Modulating malignant epithelial tumor cell adhesion, migration and mechanics with nanorod surfaces.
ABSTRACT The failure of tumor stents used for palliative therapy is due in part to the adhesion of tumor cells to the stent surface. It is therefore desirable to develop approaches to weaken the adhesion of malignant tumor cells to surfaces. We have previously developed SiO₂ coated nanorods that resist the adhesion of normal endothelial cells and fibroblasts. The adhesion mechanisms in malignant tumor cells are significantly altered from normal cells; therefore, it is unclear if nanorods can similarly resist tumor cell adhesion. In this study, we show that the morphology of tumor epithelial cells cultured on nanorods is rounded compared to flat surfaces and associated with decreased cellular stiffness and non-muscle myosin II phosphorylation. Tumor cell viability and proliferation was unchanged on nanorods. Adherent cell numbers were significantly decreased while single tumor cell motility was increased on nanorods compared to flat surfaces. Together, these results suggest that nanorods can be used to weaken malignant tumor cell adhesion, and therefore potentially improve tumor stent performance.
- SourceAvailable from: Alia Ghoneum[Show abstract] [Hide abstract]
ABSTRACT: Nanoparticles have recently gained increased attention as drug delivery systems for the treatment of cancer due to their minute size and unique chemical properties. However, very few studies have tested the biophysical changes associated with nanoparticles on metastatic cancer cells at the cellular and sub-cellular scales. Here, we investigated the mechanical and morphological properties of cancer cells by measuring the changes in cell Young's Modulus using AFM, filopodial retraction (FR) by time lapse optical light microscopy imaging and filopodial disorganization by high resolution AFM imaging of cells upon treatment with nanoparticles. In the current study, nanomechanical changes in live murine metastatic breast cancer cells (4T1) post exposure to a nanodiamond/nanoplatinum mixture dispersed in aqueous solution (DPV576), were monitored. Results showed a decrease in Young's modulus at two hours post treatment with DPV576 in a dose dependent manner. Partial FR at 20 min and complete FR at 40 min were observed. Moreover, analysis of the retraction distance (in microns) measured over time (minutes), showed that a DPV576 concentration of 15%v/v yielded the highest FR rate. In addition, DPV576 treated cells showed early signs of filopodial disorganization and disintegration. This study demonstrates the changes in cell stiffness and tracks early structural alterations of metastatic breast cancer cells post treatment with DPV576, which may have important implications in the role of nanodiamond/nanoplatinum based cancer cell therapy and sensitization to chemotherapy drugs.Nanotechnology 10/2014; · 3.67 Impact Factor
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ABSTRACT: We report a general approach for the synthesis of large-scale gallium nitride (GaN) nanostructures by the graphene oxide (GO) assisted chemical vapor deposition (CVD) method. A modulation effect of GaN nanostructures on cell adhesion has been observed. The morphology of the GaN surface can be controlled by GO concentrations. This approach, which is based on the predictable choice of the ratio of GO to catalysts, can be readily extended to the synthesis of other materials with controllable nanostructures. Cell studies show that GaN nanostructures reduced cell adhesion significantly compared to GaN flat surfaces. The cell-repelling property is related to the nanostructure and surface wettability. These observations of the modulation effect on cell behaviors suggest new opportunities for novel GaN nanomaterial-based biomedical devices. We believe that potential applications will emerge in the biomedical and biotechnological fields.Nanoscale 09/2013; · 6.74 Impact Factor
Modulating malignant epithelial tumor cell adhesion,
migration and mechanics with nanorod surfaces
Jiyeon Lee & Byung Hwan Chu & Shamik Sen &
Anand Gupte & T. J. Chancellor & Chih-Yang Chang &
Fan Ren & Sanjay Kumar & Tanmay P. Lele
# Springer Science+Business Media, LLC 2010
Abstract The failure of tumor stents used for palliative
surface. It is therefore desirable to develop approaches to
weaken the adhesion of malignant tumor cells to surfaces. We
have previously developed SiO2coated nanorods that resist
the adhesion of normal endothelial cells and fibroblasts. The
adhesion mechanisms in malignant tumor cells are signifi-
cantly altered from normal cells; therefore, it is unclear if
nanorods can similarly resist tumor cell adhesion. In this
study, we show that the morphology of tumor epithelial cells
cultured on nanorods is rounded compared to flat surfaces
and associated with decreased cellular stiffness and non-
muscle myosin II phosphorylation. Tumor cell viability and
proliferation was unchanged on nanorods. Adherent cell
numbers were significantly decreased while single tumor cell
motility was increased on nanorods compared to flat
surfaces. Together, these results suggest that nanorods can
be used to weaken malignant tumor cell adhesion, and
therefore potentially improve tumor stent performance.
Keywords Nanostructured materials.Tumor cell
Tumors that occlude the gastrointestinal, pancreatic and
biliary ducts are typically surgically removed, and metallic
stents are placed in the ducts for preventing subsequent
collapse of the injured tissue (Dormann et al. 2004;
McLoughlin and Byrne 2008). However, tumor cell
adhesion, migration and proliferation on the installed stents
cause stent re-blockage which occurs in 25 to 50% of cases.
This requires further surgical interventions for stent
removal and causes severe complications in the manage-
ment of malignancy (Siersema 2008). To overcome such
recurrent problems with metallic stents, plastic-covered
stents have been developed (Han et al. 2003; Isayama et
al. 2002; Togawa et al. 2008). However, plastic-covered
stents tend to migrate to other organs (Costamagna et al.
2006; McLoughlin and Byrne 2008) and have poor
performance compared to metallic stents (Costamagna et
al. 2006; Perdue et al. 2008). Thus, prevention of tumor cell
adhesion to the stent surface remains a key challenge
(Costamagna et al. 2006; Han et al. 2003; Isayama et al.
2002; Perdue et al. 2008; Siersema 2008; Togawa et al.
One approach to reduce the blockage of stents is to
fabricate nanostructured features on the stent surface
that will interfere with tumor cell adhesion. A number
of studies have shown that cell adhesion (Arnold et al.
2004; Choi et al. 2007; Milner and Siedlecki 2007),
assembly (Karuri et al. 2008), and migration (Yim et al.
2005) are sensitive to the micro- and nano-scale topogra-
phy of the culture substrate (Balasundaram and Webster
Electronic supplementary material The online version of this article
(doi:10.1007/s10544-010-9473-7) contains supplementary material,
which is available to authorized users.
J. Lee:B. H. Chu:T. J. Chancellor:C.-Y. Chang:F. Ren:
T. P. Lele (*)
Department of Chemical Engineering, University of Florida,
Gainesville, FL 32611, USA
S. Sen:S. Kumar
Department of Bioengineering, University of California,
Berkeley, CA 94720, USA
Division of Gastroenterology, Department of Medicine,
University of Florida,
Gainesville, FL 32610, USA
2006; Chun and Webster 2009). These studies have been
carried out for cells of non-tumor origin, but there are
relatively few studies on tumor cell interactions with
nanostructured materials. One study showed that the
spreading and proliferation of human osteosarcoma cells
decreases on micro-grid titanium coated silicon surfaces
with increasing surface roughness (Mwenifumbo et al.
2007). Similarly, the adherent human hepatocellular
carcinoma cell number on a silicon nanowire surface was
decreased by 60.5% compared to a bare silicon wafer (Qi
et al. 2007). We recently reported that coating surfaces
with dense monolayers of randomly oriented, upright
nanorods significantly reduces adhesion and viability of
fibroblasts and endothelial cells (Lee et al. 2009). Cells
on nanorods were unable to assemble focal adhesions
and stress fibers, which we hypothesized to be due to
disruption of integrin clustering on nanorod substrates
(Lee et al. 2009). Given that tumor cells have significantly
altered adhesive pathways compared to normal cells
(Desgrosellier and Cheresh 2010), it is unclear if a similar
approach can be used to modulate the adhesion of
malignant tumor cells responsible for stent occlusion.
In this paper, we investigated the effect of nanorod
coatings on the adhesion, motility, and mechanics of
malignant, human esophageal epithelial cells. Malignant
tumor cells cultured on nanorod-coated surfaces had
significantly decreased non-muscle myosin II activity,
decreased stiffness and increased motility. The lack of firm
adhesion correlated with an overall decrease in the tumor
cell number. Our results suggest that nanorod-based coat-
ings may be a promising approach to decrease tumor
adhesion to stent surfaces.
2 Materials and methods
2.1 Growth of nanorods
A solution-based hydrothermal growth method was used
for fabricating ZnO nanorods on the substrates (Kang et
al. 2007). Briefly, ZnO nanocrystal seed solutions
containing 15 mM zinc acetate dihydrate (Sigma Aldrich,
St. Louis, MO) and 30 mM of NaOH (Sigma Aldrich, St.
Louis, MO) were prepared at 60°C for 2 h and spin-
coated onto the substrates. Nanorods were grown by
placing seed-coated substrates upside down in an
aqueous nutrient solution of 20 mM zinc nitrate
hexahydrate and 20 mM hexamethylenetriamine (Sigma
Aldrich, St. Louis, MO). A Unaxis 790 plasma enhanced
chemical vapor deposition (PECVD) system was used to
deposit SiO2on the ZnO nanorods at 50°C using N2O and
2% SiH4balanced by nitrogen as reported before (Chu et
2.2 Cell culture
Twenty-two millimeter square glass cover slips (Corning,
Inc., Lowell, MA) were used as control substrates. All of
the substrates were placed on petri dishes and sterilized
with UV for 5 min, and washed with 70% ethanol and de-
ionized water. Before cell culture, the substrates were
treated with 5 μg/ml human fibronectin (FN) (BD bio-
sciences, Bedford, MA) at 4°C overnight. OE33 (human
esophageal epithelial tumor cells) cells were cultured in
RPMI supplemented with 10% donor bovine serum (DBS)
and 200 mM L-Glutamine (Sigma, St. Louis, MO).
2.3 Cell viability assay
Cells cultured for 24 h on each substrate were stained with the
live/dead viability/cytotoxicity kit for mammalian cells (Invi-
ten fluorescent images taken randomly using a 20× objective.
Three independent experiments of cell viability were per-
of nanorods, OE33 media was incubated with sterilized
nanorods or with glass for 1, 3 and 7 days in an incubator.
The conditioned media was next used to culture cells for 24 h.
Cell morphology and numbers with nanorod-incubated media
was compared to that with glass-incubated media.
2.4 5-bromo-2-deoxyuridine (BrdU) staining
Ten micrometer BrdU (Sigma Aldrich, St. Louis, MO) was
added to cells on glass and nanorods (Ammoun et al. 2006).
After 20 h of incubation, cells were fixed with 4%
paraformaldehyde for 20 min and washed several times with
PBS. 2 M HCl was added to the cells and incubated for
20 min at room temperature. Cells were permeabilized with
0.2% Triton X-100 supplemented with bovine serum albu-
min. Cells were stained with primary anti-BrdU IgG (Sigma
Aldrich, St. Louis, MO) and goat anti-mouse secondary
antibody conjugated with Alexa Fluor 488 (Invitrogen,
Eugene, OR). The number of attached and proliferated cells
on glass and nanorods was counted with ten randomly taken
images using a 20× objective. Three independent experiments
were performed and the data were pooled. A similar fixation
and staining protocol was followed for immunostaining of
adhesion proteins (Lee et al. 2008, 2009).
2.5 Scanning electron microscopy (SEM)
After 24 h of culture, cells were prepared for SEM by fixation
with2%glutaraldehyde buffered inPBS and post-fixedin1%
osmium tetroxide and dehydrated in graded ethanol concen-
trations. Critical point drying (CPD) was performed on a Bal-
Tec 030 instrument (ICBR Electron Microscopy Core Lab,
University of Florida) and Au/Pd (50 Å) was deposited on the
substrate. SEM was performed on a Hitachi S-4000 FE-SEM
Images of samples were taken at 1.0–2.0 k× magnifications.
2.6 Cell motility assay
Phase contrast imaging was performed for 12 h on a Nikon
TE 2000 microscope with a humidified incubator (In Vivo
Scientific, St. Louis, MO). Images were collected every
10 min using a 10× objective. The images were then analyzed
using a Matlab program that tracked the position of the
calculated from the data using non-overlapping time intervals
(Dickinson and Tranquillo 1993). The speed of each cell was
determined from the average displacement in a tracking
interval of 10 min. The persistence time of each cell was
obtained using nonlinear least-square regression of the mean
squared displacement with a persistent random walk model
for cell migration as reported elsewhere (Harms et al. 2005).
2.7 Cell stiffness measurement by atomic force microscopy
Cells were cultured on FN-coated glass and nanorods for
20 h. An Asylum MFP3D AFM (Asylum Research, CA)
coupled to a Nikon TE2000U epifluorescence microscope
was used for measuring cell stiffness (Sen and Kumar
2009). The pyramid-tip had a spring constant of 60 pN/nm,
and tip half-angle was 37°. One hundred twenty-two cells
on glass and 87 cells on nanorods were measured. Each
profile was fit with a modified Hertzian model.
2.8 Western blotting
Cells cultured on 76.2 mm × 25.4 mm glass and same size
of nanorods were washed with cold PBS and lysed with cell
lysis buffer (Cell Signaling Technology, Inc., MA) for
10 min on ice. Cells were then collected and centrifuged at
10,000 rpm for 10 min at 4°C. The supernatant was then
collected and SDS-sample buffer was added and stored at
−20°C until used. The samples were separated on 10% SDS
polyacrylamide gels and then transferred onto a PVDF
membrane. The membranes were blocked with 5% milk in
TBST at room temperature for 30 min. The membranes
were treated with phospho-myosin light chain 2 antibody
(Cell Signaling Technology, Inc., MA) at 1:1,000 dilutions in
5% milk overnight at 4°C. The membranes were then washed
three times in TBST and treated with peroxidase conjugated
secondary antibody at 1:10,000 in 5% milk in TBST for 2 h.
Blots were developed using SuperSignal West Pico Chemi-
luminescent reagent (Pierce Biotechnology, IL) and exposed
to X-OMAT film (Eastman Kodak Inc., NY).
3.1 Decrease in adhesion of esophageal epithelial tumor
cells on nanorods
We used a previously developed method to grow SiO2coated
nanorods on glass surfaces (Fig. 1(a) and (b)) (Chu et al.
2008). Transmission electron microscopy (TEM) and electri-
cal conductance measurements confirmed that the nanorods
were uniformly covered by SiO2without any defects (Chu et
al. 2008). Nanorod surfaces were then coated with fibronectin
0 × 104
4 × 104
8 × 104
10 × 104
Number of attached
OE33 per cm2
BrdU positive cells (%)
Fig. 1 Esophageal epithelial
tumor cell adhesion was de-
creased on nanorods. (a, b)
SEM images of nanorod mor-
phology. Upright nanorods were
covered on the underlying glass
substrate uniformly. (c) Numb-
ers of attached OE33 cells were
reduced by 50% on nanorods
compared to the flat glass sur-
face after 24 h culture. (d) Cell
proliferation is unchanged on
nanorods compared to glass as
measured by BrdU incorpora-
tion. Bars indicate the standard
error of the mean (SEM). *
indicates statistically significant
and tumor epithelial cells were cultured onthe substrates. After
24 h of culture, the number of adherent tumor cells was
observed to be nearly 50% lower on nanorod surfaces
compared to glass (Fig. 1(c)). This decrease was not due to
toxicity of materials leached from the nanorods themselves
(supplementary Fig. 1). We have also previously shown that
the SiO2 coated nanorod surfaces are hydrophilic, and
fibronectin adsorption is unaltered on these surfaces (Lee et
al. 2009). This argues against altered matrix protein adsorp-
tion as a potential cause of the decrease in tumor cell
3.2 Viability and proliferation is unchanged in tumor cells
Staining with calcein AM (4 μM) and ethidium homodimer-1
(EthD-1) showed that adherent tumor cells on glass and
nanorods were both equally viable (data not shown). BrdU
staining revealed that tumor cell proliferation on nanorods
was similar to thaton glass at 24 h (Fig. 1(d)). Together, these
results suggest that the decrease of adherent tumor cells on
nanorods is due to weakened adhesion rather than a decrease
in proliferation rate or cell viability. The fact the proliferation
and viability is unchanged despite weak tumor cell adhesion
is consistent with the fact that malignant tumor cells lose
their dependence on firm adhesion for survival (Paszek et al.
2005; Tilghman and Parsons 2008).
3.3 Tumor cells cultured on nanorods have decreased
While tumor cells were able to form colonies on nanorods,
individual cells in colonies were rounded on nanorods
compared to glass (Fig. 2). We next stained cells for
vinculin and imaged cells with confocal fluorescence
microscopy, but clearly defined focal adhesions proved
difficult to detect on both glass and nanorods (supplemen-
tary Fig. 2). Cells at the periphery of the colonies were
10 µm10 µm
5 µm10 µm
Fig. 2 Individual tumor cells in
colonies were rounded on nano-
rods unlike cells on glass. SEM
images of colony on nanorods
and glass. Arrows point to
lamellipodial structures on glass
surface; similar structures were
not strongly appeared on
Fig. 3 Non-muscle myosin II
activity is significantly reduced
in cells on nanorods compared
to cells on glass. Western Blot of
phosphorylated myosin shows
decreased levels in tumor cells
on nanorods. The comparison
was made for identical levels of
GAPDH to account for the
decrease in cell number on
observed to form lamellipodial structures on glass (arrows
in Fig. 2), but similar structures were less visible on
nanorods. These results raised the possibility that nanorods
could potentially decrease intracellular tension in the tumor
To evaluate this possibility directly, we next measured
the levels of phosphorylated non-muscle myosin II as a
measure of intracellular contractility in tumor cells. As seen
in Fig. 3, the level of phosphorylated myosin II is
significantly decreased in tumor cells adherent to nanorods
compared to flat surfaces. These results provide an
explanation for the rounded cell morphologies seen in
tumor cell colonies on nanorods. It is known that the levels
of phosphorylated non-muscle myosin II correlate with the
stiffness of the cortical actomyosin cytoskeleton in adherent
cells (Clark et al. 2007; Hale et al. 2009). We therefore
measured stiffness of the adherent tumor cell cortex using
atomic force microscopy (AFM) (Rotsch et al. 1999; Sen et
al. 2005). As cell tension is proportional to cortical stiffness
(Rotsch et al. 1999), the stiffness can be considered an
indirect readout of cell tension. Our measurements revealed
that the stiffness of single tumor cells on nanorods was
decreased by nearly 50% of that on glass (Fig. 4).
3.4 Single tumor cell motility is increased on nanorods
Cell motility has been previously shown to be sensitive to
micro- and nano-scale surface topology (Park et al. 2009;
Patel et al. 2010; Thakar et al. 2008; Westcott et al. 2009).
For example, fibroblasts migrate faster on surfaces with
500 nm nanoholes compared to the corresponding flat glass
surface (Westcott et al. 2009). Similarly, on TiO2nanotube
surfaces, mesenchymal stem cells and fibroblasts moved
faster on 15 nm nanotubes compared with the smooth
surface (Park et al. 2007, 2009). However, it is not clear if
tumor cell motility is similarly sensitive to nanostructure.
We therefore measured the single tumor cell migration
speed and persistence time on nanorods. The average cell
speed of single tumor cells and the mean persistence time
were both found to be increased on nanorods compared
with glass (Fig. 5(a) and (b)).
In this paper, we provide new evidence that actomyosin
contractility (as quantified by non-muscle myosin II
13579 11 13
OE33 cell stiffness (kPa)
13579 11 13
OE33 cell stiffness (kPa)
Mean stiffness (kPa)
Fig. 4 Tumor cells are softer on nanorods compared to glass. (a) Histograms of single cell stiffnesses measured by AFM on nanorods and glass.
(b) The mean cell stiffness on nanorods was decreased by 50% compared to that on glass
Average speed of cell
Persistence time (min)
Fig. 5 OE33 cell motility is
altered on nanorods. (a) The
average speed of OE33 on
nanorods was higher than that
on glass (n=15 for glass, n=16
for nanorods). (b) The mean
persistence time is longer on
nanorods than on glass (n=9 for
glass, n=11 for nanorods). Bars
indicate SEM. * indicates a
statistically significant differ-
phosphorylation) is decreased in tumor cells on nanorods.
Because intracellular tension is balanced by the substrate
at adhesive sites, the decrease in myosin activity is
expected to correlate with a decrease in cell spreading
and adherent cell numbers. Consistent with this, we
observed rounded cell morphologies (for both single cells
and cells in colonies). We also found a nearly two-fold
decrease in the adherent cell number. Interestingly, we
observed a decrease in cortical stiffness as measured by
AFM, which has been shown to correlate with myosin
activity previously (Sen and Kumar 2009). Weakened
adhesion may be responsible for the observed increase in
motility on nanorods due to easier detachment of the
trailing edge of cells (Harms et al. 2005; Palecek et al.
1997). Therefore, our different observations can be
explained based on the measured decrease in myosin-
based intracellular tension. Additionally, we observed that
tumor cell proliferation rate and viability was unchanged
on nanorods—this is not surprising given that tumor cells
lose their dependence on firm adhesion for survival and
proliferation (Paszek et al. 2005; Tilghman and Parsons
The mechanism of how nanorods alter non-muscle
myosin II activity may be (at least in part) due to the
nano-scale control of integrin clustering. The clustering of
integrins occurs through crosslinking by intracellular
proteins like talin (Ye et al. 2010) which causes the
formation of stable adhesions that are physically linked to
the intracellular actomyosin cytoskeleton. Interfering with
integrin clustering interferes with focal adhesion assembly
(Arnold et al. 2004; Cavalcanti-Adam et al. 2006, 2007)
and feeds back to change actomyosin contractility (Ingber
2006). Work by Spatz and co-workers has shown that
integrin clustering requires that adjacent ligated integrin
molecules be at a distance of less than 70 nm (Arnold et al.
2004; Cavalcanti-Adam et al. 2006, 2007). Distances
higher than these reduce clustering and focal adhesion
formation. A similar mechanism may be responsible for our
results, although potential intracellular toxicity due to
ingestion of nanorods by the cells (Kim et al. 2007) cannot
be ruled out.
In summary, our results suggest that it is possible to
modulate malignant tumor cell adhesion, migration and
mechanics with nanorod surfaces. The weakened adhesion
raises the possibility that increased tumor cell detachment
may occur under shear forces which are commonly
encountered in the body (although not studied here). Our
results suggest that nanostructure-based approaches may be
a powerful yet simple approach to modulate tumor cell
adhesion, which could potentially be used in improving
tumor stent performance.
study. This work was supported by the American Heart Association
(0735203N-TPL), the National Science Foundation (00072397-TPL),
the National Institutes of Health (Director’s New Innovator Award
1DP2OD004213, a part of the NIH Roadmap for Medical Research,
SK; NCI PSOC Grant 1U54CA143836, SK), and the Arnold and
Mabel Beckman Foundation (SK).
We are grateful to D. Lovett for help in the SEM
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