Mechanical Properties Of Cancer Cells Research Articles

Investigation of the mechanical effects of targeted drugs on cancerous cells based on atomic force microscopy.

Cancer is currently drawing more and more attention as the leading factor in death worldwide. However, little research has been directed towards investigating the micro/nanoscale mechanical properties of cancer cells treated by targeted drugs to evaluate the model systems of targeted drugs using atomic force microscopy (AFM) nano-indentation, especially in light of the multiple drugs targeting various cancerous cells. This paper aims to compare the mechanical effects of sorafenib tosylate and osimertinib mesylate on hepatoma carcinoma cells and lung cancerous cells using atomic force microscopy from the perspective of a model system based on nano-indentation at the micro/nanoscale, which has rarely been investigated. The Sneddon model is applied to fit the force-distance curves, and the mechanical properties, i.e., Young's moduli, can then be calculated. For the SMMC-7721 cells, osimertinib mesylate is a more effective inhibitor than sorafenib tosylate. For the A549 cells, osimertinib mesylate and sorafenib tosylate both have an obvious inhibitory effect. The experimental results may make possible contributions to the diagnosis and treatment of early-stage cancers.

Single Cell Hydrodynamic Stretching and Microsieve Filtration Reveal Genetic, Phenotypic and Treatment-Related Links to Cellular Deformability.

Deformability is shown to correlate with the invasiveness and metastasis of cancer cells. Recent studies suggest epithelial-to-mesenchymal transition (EMT) might enable cancer metastasis. However, the correlation of EMT with cancer cell deformability has not been well elucidated. Cellular deformability could also help evaluate the drug response of cancer cells. Here, we combine hydrodynamic stretching and microsieve filtration to study cellular deformability in several cellular models. Hydrodynamic stretching uses extensional flow to rapidly quantify cellular deformability and size with high throughput at the single cell level. Microsieve filtration can rapidly estimate relative deformability in cellular populations. We show that colorectal cancer cell line RKO with the mesenchymal-like feature is more flexible than the epithelial-like HCT116. In another model, the breast epithelial cells MCF10A with deletion of the TP53 gene are also significantly more deformable compared to their isogenic wildtype counterpart, indicating a potential genetic link to cellular deformability. We also find that the drug docetaxel leads to an increase in the size of A549 lung cancer cells. The ability to associate mechanical properties of cancer cells with their phenotypes and genetics using single cell hydrodynamic stretching or the microsieve may help to deepen our understanding of the basic properties of cancer progression.

Mechanical Property Changes in Breast Cancer Cells Induced by Stimulation with Macrophage Secretions in Vitro.

The contribution of secretions from tumor-associated macrophage (TAM)-like cells to the stimulation of mechanical property changes in murine breast cancer cells was studied using an in vitro model system. A murine breast cancer cell line (FP10SC2) was stimulated by adding macrophage (J774.2) cultivation medium containing stimulation molecules secreted from the macrophages, and changes in mechanical properties were compared before and after stimulation. As a result, cell elasticity decreased, degradation ability of the extracellular matrix increased, and the expression of plakoglobin was upregulated. These results indicate that cancer cell malignancy is upregulated by this stimulation. Moreover, changes in intercellular adhesion strengths between pairs of cancer cells were measured before and after stimulation using atomic force microscopy (AFM). The maximum force required to separate cells was increased by stimulation with the secreted factors. These results indicate the possibility that TAMs cause changes in the mechanical properties of cancer cells in tumor microenvironments, and in vitro measurements of mechanical property changes in cancer cells will be useful to study interactions between cells in tumor microenvironments.

Amplification of nuclear deformation of breast cancer cells by seeding on micropatterned surfaces to better distinguish their malignancies

Information about the mechanical properties of cancer cells leads to new insights about their malignancy levels. The more flexible the cancer cells and their nuclei are, the more aggressive and invasive they are. Flexibility is a result of composition and properties of molecular constituents of cells and its extent is expressed by deformation. Differences in the mechanical properties could be modulated by topography and chemistry of the substrate. In this study, the main hypothesis is that the difference in the mechanical properties of malignant and benign breast cancer cells could be used as a discriminator of these cells and reflected by the extent of nuclear deformation on micropatterned substrates. We compared benign (MCF10A), malignantnoninvasive (MCF7), and malignant highly invasive (MDAMB231) breast cancer cell lines using their nuclear deformability on micropatterned surfaces designed with square prism-shaped micropillars of poly(methyl methacrylate) (PMMA) (8 μm high, 4 × 4 μm2 area, 4 μm gap). Several shape descriptors (circularity, solidity, roundness, aspect ratio) were used to analyze nuclear deformation. We were able to discriminate the three cells when the descriptor circularity and hydrophobic micropatterned surfaces were used. The cells showed nuclear deformability in the order following the extent of their malignancies. The most aggressive cell, MDAMB231, had the lowest circularity value, 0.37, whereas the noninvasive malignant, MCF7, and benign, MCF10A, cells had higher values 0.47 and 0.77, respectively. Mechanism of the deformation was shown at the molecular level that the expression of Lamin A/C and Nesprin-2 genes decreased with increased nuclear deformation. In summary, biomechanical properties of cells can provide useful information about their cancer state and they can be reflected in the biological markers.

3D Microenvironment Stiffness Regulates Tumor Spheroid Growth and Mechanics via p21 and ROCK.

The mechanical properties of cancer cells and their microenvironment contribute to breast cancer progression. While mechanosensing has been extensively studied using 2D substrates, much less is known about it in a physiologically more relevant 3D context. Here it is demonstrated that breast cancer tumor spheroids, growing in 3D polyethylene glycol-heparin hydrogels, are sensitive to their environment stiffness. During tumor spheroid growth, compressive stresses of up to 2 kPa build up, as quantitated using elastic polymer beads as stress sensors. Atomic force microscopy reveals that tumor spheroid stiffness increases with hydrogel stiffness. Also, constituent cell stiffness increases in a Rho associated kinase (ROCK)- and F-actin-dependent manner. Increased hydrogel stiffness correlated with attenuated tumor spheroid growth, a higher proportion of cells in G0/G1 phase, and elevated levels of the cyclin-dependent kinase inhibitor p21. Drug-mediated ROCK inhibition not only reverses cell stiffening upon culture in stiff hydrogels but also increases tumor spheroid growth. Taken together, a mechanism by which the growth of a tumor spheroid can be regulated via cytoskeleton rearrangements in response to its mechanoenvironment is revealed here. Thus, the findings contribute to a better understanding of how cancer cells react to compressive stress when growing under confinement in stiff environments.

UBTD1 is a mechano-regulator controlling cancer aggressiveness.

Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with β-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase β-TrCP Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

Characterization of the mechanical properties of cancer cells in 3D matrices in response to collagen concentration and cytoskeletal inhibitors.

Cellular processes, such as cell migration, adhesion, and proliferation depend on the interaction between the intracellular environment and the extracellular matrix (ECM). While many studies have explored the role of the microenvironment on cell behavior, the influence of 3D matrix mechanics on intracellular activity is not completely understood. To characterize the relationship between the mechanical components of the microenvironment and intracellular behavior, we use particle-tracking microrheology of metastatic breast cancer cells embedded in 3D collagen gels to quantify the intracellular activity from which the molecular motor activity and stiffness can be determined. Our results show that increasing collagen concentration of the 3D environments leads to an increase in intracellular stiffness and motor activity. Furthermore, our studies demonstrate that intracellular fluctuations depend on collagen concentration, even in the presence of a number of frontline chemotherapeutic and anti-MMP drugs, indicating that ECM concentration is an important and indispensable parameter to consider in drug screening.

Abstract OT1-06-05: Atomic force microscopy (AFM) - a novel nanotool for cancer diagnostics: A prospective, blinded study of nanomechanical profiling of human breast tissue as a potential biomarker for stratifying low- and high-risk breast cancer subtypes

Abstract Background The crucial point in making treatment decisions for breast cancer patients is the assessment of tumour aggressiveness. The established prognostic markers may be insufficient to stratify cancer patients into treatment relevant risk groups. Emerging evidence indicates that mechanical properties of cancer cells and their microenvironment that occur on a nanometre scale play a critical role in cancer invasion and metastases. Therefore, detecting these nanomechanical changes could serve as biomarker of cancer aggressiveness. Trial design We conduct a prospective, blinded study in a routine clinical setting. Using minimal invasive breast biopsies we measure the nanomechanical (stiffness) properties of human breast tissue with our atomic force microscope (AFM) based method known as ARTIDIS (Automated and Reliable Tissue Diagnostics). These properties can only be measured using fresh (non-fixed) tissue under physiological conditions (Custodiol transplant buffer). This novel method is based on the use of a micro-fabricated 20nm-sharp tip that indents several thousand individual locations across tissue specimens within 60-180 minutes. Each indentation effectively measures the stiffness of local structures (e.g. cancer cells, extracellular matrix) located under the tip. Thus we obtain a quantitative, biopsy-wide, nanomechanical profile. Post-AFM the same biopsy is used for routine histopathological diagnosis, the current diagnostic gold standard to which the nanomechanical profile is then correlated. Eligibility criteria All women undergoing a minimal invasive breast biopsy (core needle or vacuum assisted biopsy) at the breast centre of the University of Basel. Exclusion criteria: age younger than 18years, necrotic/disintegrated biopsy, and technical limitations Specific aims Our primary endpoint is to differentiate benign from cancerous breast lesions based on their nanomechanical properties. Our secondary endpoint is to subclassify biopsies with cancerous lesions into the current four main breast cancer subgroups (Luminal A, Luminal B, HER2+ and basal-like). Statistical analysis The full dataset will include all patients with valid AFM measurements. Primary analysis: the proportion of true positive results divided by the total number of patients with malignant tumour (sensitivity) will be estimated and presented together with its 95% confidence interval. The histological diagnosis of the same biopsy as analysed by AFM will serve as gold standard. Present accrual and target accrual Present accrual as of June 12, 2017: 200 breast tissue biopsies. Target accrual is 508 biopsies. This will allow for a power of 0.8 and a sensitivity of 90%. Contact information: Rosemarie.Burian@usb.ch Citation Format: Burian R, Appenzeller T, Oertle P, Raez C, Lim R, Forte S, Dellas S, Münst S, Obermann E, Plodinec M. Atomic force microscopy (AFM) - a novel nanotool for cancer diagnostics: A prospective, blinded study of nanomechanical profiling of human breast tissue as a potential biomarker for stratifying low- and high-risk breast cancer subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-06-05.

Mechanical properties of cancer cells depend on number of passages: Atomic force microscopy indentation study

Here we investigate one of the key questions in cell biology, if the properties of cell lines depend on the number of passages in-vitro. It is generally assumed that the change of cell properties (phenotypic drift) is insignificant when the number of passages is low (<10); the changes were reported for passages higher than 30–40. We used quantitative indentation models to extract information on the elastic modulus of the cell body and parameters of the pericellular brush layer from indentation force curves, which are recorded by means of atomic force microscopy (AFM). Using this method, we tested the change of the cell properties of human cancer breast epithelial cell line, MCF-7 (ATCC® HTB-22™), within the passages between 2 and 10. In contrast to the previous expectations, we observed a substantial transient change of the elastic modulus of the cell body during the first four passages (up to 4 times). The changes in the parameters of the pericellular coat were less dramatic (up to 2 times) but still statistically significant.

Nanomechanical profiling of human breast tumors as prognostic marker for breast cancer.

11618 Background: Assessment of tumor aggressiveness is crucial when making treatment decisions. Established prognostic markers may be insufficient to stratify cancer patients into treatment relevant risk groups. Emerging evidence indicates mechanical properties of cancer cells and their microenvironment play a vital role in cancer invasion and metastases. Detecting and measuring these nanomechanical changes could be a marker of cancer aggressiveness. Methods: We developed an atomic force microscope (AFM) based method: ARTIDIS (Automated and Reliable Tissue Diagnostics) for measuring nanomechanical properties of human tissue biopsies. These were performed on fresh, non-fixed tissue under physiological conditions. This novel method uses a micro-fabricated 20nm tip indenting and measuring stiffness of thousands of locations within 60-180minutes. This quantitative, biopsy-wide, nanomechanical profile strongly correlates to the tissue's biological composition. Post-AFM this biopsy is analyzed by pathology. We sought to differentiate benign from cancerous lesions based on nanomechanical properties; then link the cancerous nanomechanical profiles prospectively to the clinical outcomes. Results: Our results demonstrate the first AFM based nanomechanical profiling to detect aggressive breast cancer subtypes using fresh tissue in a clinical setting. We have shown that nanomechanical profiles of human breast cancer biopsies display stiffness profiles distinct from surrounding normal tissue. Breast cancer subtypes were distinguishable by their nanomechanical properties only. We have discovered specific nanomechanical profiles of tumor subtypes likely to metastasize. When the primary tumor displayed the same soft nanomechanical profile as adjacent tissue, this was associated with positive nodal status. Conclusions: Our results demontrate nanomechanical profiling is a fast and sensitive method to stratify malignant biopsies into relevant subgroups in a clinical setting. Relative stiffness and distribution values provide a nanomechanical profile indicating cancer aggressiveness. This will help optimize specific cancer diagnosis, orientate therapy choice and support patient follow up.

Fabrication of atomic force microscope spherical tips and its application in determining the mechanical property of cancer cells

The process of cancer metastasis is closely related to the mechanical property of cells. Using the atomic force microscope (AFM)-based nanoindentation technique, the mechanical properties of cancer cells can be measured in liquid and at 37°C. However, the conventional AFM tip is too sharp to finish this process. The AFM tip with a microsphere at the end is usually used. How to adhere a microsphere to the tip apex has become a big concern up to now. In this work, an easy and simple method based on the employment of carbon nanotube bundles is presented. The microsphere is successfully adhered to the tip and the elastic constant of the cantilever is calibrated with the Cleveland method. Using the developed tip, the nanoindentation tests on two kinds of lung cancer cells (Anip-973 and AGZY-83a), which exhibit different metastatic properties, are carried out in liquid and at 37°C. Based on the Hertz contact equation between the spherical tip and the cell, the stress relaxation model is used to calculate the Young's modulus and viscoelastic properties of the cells. Experimental results confirm the feasibility of the method proposed in this work.

Quantifying Cellular Elasticity using Quantitative Phase Microscopy Measurements of Electromagnetically Actuated Magnetic Microsphere Indentation

Metastasis is responsible for 90% of cancer cell deaths, and mechanical properties of cancer cells are an important and emerging indicator of cancer cell metastatic potential. Therefore, screening the mechanical properties of cancer cells, alone and in response to chemotherapy, provides an important indicator of disease progression and drug effectiveness. There are many existing approaches to measuring cell mechanical properties, however the mechanical constraints of these systems cannot be readily combined with measurements of cell growth or death to quantify the full response of cancer cells to potential therapies. Quantitative phase microscopy (QPM) is an established approach for determining the growth response of cancer cells to a variety of chemotherapies, from small-molecule inhibitors to adoptive immunotherapies, by quantifying the rate of increase or decrease in cell mass over time. In this work we describe a system based on QPM that quantifies cell mechanical properties using an Arudino microcontroller to control electromagnet-driven oscillation and indentation of magnetic nickel microspheres distributed on top of adherent cells in vitro. QPM measures cell mass as well as magnetic microsphere indentation and relaxation over time, and can therefore simultaneously quantify cell growth, stiffness, and viscosity. Electromagnet actuation allows for rapid modulation of the indentation force applied to cells for simultaneous, high-throughput measurements of mechanical responses at up to several hundred locations within each field of view. In combination with the ability of QPM to rapidly determine the effects of chemotherapeutics on cancer cell growth, this system will enable selection of treatments to better target both the growth and mechanical properties of cancer cells, in an effort to select and design optimal chemotherapeutic strategies to combat metastasis.

A novel method to calculate the mechanical properties of cancer cells based on atomic force microscopy.

Mechanical properties, as the inherent characteristics of cells, play a critical role in many essential physiological processes, including cell differentiation, migration, and growth. The mechanical properties of cells are one of the criteria that help to determine whether the tissue contains lesions at the single cell level, and it is very important for the early prevention and accurate diagnosis of diseases. Atomic force microscopy (AFM) makes it possible to measure the mechanical properties at single cell level in physiological state. This paper presents a novel method to calculate the mechanical properties of cancer cells more accurately through Atomic force microscopy. A new induced equation of Hertz's model, called differential Hertz's model, has been proposed to calculate the mechanical properties of cancer cells. Moreover, the substrate effect has also been effectively reduced through comparing the calculated mechanical properties of cell at different cell surface areas. The results indicate that the method utilized to calculate the mechanical properties of cells can effectively eliminate the errors in calculation, caused by the thermal drift of AFM system and the substrate effect, and thus improve the calculation accuracy. The mechanical properties calculated by our method in this study are closer to the actual value. Thus, this method shows potential for use in establishing a standard library of Young's modulus.

Alterations in cancer cell mechanical properties after fluid shear stress exposure: a micropipette aspiration study.

Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young’s modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm2) and low (510 dyn/cm2) FSS. The PrEC LH cells were ~140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ~77% in Young’s modulus after exposure to high FSS and a ~47% increase in Young’s modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young’s modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young’s modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future.

211 癌細胞の機械的性質同定のための逆解析に関する研究(OS04-2 バイオエンジニアリング(2)バイオメカニクス・バイオマテリアル・バイオミメティクス,オーガナイズドセッション4:「バイオエンジニアリング(2)バイオメカニクス・バイオマテリアル・バイオミメティクス」)

211 癌細胞の機械的性質同定のための逆解析に関する研究(OS04-2 バイオエンジニアリング(2)バイオメカニクス・バイオマテリアル・バイオミメティクス,オーガナイズドセッション4:「バイオエンジニアリング(2)バイオメカニクス・バイオマテリアル・バイオミメティクス」)

Abstract 3766: Mechanical properties of cancer cells: a possible biomarker for stemness.

Abstract There is evidence that mechanical properties and deformability can be used as a biomarker to distinguish between healthy and cancerous cells. A number of biophysical techniques such as atomic force microscopy (AFM), and optical tweezers have been used to measure the mechanical properties of cancer cells. Deformability of a whole cell, which depends on the properties of the cytoplasm, the cytoskeleton and the nucleus, can be defined in terms of the strain response of the cell to an applied stress. Two different cell mechanical behaviors have been observed: 1) circulating white blood cells behave as liquid drops with a cortical tension; 2) most tissue cells behave as viscoelastic solids. In this study, micropipette aspiration was used to investigate deformability differences between two breast cancer cell lines: BT-20 and Hs578T. Hs578T breast cancer cells have been reported to have a stem-like phenotype, whereas BT-20 cells are more recognized as being non-stem-like. Cancer cells were aspirated one-by-one at controlled pressures into small glass micropipettes with radius, Rp, while the length of the aspirated section of the cell inside the micropipette, L, was measured. Two different aspiration procedures have been developed: 1) ramp test and 2) creep test. In the ramp test, suction pressure was increased linearly using a syringe pump, while for the creep test, the pressure was increased rapidly and then kept constant during the experiment. Using the ramp test, graphs of cell deformation (L/Rp) versus applied pressure, showed a linear trend for small deformations for both BT-20 and Hs578T cells, while for large deformations, the graphs were no longer linear. One explanation for this, was that above a deformation threshold the cells were exhibiting liquid-like behavior. This was tested using a constant aspiration pressure in the creep test. It was seen that half of the cells fully entered the micropipettes at constant pressure, a character of liquid drops, while the rest reached an equilibrium position, which implies a viscoelastic behavior for the cells. It could be concluded that for small deformations, cells mostly have solid-like behavior, while for large deformations they could exhibit liquid-like or viscoelastic behaviors. We also found that stem-like cancer cells are softer than non-stem-like cells with no significant differences between the mechanical properties of their cytoplasmic and nuclear regions, which allows them to deform more easily while undergoing extravasation and intravasation processes during metastasis. Our hypothesis is that the stem-like or non-stem-like phenotype of cancer cells is correlated with differences in mechanical properties. If these differences are significant enough, mechanical properties could be used as a biomarker for stemness of cells, which could eventually lead to a new diagnostic method in cancer research. This work was supported by grant CBET-1106118 from the National Science Foundation. Citation Format: Ameneh Mohammadalipour, Fabian Benencia, Monica M. Burdick, David F. J. Tees. Mechanical properties of cancer cells: a possible biomarker for stemness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3766. doi:10.1158/1538-7445.AM2013-3766

Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential

We quantified mechanical properties of cancer cells differing in metastatic potential. These cells included normal and H-ras-transformed NIH3T3 fibroblast cells, normal and oncoprotein-overexpressing MCF10A breast cancer cells, and weakly and strongly metastatic cancer cell line pairs originating from human cancers of the skin (A375P and A375SM cells), kidney (SN12C and SN12PM6 cells), prostate (PC3M and PC3MLN4 cells), and bladder (253J and 253JB5 cells). Using magnetic twisting cytometry, cytoskeletal stiffness (g') and internal friction (g″) were measured over a wide frequency range. The dependencies of g' and g″ upon frequency were used to determine the power law exponent x which is a direct measure of cytoskeletal fluidity and quantifies where the cytoskeleton resides along the spectrum of solid-like (x=1) to fluid-like (x=2) states. Cytoskeletal fluidity x increased following transformation by H-ras oncogene expression in NIH3T3 cells, overexpression of ErbB2 and 14-3-3-ζ in MCF10A cells, and implantation and growth of PC3M and 253J cells in the prostate and bladder, respectively. Each of these perturbations that had previously been shown to enhance cancer cell motility and invasion are shown here to shift the cytoskeleton towards a more fluid-like state. In contrast, strongly metastatic A375SM and SN12PM6 cells that disseminate by lodging in the microcirculation of peripheral organs had smaller x than did their weakly metastatic cell line pairs A375P and SN12C, respectively. Thus, enhanced hematological dissemination was associated with decreased x and a shift towards a more solid-like cytoskeleton. Taken together, these results are consistent with the notion that adaptations known to enhance metastatic ability in cancer cell lines define a spectrum of fluid-like versus solid-like states, and the position of the cancer cell within this spectrum may be a determinant of cancer progression.

Investigation of mechanical properties of breast cancer cells using micropipette aspiration technique

Characterization of the mechanical properties of cancer cells is a promising diagnostic method for recognizing cancerous cells in the very early stages of the disease. In this study, the micropipette aspiration technique was used to investigate deformability differences between two types of breast cancer cell line: BT‐20 and Hs578T. Hs578T breast cancer cells have been reported having stem cell‐like properties, whereas BT‐20 cells are more recognized as non‐stem cell‐like cancer cells. Using a controlled aspiration pressure, a cancer cell was aspirated into a small glass micropipette while the length of the aspirated section of the cell inside the micropipette was measured. For a solid‐like cell, the Young's modulus can be calculated from the slope of a pressure versus aspiration length graph. The Hs578T cell line was found to have a Young's modulus larger than that of the BT‐20 cell line. This supports our hypothesis that the technique can be used for the characterization of cancer cells by their mechanical properties, which could lead to a new method of detecting circulating tumor cells. This work was supported by grant CBET‐1106118 from the National Science Foundation.

Calculation of the intracellular elastic modulus based on an atomic force microscope micro-cutting system

Better understanding of variations in the mechanical properties of cancer cells could help to provide novel solutions for the diagnosis, prevention, and treatment of cancers. We therefore developed a calculation model of the intracellular elastic modulus based on the contact pressure between the silicon tip of an atomic force microscope and the target cells, and cutting depth. Ovarian cells (UACC-1598) and colon cancer cells (NCI-H716) were cut into sequential layers using an atomic force microscope silicon tip. The cutting area on the cells was 8 μm × 8 μm, and the loading force acting on the cells was increased from 17.523 to 32.126 μN. The elastic modulus distribution was measured after each cutting process. There were significant differences in contact pressure and cutting depth between different cells under the same loading force, which could be attributed to differences in their intrinsic structures and mechanical properties. The differences between the average elastic modulus and surface elastic modulus for UACC-1598 and NCI-H716 cells were 0.288±0.08 kPa and 0.376±0.16 kPa, respectively. These results demonstrate that this micro-cutting method can be used to measure intracellular mechanical properties, which could in turn provide a more accurate experimental basis for the development of novel methods for the diagnosis and treatment of various diseases.

How Changes in Cell Mechanical Properties Induce Cancerous Behavior

Tumor growth and metastasis are ultimately mechanical processes involving cell migration and uncontrolled division. Using a 3D discrete model of cells, we show that increased compliance as observed for cancer cells causes them to grow at a much faster rate compared to surrounding healthy cells. We also show how changes in intercellular binding influence tumor malignancy and metastatic potential. These findings suggest that changes in the mechanical properties of cancer cells is the proximate cause of uncontrolled division and migration and various biochemical factors drive cancer progression via this mechanism.