such a way as to differentiate or proliferate in response to appropriate biological stimuli. Experiments have shown that, besides other factors [58,59], the mechanical structure of cellular micro-environments plays an important role in cell differentiation and proliferation [22,23,31,67]. For instance, Mesenchymal Stem Cells (MSCs) differentiate into specific phenotypes with high sensitivity to the tissue rigidity where they reside in.…”

Measuring Cell Viscoelastic Properties Using a Microfluidic Extensional Flow Device

“…Although it has been long understood that soluble factors from the cellular microenvironment can strongly influence cellular behavior, it is becoming increasingly clear that physical, and especially mechanical, inputs can also affect cell behaviors such as migration, proliferation, and differentiation (1)(2)(3)(4). Cells frequently respond to mechanical stimuli by adaptively tuning their intrinsic mechanical properties, and significant evidence suggests that this ''mechanoadaptation'' is key to transducing these inputs into biochemical signals that mediate cell behavior.…”