How Changes in Cell Mechanical Properties Induce Cancerous Behavior (original) (raw)
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Frontiers in oncology, 2013
Malignant transformation, though primarily driven by genetic mutations in cells, is also accompanied by specific changes in cellular and extra-cellular mechanical properties such as stiffness and adhesivity. As the transformed cells grow into tumors, they interact with their surroundings via physical contacts and the application of forces. These forces can lead to changes in the mechanical regulation of cell fate based on the mechanical properties of the cells and their surrounding environment. A comprehensive understanding of cancer progression requires the study of how specific changes in mechanical properties influences collective cell behavior during tumor growth and metastasis. Here we review some key results from computational models describing the effect of changes in cellular and extra-cellular mechanical properties and identify mechanistic pathways for cancer progression that can be targeted for the prediction, treatment, and prevention of cancer.
Mechanical and Systems Biology of Cancer
Computational and Structural Biotechnology Journal
Mechanics and biochemical signaling are both often deregulated in cancer, leading to cancer cell phenotypes that exhibit increased invasiveness, proliferation, and survival. The dynamics and interactions of cytoskeletal components control basic mechanical properties, such as cell tension, stiffness, and engagement with the extracellular environment, which can lead to extracellular matrix remodeling. Intracellular mechanics can alter signaling and transcription factors, impacting cell decision making. Additionally, signaling from soluble and mechanical factors in the extracellular environment, such as substrate stiffness and ligand density, can modulate cytoskeletal dynamics. Computational models closely integrated with experimental support, incorporating cancer-specific parameters, can provide quantitative assessments and serve as predictive tools toward dissecting the feedback between signaling and mechanics and across multiple scales and domains in tumor progression.
Journal of The Mechanical Behavior of Biomedical Materials, 2017
A robust computational model of a cancer cell is presented using finite element modeling. The model accurately captures nuances of the various components of the cellular substructure. The role of degradation of cytoskeleton on overall elastic properties of the cancer cell is reported. The motivation for degraded cancer cellular substructure, the cytoskeleton is the observation that the innate mechanics of cytoskeleton is disrupted by various anti-cancer drugs as therapeutic treatments for the destruction of the cancer tumors. We report a significant influence on the degradation of the cytoskeleton on the mechanics of cancer cell. Further, a simulations based study is reported where we evaluate mechanical properties of the cancer cell attached to a variety of substrates. The loading of the cancer cell is less influenced by nature of the substrate, but low modulus substrates such as osteoblasts and hydrogels indicate a significant change in unloading behavior and also the plastic deformation. Overall, softer substrates such as osteoblasts and other bone cells result in a much altered unloading response as well as significant plastic deformation. These substrates are relevant to metastasis wherein certain type of cancers such as prostate and breast cancer cells migrate to the bone and colonize through mesenchymal to epithelial transition. The modeling study presented here is an important first step in the development of strong predictive methodologies for cancer progression.
Evolution of cell motility in an individual-based model of tumour growth
Journal of theoretical biology, 2009
Tumour invasion is driven by proliferation and importantly migration into the surrounding tissue. Cancer cell motility is also critical in the formation of metastases and is therefore a fundamental issue in cancer research. In this paper we investigate the emergence of cancer cell motility in an evolving tumour population using an individual-based modelling approach. In this model of tumour growth each cell is equipped with a microenvironment response network that determines the behaviour or phenotype of the cell based on the local environment. The response network is modelled using a feed-forward neural network, which is subject to mutations when the cells divide. With this model we have investigated the impact of the microenvironment on the emergence of a motile invasive phenotype. The results show that when a motile phenotype emerges the dynamics of the model are radically changed and we observe faster growing tumours exhibiting diffuse morphologies.
Predicting the role of microstructural and biomechanical cues in tumor growth and spreading
International Journal for Numerical Methods in Biomedical Engineering, 2017
A multitude of mathematical and computational approaches have been proposed for predicting tumor growth. Yet, most models treat malignant masses as fluids neglecting microstructural and biomechanical features of the tumor extracellular matrix (ECM). Here, a continuum porous media model is developed within the thermodynamically constrained averaging theory (TCAT) framework for elucidating the role of these mechanical cues in regulating tumor growth and spreading. The model comprises three fluid phasestumor cells, host cells, and interstitial fluidand a solid phasethe ECMconsidered as an elasto-visco-plastic medium. After validating the computational model against a multicellular tumor spheroid of glioblastoma multiforme, the effect on tumor development of ECM stiffness, adhesion with tumor cells and porosity is investigated. It is shown that stiffer matrices and higher cell-matrix adhesion limit tumor growth and spreading towards the surrounding tissue. A decrease in ECM Young's modulus E from 600 to 200 Pa induces a 60% increase in tumor mass within 8 days of observation. Similarly, a decrease of the adhesion parameter µ from 40 to 5 is responsible for an increase in tumor mass of 100%. On the other hand, higher matrix porosities favor the growth of the malignant mass and the dissemination of tumor cells. A modest increase in the porosity parameter from 0.7 to 0.9 is associated with a 300% increase in tumor mass. This model could be used for predicting the response of malignant masses to novel therapeutic agents affecting directly the tumor microenvironment and its micromechanical cues.
Scientific Reports, 2016
Three-dimensional (3D) cell cultures represent fundamental tools for the comprehension of cellular phenomena both in normal and in pathological conditions. In particular, mechanical and chemical stimuli play a relevant role on cell fate, cancer onset and malignant evolution. Here, we use mechanically-tuned alginate hydrogels to study the role of substrate elasticity on breast adenocarcinoma cell activity. The hydrogel elastic modulus (E) was measured via atomic force microscopy (AFM) and a remarkable range (150-4000 kPa) was obtained. A breast cancer cell line, MCF-7, was seeded within the 3D gels, on standard Petri and alginate-coated dishes (2D controls). Cells showed dramatic morphological differences when cultured in 3D versus 2D, exhibiting a flat shape in both 2D conditions, while maintaining a circular, spheroid-organized (cluster) conformation within the gels, similar to those in vivo. Moreover, we observed a strict correlation between cell viability and substrate elasticity; in particular, the number of MCF-7 cells decreased constantly with increasing hydrogel elasticity. Remarkably, the highest cellular proliferation rate, associated with the formation of cell clusters, occurred at two weeks only in the softest hydrogels (E = 150-200 kPa), highlighting the need to adopt more realistic and a priori defined models for in vitro cancer studies.
Multi-scale models of cell and tissue dynamics
Philosophical Transactions of The Royal Society A: Mathematical, Physical and Engineering Sciences, 2009
Cell and tissue movement are essential processes at various stages in the life cycle of most organisms. Early development of multicellular organisms involves individual and collective cell movement, leukocytes must migrate toward sites of infection as part of the immune response, and in cancer directed movement is involved in invasion and metastasis. The forces needed to drive movement arise from actin polymerization, molecular motors and other processes, but understanding the cell-or tissue-level organization of these processes that is needed to produce the forces necessary for directed movement at the appropriate point in the cell or tissue is a major challenge. In this paper we present three models that deal with the mechanics of cells and tissues: a model of an arbitrarily deformable single cell, a discrete model of the onset of tumor growth in which each cell is treated individually, and a hybrid continuum-discrete model of later stages of tumor growth. While the models are different in scope, their underlying mechanical and mathematical principles are similar and can be applied to a variety of biological systems.