Correlating the viscoelasticity of breast cancer cells with their malignancy

Initiation and development of cancer are usually accompanied by alterations in the cellular mechanical properties such as its stiffness and viscosity. Understanding the viscoelasticity of cancer cells can provide a better insight into the mechanics of the metastasis of cancer cells. Here, we use atomic force microscopy to compare the viscoelasticity of mammary epithelial cells with different metastatic potentials in their adherent and suspended states. We measure cell elasticity through the spatial mapping of Young's modulus using the force-indentation technique and cell viscosity using stress relaxation. The viscoelastic properties of cancer cells are associated with their malignancy and intrinsic cytoskeletal structures. Our results suggest that the Young's modulus of adherent cells inversely correlates to their malignancy and that the F-actin arrangement and intensity support the mechanical phenotype. For suspended cells, we observe that they exhibit lower elasticity than adhered cells due to the distribution of actin filaments at the cell cortex as well as reduced polymerization. Our viscosity results suggest that in both adhered and suspended cases, normal breast epithelial cells exhibit higher viscosity than that of cancer cells. Actin distribution and higher nucleus to cytoplasmic ratio in cancer cells are observed to be the two main factors in determining cell viscosity.

[1]  F. Guilak,et al.  Viscoelastic properties of zonal articular chondrocytes measured by atomic force microscopy. , 2006, Osteoarthritis and cartilage.

[2]  Denis Wirtz,et al.  The physics of cancer: the role of physical interactions and mechanical forces in metastasis , 2011, Nature Reviews Cancer.

[3]  Alan Hall,et al.  The cytoskeleton and cancer , 2009, Cancer and Metastasis Reviews.

[4]  Stefan Schinkinger,et al.  Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence. , 2005, Biophysical journal.

[5]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[6]  Denis Wirtz,et al.  Mismatch in mechanical and adhesive properties induces pulsating cancer cell migration in epithelial monolayer. , 2012, Biophysical journal.

[7]  Christopher S. Poultney,et al.  A physical sciences network characterization of non-tumorigenic and metastatic cells , 2013, Scientific Reports.

[8]  D. Ingber,et al.  Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus , 2009, Nature Reviews Molecular Cell Biology.

[9]  Masoud Agah,et al.  The effects of cancer progression on the viscoelasticity of ovarian cell cytoskeleton structures. , 2012, Nanomedicine : nanotechnology, biology, and medicine.

[10]  Aaron L Fogelson,et al.  Blood clot formation under flow: the importance of factor XI depends strongly on platelet count. , 2012, Biophysical journal.

[11]  Manfred Radmacher,et al.  Comparison of viscoelastic properties of cancer and normal thyroid cells on different stiffness substrates , 2016, European Biophysics Journal.

[12]  Eric Mazur,et al.  Viscoelastic retraction of single living stress fibers and its impact on cell shape, cytoskeletal organization, and extracellular matrix mechanics. , 2006, Biophysical journal.

[13]  Sanjay Kumar,et al.  Mechanics, malignancy, and metastasis: The force journey of a tumor cell , 2009, Cancer and Metastasis Reviews.

[14]  Manfred Radmacher,et al.  Comparison of mechanical properties of normal and malignant thyroid cells. , 2012, Micron.

[15]  S. Lakhani,et al.  Molecular evolution of breast cancer , 2005, The Journal of pathology.

[16]  A. Castro,et al.  Partial inhibition of Cdk1 in G2 phase overrides the SAC and decouples mitotic events , 2014, Cell cycle.

[17]  J. Rao,et al.  Nanomechanical analysis of cells from cancer patients. , 2007, Nature nanotechnology.

[18]  Yiider Tseng,et al.  Micro-organization and visco-elasticity of the interphase nucleus revealed by particle nanotracking , 2004, Journal of Cell Science.

[19]  Nisha M. Ramdas,et al.  Cytoskeletal control of nuclear morphology and chromatin organization. , 2015, Journal of molecular biology.

[20]  W. Kraus,et al.  Endothelial, cardiac muscle and skeletal muscle exhibit different viscous and elastic properties as determined by atomic force microscopy. , 2001, Journal of biomechanics.

[21]  Yangzhe Wu,et al.  BRMS1 expression alters the ultrastructural, biomechanical and biochemical properties of MDA-MB-435 human breast carcinoma cells: an AFM and Raman microspectroscopy study. , 2010, Cancer letters.

[22]  Shunsuke Yuba,et al.  Actin-based biomechanical features of suspended normal and cancer cells. , 2013, Journal of bioscience and bioengineering.

[23]  R. Waugh,et al.  Passive mechanical behavior of human neutrophils: effects of colchicine and paclitaxel. , 1998, Biophysical journal.

[24]  C. Lim,et al.  Biomechanics approaches to studying human diseases. , 2007, Trends in biotechnology.

[25]  Kozaburo Hayashi,et al.  Stiffness of cancer cells measured with an AFM indentation method. , 2015, Journal of the mechanical behavior of biomedical materials.

[26]  G Ciasca,et al.  Mechanical and structural comparison between primary tumor and lymph node metastasis cells in colorectal cancer. , 2015, Soft matter.

[27]  J. Lammerding,et al.  Nuclear mechanics in cancer. , 2014, Advances in experimental medicine and biology.

[28]  Andreas Janshoff,et al.  Atomic force microscopy-based microrheology reveals significant differences in the viscoelastic response between malign and benign cell lines , 2014, Open Biology.

[29]  H. Butt,et al.  Comparative analysis of viscosity of complex liquids and cytoplasm of mammalian cells at the nanoscale. , 2011, Nano letters.

[30]  Mauro Ferrari,et al.  Microfluidic cytometric analysis of cancer cell transportability and invasiveness , 2015, Scientific Reports.

[31]  Byungkyu Kim,et al.  Cell Stiffness Is a Biomarker of the Metastatic Potential of Ovarian Cancer Cells , 2012, PloS one.

[32]  Robert Ros,et al.  Correlating confocal microscopy and atomic force indentation reveals metastatic cancer cells stiffen during invasion into collagen I matrices , 2016, Scientific Reports.

[33]  Katarina Wolf,et al.  Cancer cell migration in 3D tissue: Negotiating space by proteolysis and nuclear deformability , 2015, Cell adhesion & migration.

[34]  T. Berdyyeva,et al.  Human epithelial cells increase their rigidity with ageing in vitro: direct measurements , 2004, Physics in medicine and biology.

[35]  C. Lim,et al.  AFM indentation study of breast cancer cells. , 2008, Biochemical and biophysical research communications.

[36]  Patrick J. Prendergast,et al.  AFM INDENTATION ON OSTEOBLASTS SHOWS THAT ELASTICITY CHANGES DURING THE CELL CYCLE , 2008 .

[37]  M. Lekka,et al.  Cancer cell recognition--mechanical phenotype. , 2012, Micron.

[38]  Z. Stachura,et al.  Elasticity of normal and cancerous human bladder cells studied by scanning force microscopy , 1999, European Biophysics Journal.

[39]  Chwee Teck Lim,et al.  Cell biomechanics and its applications in human disease diagnosis , 2015 .