Cancer Cell Stiffness: Integrated Roles of Three-Dimensional Matrix Stiffness and Transforming Potential

Baker, Erin L.; Lü, Jing; Yu, Dihua; Bonnecaze, Roger T.; Zaman, Muhammad H.

doi:10.1016/j.bpj.2010.07.051

Cited by 137 publications

(124 citation statements)

References 58 publications

(100 reference statements)

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“…Most studies have focused on the mechanical cross talk between the cell and its microenvironment at the whole-cell or the tissue level. It has been shown recently that intracellular mechanics could also be used to differentiate cancer cells from normal cells (6)(7)(8)(9). Several intracellular elements participate in the mechanical response of the cytoplasm, and most of them may be modified during cancer progression.…”

mentioning

confidence: 99%

Mapping intracellular mechanics on micropatterned substrates

Mandal

Asnacios

Goud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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The mechanical properties of cells impact on their architecture, their migration, intracellular trafficking, and many other cellular functions and have been shown to be modified during cancer progression. We have developed an approach to map the intracellular mechanical properties of living cells by combining micropatterning and optical tweezers-based active microrheology. We optically trap micrometersized beads internalized in cells plated on crossbow-shaped adhesive micropatterns and track their displacement following a step displacement of the cell. The local intracellular complex shear modulus is measured from the relaxation of the bead position assuming that the intracellular microenvironment of the bead obeys power-law rheology. We also analyze the data with a standard viscoelastic model and compare with the power-law approach. We show that the shear modulus decreases from the cell center to the periphery and from the cell rear to the front along the polarity axis of the micropattern. We use a variety of inhibitors to quantify the spatial contribution of the cytoskeleton, intracellular membranes, and ATPdependent active forces to intracellular mechanics and apply our technique to differentiate normal and cancer cells.ell mechanics play a crucial role in many cellular functions that are critical during development or are altered during pathologies such as cancers. For instance, cell migration, cell adhesion, and cell division have all been shown to depend on cell mechanics (1-5). Most studies have focused on the mechanical cross talk between the cell and its microenvironment at the whole-cell or the tissue level. It has been shown recently that intracellular mechanics could also be used to differentiate cancer cells from normal cells (6-9). Several intracellular elements participate in the mechanical response of the cytoplasm, and most of them may be modified during cancer progression. The three types of fibers constituting the cytoskeleton, actin, microtubules, and intermediate filaments, clearly contribute to cell mechanics (10-13). The role of internal membranes, molecular crowding, or active force generators in the cytoplasm is less documented but could also be significant. During cancer development, signaling associated to the cytoskeleton as well as membrane trafficking, cell polarity, and intracellular organization are deregulated (14-16), supporting the idea that the mechanics of the interior of cancer cells could differ from that of normal cells.Passive or active microrheology techniques have been developed to measure intracellular mechanical properties, mostly based on the tracking of endogenous granules or internalized particles (17)(18)(19)(20)(21)(22). The experimental results are generally analyzed using two main classes of models, viscoelastic models with a finite number of viscous (dashpots) and elastic (springs) elements and power-law (PL) models (see refs. 23-26 for reviews). An increasing amount of experimental evidence points to weak PL rheology as a common feature of cell mechanical res...

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mentioning

confidence: 99%

Mapping intracellular mechanics on micropatterned substrates

Mandal

Asnacios

Goud

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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“…These stresses are transmitted to the surrounding extracellular matrix, generating radial compressive forces and circumferential tensile forces (2). The matrix is also becoming stiffer and more dense (3), and, at the invasive front, the matrix becomes reorganized, favoring tumor cell invasion (4). As the fluid pressure in the tumor increases due to the increase in tumor-associated angiogenesis, interstitial flow and lymphatic drainage increase (5).…”

Section: Solid Stress In the Tumor Microenvironmentmentioning

confidence: 98%

Biomechanical Forces Shape the Tumor Microenvironment

2011

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The importance of the tumor microenvironment in cancer progression is indisputable, yet a key component of the microenvironment--biomechanical forces--remains poorly understood. Tumor growth and progression is paralleled by a host of physical changes in the tumor microenvironment, such as growth-induced solid stresses, increased matrix stiffness, high fluid pressure, and increased interstitial flow. These changes to the biomechanical microenvironment promote tumorigenesis and tumor cell invasion and induce stromal cells--such as fibroblasts, immune cells, and endothelial cells--to change behavior and support cancer progression. This review highlights what we currently know about the biomechanical forces generated in the tumor microenvironment, how they arise, and how these forces can dramatically influence cell behavior, drawing not only upon studies directly related to cancer and tumor cells, but also work in other fields that have shown the effects of these types of mechanical forces vis-à-vis cell behaviors relevant to the tumor microenvironment. By understanding how all of these biomechanical forces can affect tumor cells, stromal cells, and tumor-stromal crosstalk, as well as alter how tumor and stromal cells perceive other extracellular signals in the tumor microenvironment, we can develop new approaches for diagnosis, prognosis, and ultimately treatment of cancer.

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“…An example is the increased cellular stiffness of fibroblasts when adhered to substrates of increasing firmness (Gupta et al, 2015;Solon et al, 2007). By and large, the stiffness of a cell is dictated by its cytoskeleton, a highly dynamic network of interconnected proteins that supports the cell, giving it shape, and is responsible for cellular processes such as migration, receptor internalization, endocytosis, exocytosis, and interactions with the surrounding substrate and neighboring cells (Baker et al, 2010;Kim and Coulombe, 2010). The cytoskeleton is also the amalgamating center for inbound intracellular signals from biophysical cues and outbound communication transduction pathways from the nucleus, acting as a vital information highway necessary for cell maintenance, homeostatic regulation and locomotion (Bezanilla et al, 2015;Mullins, 2010).…”

Section: Introductionmentioning

confidence: 99%

Non-invasive single-cell biomechanical analysis using live-imaging datasets

Pearson

Lund

Lin

et al. 2016

Journal of Cell Science

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The physiological state of a cell is governed by a multitude of processes and can be described by a combination of mechanical, spatial and temporal properties. Quantifying cell dynamics at multiple scales is essential for comprehensive studies of cellular function, and remains a challenge for traditional end-point assays. We introduce an efficient, non-invasive computational tool that takes time-lapse images as input to automatically detect, segment and analyze unlabeled live cells; the program then outputs kinematic cellular shape and migration parameters, while simultaneously measuring cellular stiffness and viscosity. We demonstrate the capabilities of the program by testing it on human mesenchymal stem cells (huMSCs) induced to differentiate towards the osteoblastic (huOB) lineage, and T-lymphocyte cells (T cells) of naïve and stimulated phenotypes. The program detected relative cellular stiffness differences in huMSCs and huOBs that were comparable to those obtained with studies that utilize atomic force microscopy; it further distinguished naïve from stimulated T cells, based on characteristics necessary to invoke an immune response. In summary, we introduce an integrated tool to decipher spatiotemporal and intracellular dynamics of cells, providing a new and alternative approach for cell characterization.

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Cancer Cell Stiffness: Integrated Roles of Three-Dimensional Matrix Stiffness and Transforming Potential

Cited by 137 publications

References 58 publications

Mapping intracellular mechanics on micropatterned substrates

Mapping intracellular mechanics on micropatterned substrates

Biomechanical Forces Shape the Tumor Microenvironment

Non-invasive single-cell biomechanical analysis using live-imaging datasets

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