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Special Issue: Challenges and Opportunities in Breast Cancer Epithelial-mesenchymal transition and stemness of breast cancer cells: Effect of viscoelasticity of the substrate to mimics microenvironment Metastasis is one of the greatest challenges in cancer treatment today. Normal mammary epithelial cells are optimally supported by interaction with a soft matrix (microenvironment) with elastic modulus of about 800 Pa. However, after transformation, breast tissue becomes progressively stiffer and tumour cells become significantly more contractile and hyper-responsive to matrix elasticity. In addition, importantly, the cancer cells penetrate into blood vessel and enter the circulation during metastasis. The modulus of fluid such as blood or mucus has very low stiffness of around 50 Pa. For this reason, the critical association between cancer cell phenotype and the change of matrix rigidity with an order of magnitude smaller should be emphasizing. This review highlights the current understanding of epithelial-mesenchymal transition and cancer stem cells in metastasis, and identified importance for investigation on artificial extracellular matrix with different viscoelastic properties, which is required to mimics in vivo microenvironment. The substrate damping coefficient (tan) as potential physical parameter emerged the important linkage to cellular motility, cancer stemness, and epithelial-mesenchymal transition induction. Although further investigation is required to clarify the efficacy of environmental stimuli (tan) for tumors exhibiting stem cell-like properties, this review indicates that the cancer cells incubated on softer substrate might lead to express cancer stem cell biomarkers exhibiting high expression. Keywords: breast cancer, metastasis, epithelial-mesenchymal transition, cancer stem cells, viscoelastic properties, microenvironment ESMED Medical research Archives 11(10), (2023). doi.org/10.18103/mra. v11 i10.4580 |
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In the last 20 years, there has been a strong emphasis on the development
of polymer nanocomposites, where at least one of the dimensions of the
filler material is of the order of a nanometer. Polymer nanocomposites
are fundamentally different from traditional filled polymers because of
the immense internal interfacial area and the nanoscopic nature of the
nanomaterials. The new multifunctional properties derived from the nano-structure
of nanocomposites provide an opportunity to circumvent the traditional
properties associated with traditional composites. Numerous examples can
be found in the literature that show significant improvements in multifunctional
properties of the nanocomposites and this new class materials now being
introduced in structural applications, such as gas barrier film, flame
retardant product, and other load-bearing applications. This review offers
a comprehensive review on the basic concept, technology and application
for polymer nanocomposites. Okamoto, M. Polymer Nanocomposites. Eng 2023, 4, 457–479. https://doi.org/10.3390/eng4010028 |
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Aim: This study aimed to examine the effect of polymer substrate surface
topography and stiffness on the direct relationship between drug susceptibility
and mesenchymal properties of cancer cells in both normal and hypoxic conditions. Methods: The combination of both surface topographies (fiber alignments) and different stiffness of poly(L-lactic acid) (PLLA) substrates has been used to evaluate the effect of the surface topographies and stiffness of the substrate on the direct relation between anti-cancer drug (CDDP) sensitivity for MDA-MB-231cells and mesenchymal properties with induction of epithelial–mesenchymal transition (EMT). Results: The CDDP treatment in hypoxia indicates weakened cell adhesion in MDA-MB-231 cells as well as a significant level of repression in E-cadherin (CDH1). The robust connection between the drug sensitivity and repression of epithelial cell marker of E-cadherin (CDH1) mediated by substrate surface topography had an implication in the anti-cancer drug resistance of MDA-MB-231cells. Conclusion: PLLA substrates did not cause so significant change in induction and acquisition of the EMT, indicating the EMT has no effect on the drug susceptibility. OBM Genetics (Link: http://www.lidsen.com/journals/genetics) doi: 10.21926/obm.genet.2202155 |
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Acrylamide copolymer-based gel substrates with different viscoelasticity
were employed to evaluate the viscoelasticity effect on the direct relation
among cancer stemness, cellular motility and mesenchymal properties with
induction of epithelial–mesenchymal transition (EMT) of human breast adenocarcinoma
(MCF-7) cells in both normoxia and hypoxia. Cellular migration speed (S)
of MCF-7 cells was significantly upregulated with decreasing in coefficient
of damping (tan). The softer gel substrate produced a large amount of
surface molecule of cancer stem cells (CSC) marker CD44. In contrast, for
the stem cell biomarker CD133 expression, their tan-dependent manner was
not contributed by EMT phenomenon and was an independent from acquisition
of the EMT. The substrate damping as potential physical parameter emerged
the important linkage to cellular motility, cancer stemness, and EMT induction. Nihon Reoroji Gakkaishi, 49, 3, 163-170, 2021 |
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To broaden the knowledge regarding regenerative medicine in natural rubber
latex (NRL) nanoparticles, we have examined the chondrogenesis of human
mesenchymal stem cells (hMSCs) with NRL nanoparticles in hypoxia. We have
successfully fabricated the cartilage/NRL biocomposites via hMSCs spheroid
under hypoxic condition, where the administration of NRL nanoparticles
exhibits the suppression of the spheroid contraction due to the cellular
proliferation of hMSCs. It has been emerged that the NRL nanoparticles
acted as a main component, which provides surface heterogeneity of the
spheroid, leading to the mechanically stable structure with higher modulus
in comparison with the control as revealed by atomic force microscopy microindentation.
In hypoxia the effective gene expression of in vitro chondrogenesis of
hMSCs with administration of NRL was confirmed as revealed by the chondrogenic
gene expression analysis as compared with that in normoxia. Nanocomposites6,137-148,2020 |
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The presented research aims to verify whether physicochemical properties
of lung fibroblasts, modified by substrate stiffness, can be used to discriminate
between normal and fibrotic cells from idiopathic pulmonary fibrosis (IPF).
The impact of polydimethylsiloxane (PDMS) substrate stiffness on the physicochemical
properties of normal (LL24) and IPF-derived lung fibroblasts (LL97A) was
examined in detail. The growth and elasticity of cells were assessed using
fluorescence microscopy and atomic force microscopy working in force spectroscopy
mode, respectively. The number of fibroblasts, as well as their shape and
the arrangement, strongly depends on the mechanical properties of the substrate.
Moreover, normal fibroblasts remain more rigid as compared to their fibrotic
counterparts, which may indicate the impairments of IPF-derived fibroblasts
induced by the fibrosis process. The chemical properties of normal and
IPF-derived lung fibroblasts inspected using time-of-flight secondary ion
mass spectrometry, and analyzed complexly with principal component analysis
(PCA), show a significant difference in the distribution of cholesterol
and phospholipids. Based on the observed distinctions between healthy and
fibrotic cells, the mechanical properties of cells may serve as prospective
diagnostic biomarkers enabling fast and reliable identification of idiopathic
pulmonary fibrosis (IPF). Materials Biomaterial Section (MDPI) 13, 4495-, 2020 |
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The induction of epithelial-mesenchymal transition (EMT) is believed to
promote tumor cell motility and invasion. Using polymeric gel substrates
with different viscoelasticity as microenvironment of cell culture substrates
that influences cancer progression and metastatic potential, we have examined
the effect of the viscoelasticity on the direct relation between cellular
motility and mesenchymal properties with induction of EMT in MDA-MB-231
cells. The MDA-MB-231 cells cultured on gel substrates showed different
cellular morphologies and these morphological differences were robustly
correlated with cellular migration speed (S) and damping coefficient (tan)
of gel substrates (not substrate stiffness). The linkage between the acquisition
of the mesenchymal phenotype in the cells through the induction of EMT
mediated by stiffer substrate and the promotion of the cellular motility
were not observed. Understanding the biology of EMT with or without linkage
to the cellular motility provides new approaches in development new therapeutic
strategies. Materials Today Chemistry 13, 8-17,2019 |
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Natural rubber latex (NRL) is mainly used around traditional industrial
products, but currently their target application is continuously expanding
into tissue engineering. Here, we have presented the chondrogenesis ability
of NRL nanoparticles against human mesenchymal stem cells (hMSCs). The
effective gene expression of in vitro chondrogenesis of hMSCs with administration
of NRL was confirmed as revealed by the chondrogenic gene expression analysis.
We have successfully for the first time fabricated the cartilage/NRL biocomposites
via hMSC spheroid formation, where the administration of NRL nanoparticles
exhibited the mechanically stable structure with hard surface structure
in the spheroid. Materials Today Chemistry, 12, 315-323, 2019 |
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In the research we obtained porous scaffolds based on poly(L-lactide) and
synthetic hydroxyapatite(HA) using thermal induced phase separation technique
(TIPS) supported by salt leaching process(SL). The obtained series of composite
foams differ in hydroxyapatite content(10,25,50,75,90 wt% of the HA in
PLLA/HA systems). The infestigated scaffolds porosity ranged from 88 to
98%, density from 0.024 to 0.140 g/cm3. Water contact angle measurements
indicated more hydrophilic scaffold surface with indicated more hydrophilic
scaffold surface with increasing hydroxyapatite content in the composites.
Thermogravimetric analysis revealed higher thermal stability of all composites
comparing to neat PLLA, indicated presence of -3 wt% residual sodium chloride
in the scaffolds. Differntial scanning calorimetry analysis showed nucleation
effet of hydroxyapatite and higher crystallinity of PLLA in the composites
as compared to the neat PLLA. The above tests were supplemented with compressive
strength measurements, which showed an increase in the Young's modulus
and compressive stresses values parallelly with the increase of the filler
content. Proliferation tests of MC3T3-E1 mouse calvaria pre-osteoblast
cells indicated directly proportional relationship between hydroxyapatite
content and cells proliferation rate. |
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Using polymeric fibers substrates with different mechanical features and
surface topographies (fiber alignments) as microenvironment of cell culture
substrates that influences cancer progression and metastatic potential,
we have demonstrated systematically the effect of stiffness and topographies
on two different types of breast cancer cells (MDA-MB-231 and MCF-7). The
cells cultured on different substrates both normoxic and hypoxic conditions
showed different morphologies and these morphological differences were
correlated with cellular motility and gene expression. We discussed the
effect of hypoxia on gene expression and cellular motility to understand
the cell-cell and cell-substrate interactions. The progresses of microenvironment-mediated
tumor progression in artificial extracellular matrix explored the design
criteria to understand the cancer progression mechanism and metastatic
potential. Materials Today Chemistry 29-41, 11, 2019 |
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Aim: This study was aimed to assess multiple marker-loaded plasmid DNA-calcium
phosphate (CaP) particles to allow a multiple tumor drug delivery for cancer
therapy. Despite its widespread use as an in vitro plasmid DNA (pDNA)-loaded
calcium phosphate (CaP) particles (pDNA-CaP) transfection, little attention
has been given to the multiple deliver system. Methods: In this study,
we optimized Ca:P ion ratios by varying ions concentration of simulated
body fluid solutions to induce sufficient protein expression and examined
the effect of the multiple marker-loaded pDNA-hydroxyapatite (HA) particles
including three different markers of pDNA on the transfection to human
embryonic kidney (HEK293) cells. Results: The existence of three different
proteins inside the cells were produced after successful transfection of
much higher multiple pDNAs when using the multiple plasmid-loaded (3-pDNA-HA)
particles having 2.4 µm in size. Conclusion: The 3-pDNA-HA-embedded gel substrate showed effective reverse transfection for HEK293 cells. Journal of Unexplored Medical Data doi.org/10.20517/2572-8180.2017.24 (2018) |
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To broaden the knowledge of cytotoxicity of natural rubber latex (NRL)
nanoparticles we for the first time examined the latex biocompatibility
in vitro against mouse calvaria preosteoblast cells (MC3T3-E1) and human
alveolar basal epithelial (A549) cells. For NRL nanoparticles, the half
maximal inhibitory concentration (IC50) value for MC3T3-E1 cells is one
order of magnitude higher in toxicity as compared to that of A549 cells
(3.99 mg/mL for MC3T3-E1 and 0.33 mg/mL for A549 cells). Owing to fractionation
of NRL nanoparticles by ultra-centrifuge, the effect of the non-rubber
constituents on the cytotoxicity was clarified. The suppression on the
proliferation for A549 cells incubated with NRL nanoparticles was demonstrated
by the cell cycle distribution. The in vitro study on osteogenic differentiation
and expressions of proteins and characteristic genes of MC3T3-E1 cells
demonstrated the promising results of the NRL nanoparticles for application
in bone tissue engineering. e-Journal of Soft Materials 1-10, 12, 2017 |
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To broaden the knowledge of cytotoxicity of natural rubber latex (NRL)
nanoparticles we for the first time examined the latex biocompatibility
in vitro against a panel of cancer cells (A549, A2780, and MDA-MB-231).
Owing to fractionation of NRL nanoparticles by ultra-centrifuge, the effect
of the non-rubber constituents (intermediate of 5.8 wt.% and sediment of
0.2 wt.%) on the cytotoxicity was clarified. For intermediate constituent,
the half maximal inhibitory concentration (IC50) values at 24 h was 1.05
mg/mL for A549 cells, which was one order of magnitude higher in toxicity
as compared to that for A2780 (0.24 mg/mL) and MDA-MB-231 (0.36 mg/mL)
cells. In addition, profound studies including cell cycle arrest abilities
and apoptosis induction profiles against cancer cells were discussed in
detail. It was found that the constituents exhibit some significant effect
on the cell cycle arrest and trigger apoptosis for A2780 cells. This effective
apoptosis induction profiles was more prominent in MDA-MB-231 cells incubated
with NRL nanoparticles and sediment loading conditions. The percentage
of apoptotic cells was ca. 6–8% of the total cells. Materials Today Chemistry 63-71, 5, 2017 |
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Natural rubber latex (NRL) is mainly used around traditional industrial
products, but currently their target application is continuously expanding
into tissue engineering. To broaden our knowledge of application in tissue
engineering of NRL, we have focused on the surface modification of NRL
nanoparticles through the biomineralization of hydroxyapatite (HA) using
simulated body fluid in order to create a better cytocompatibility with
controlled cell adhesion and mineralization properties in osteogenic culture
to determine the effect on bone outcomes. Using MC3T3-E1 mouse osteoblastic-like
cells incubated with NRL nanoparticles coated with HA layer, we have examined
the osteogenic differentiation and expressions of multiple proteins and
characteristic genes of mature osteoblast. We have successfully prepared
the biocomposites composed of NRL and bone tissue. Nanocomposites 76-83, 3, 2017 |
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The interpretation of the local microenvironment of extracellular matrix
for malignant tumor cells is in intimate relation with metastatic spread
of cancer cells involving the associated issues of cellular proliferation
and drug responsiveness. This study was aimed to assess the combination
of both surface topographies (fiber alignments) and different stiffness
of the polymeric substrates (PLLA and PCL) and collagen substrates (coat
and gel) to elucidate the effect of the cellular morphology on cellular
proliferation and drug sensitivities of two different types of breast cancer
cells (MDA-MB-231 and MCF-7). The morphological spreading parameter of
(Nuclear/Cytoplasm) induced by the anthropogenic substrates has correlated
intimately with the cellular proliferation and the drug sensitivity (IC50)
of cancer cells. This study demonstrated the promising results of the parameter
for the evaluation of cancer cell malignancy. Journal of Functional Biomaterials 8, 18, 2017 |
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The complexation of allophane nanoparticles with cisplatin, cis-dichlorodiammineplatinum
(II) (CDDP) to deliver platinum prodrug into cancer cells was investigated.
Using human lung carcinoma (A549) cells, profound studies including cellular
uptake (endocytosis) analysis of allophane nanoparticle, cell cycle arrest
abilities and apoptosis induction profiles were discussed in detail. As
well as the features against A549 cells to emerge a promising strategy
to enhance their anti-cancer activity and to mitigate side-effects were
discussed. Applied Clay Science 422-429, 143, 2017 |
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Progresses of microenvironment-mediated tumor progression in artificial extracellular matrix explore the design criteria to understand the cancer progression mechanism and metastatic potential. This study was aimed to assess the combination of both surface topographies (fiber alignments) and different stiffness of the polymeric substrates (PLLA and PCL) to evaluate the effect on the cellular morphologies, proliferation, motility and gene expression regarding epithelial to mesenchymal transition (EMT) of two different types of breast cancer cells (MDA-MB-231 and MCF-7). The cellular morphologies (roundness and nuclear elongation factor), E-cadherin and vimentin expression, and cellular motility in terms of cellular migration speed, persistent time and diffusivity were discussed comprehensively. We have demonstrated that the microenvironment of cell culture substrates influences cancer progression and metastatic potential. Journal of Materials Chemistry B 2588-2600, 5, 2017 |
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Clay minerals are mainly used around traditional cosmetics and industrial products, but currently their target application is continuously expanding into pharmaceutical industry and tissue engineering. To broaden the knowledge of in vitro cytotoxicity of allophane nanoparticles against human cancer cells, the cytotoxicity of both natural and synthetic allophane nanoparticles for cultured human alveolar basal epithelial (A549) cells was examined. For both natural and synthetic allophones, the A549 cell viability was maintained at > 70% for concentration up to 3160 mg/mL, implying higher biocompatibility of allophane nanoparticles as compared with that of hectorite nanoparticles. The cell adhesion kinetics coupled with cytotoxic characteristics against A549 cells was analyzed using quartz crystal microbalance (QCM) technique to distinguish the dynamic cell adhesion signatures. Applied Clay Science 485-492, 135, 2017 |
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Poly-L-lactide (PLLA)/natural hydroxyapatite (n-HA)
composite scaffolds with different morphology and porosity were prepared using
thermally induced phase separation (TIPS) technique. The morphological features
of the scaffolds were observed by field emission scanning electron microscope
(FE-SEM). The solvent concentration had much effect on the porosity and pore
morphology. The double-stranded
deoxyribonucleic acid (ds-DNA) adsorption behavior was investigating
with the aim of their applications in gene therapy. The propensity of the scaffolds and n-HA particles to adsorb ds-DNA was
assessed by batch experiments at pH 4. The aggregated size of the ds-DNA
molecules and agglomeration after adsorption were
characterized by dynamic light scattering (DLS) and Fourier
transform infrared (FTIR)
spectroscopic imaging. The adsorption data were fitted into the Freundlich equation and the adsorption parameters were assessed. Although the adsorption capacity of the scaffolds was lower as compared to n-HA particles, it was sufficient for ds-DNA adsorption. The in vitro cell culture test was conducted on the scaffolds with human mesenchymal stem cells (hMSCs). The cells on PLLA/n-HA/ds-DNA scaffold showed more significant increases than neat PLLA and PLLA/n-HA scaffolds. Polymer 73-81, 56, 2015 |
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Clay mineral
surfaces have been important for the prebiotic organization and protection of
nucleic acids. The
morphological observation to provide insight into the
adsorption structure and characteristics of single-stranded
DNA (ss-DNA)
by natural allophane particles was presented. The molecular orbital (MO) computer
simulation has been used to probe the interaction of ss-DNA and/or adenosine
5’-monophosphate and allophane with active sites. Our simulations predicted
the strand undergoes some extent of the elongation, which induces the alteration
of the conformation of the phosphate backbone, base-base distance and excluded
volume correlation among bases. This work demonstrates the ss-DNA adsorption
by the allophane particles with novel insights into the morphological features
and detailed molecular level information. The overall results support a
general adsorption mechanism for the ss-DNA/allophane complexation Applied Clay Science 591-597, 101, 2014 |
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To understand the enzymatic degradation behavior of crosslinked polylactide
(PLA), the preparation and enzymatic degradation of both thermoplastic
(linear) and crosslinked PLAs having pore structure with different dimension
were carried out. The porous structures of the linear PLA samples were
of micro and nanoporous range prepared by batch foaming at supercritical
CO2 and compared with the porous structures of crosslinked PLA (Lait-X)
created by salt leaching method. The surface and cross-sectional morphologies
of the porous structures were investigated by using scanning electron microscopy.
The morphological analysis of Lait-X porous showed a rapid loss of physical
features with 120 h of exposure to the proteinase-K enzymatic degradation
at 37 °C. Due to higher affinity for water led to enhanced enzymatic activity
as compared to the linear PLA porous structures in the micro and nanoporous
range. International Journal of Molecular Science 9793-9808, 15, 2014 |
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Allophane nanoparticles were synthesized through a hydrothermal treatment
of precursor with Si/Al molar ratio of 0.75 at 100°C for 48 h and characterized
by using field emission scanning electron microscopy, pore-size distribution
based on the Cranston-Inkley method, 29Si and 27Al magic angle spinning
nuclear magnetic resonance, X-ray diffractometry, and energy dispersive
X-ray spectroscopy. It is demonstrated that the synthetic allophane nanoparticle
leads to a novel allophane-Pt nanocomposite with the metal particle size
of ~ 2 nm and narrow size distribution. The synthetic allophane particles
promote the reduction of K2PtCl4 to Pt0 and act as a support substratum.
The molecular orbital computer simulation was performed to provide insight
into the structure and stability of Pt nanoparticles during complexation
by the functional (OH)Al(OH2) groups on the wall perforations of the synthetic
allophane. Applied Clay Science 191-196, 95, 2014 |
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