LGR5 is a marker of normal and cancer stem cells in various tissues where it functions as a receptor for R-spondins and increases canonical Wnt signalling amplitude. Here we report that LGR5 is also highly expressed in a subset of high grade neuroblastomas. Neuroblastoma is a clinically heterogenous paediatric cancer comprising a high proportion of poor prognosis cases (~40%) which are frequently lethal. Unlike many cancers, Wnt pathway mutations are not apparent in neuroblastoma, although previous microarray analyses have implicated deregulated Wnt signalling in high-risk neuroblastoma. We demonstrate that LGR5 facilitates high Wnt signalling in neuroblastoma cell lines treated with Wnt3a and R-spondins, with SK-N-BE(2)-C, SK-N-NAS and SH-SY5Y cell-lines all displaying strong Wnt induction. These lines represent MYCN-amplified, NRAS and ALK mutant neuroblastoma subtypes respectively. Wnt3a/R-Spondin treatment also promoted nuclear translocation of β-catenin, increased proliferation and activation of Wnt target genes. Strikingly, short-interfering RNA mediated knockdown of LGR5 induces dramatic Wntindependent apoptosis in all three cell-lines, accompanied by greatly diminished phosphorylation of mitogen/extracellular signal-regulated kinases (MEK1/2) and extracellular signal-regulated kinases (ERK1/2), and an increase of BimEL, an apoptosis facilitator downstream of ERK. Akt signalling is also decreased by a Rictor dependent, PDK1-independent mechanism. LGR5 expression is cell cycle regulated and LGR5 depletion triggers G1 cell-cycle arrest, increased p27 and decreased phosphorylated retinoblastoma protein. Our study therefore characterises new cancer-associated pathways regulated by LGR5, and suggest that targeting of LGR5 may be of therapeutic benefit for neuroblastomas with diverse etiologies, as well as other cancers expressing high LGR5.
Tumor growth is influenced by a wide variety of external and internal factors. One of the most important mediators of tumor development is our immune system. The nonstop surveillance of the immune system was originally expected to clear the transformed cells from the body and guard against the development of tumor. But contradictory evidences are reported to show the involvement of immune system in supporting the growth and spread of tumor. Tumor infiltrating immune cells, in addition to harboring immunosuppressive activities, also promote angiogenesis and metastasis of tumor. Many growth factors and cytokines are involved in shaping this complex immune microenvironment of the tumor. Macrophage colony-stimulating factor (MCSF) is one such growth factor which is overexpressed in many tumors. In this review, we summarize the basic biology of MCSF, its role in cancer and discuss the involvement of tumor-associated macrophages (TAMs) in tumor development.
Herein, a green method for the development of a novel biodegradable silver nanoparticles (NPs) impregnated alginate-chitosan-blended nanocarrier (Ag NPs-Alg-Chi NC) is reported. The synthesis of Ag NPs-Alg-Chi NC is based on the polyelectrolyte complex formation between alginate and chitosan. The composite NC is characterized by ultraviolet-visible spectroscopy, transmission electron microscopy, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and X-ray diffraction. The Ag NPs in the NC are found to elicit anticell proliferative effect on refractory U87MG (human glioblastoma) cells at IC50 of 2.4 μg mL(-1) for Ag NPs. The cell cycle analysis shows extensive DNA damage. Elevation in reactive oxygen species level indicates induction of oxidative stress in treated cells. Mitochondrial dysfunction in cell death is evident from the depolarization of mitochondrial membrane potential (ΔΨm ). Fluorescence and SEM images of the treated cells reveal nuclear and morphological changes characteristic of apoptosis, which is further confirmed by TUNEL assay. The induction of apoptosis at low concentration of Ag NPs present in Ag NPs-Alg-Chi NC in comparison with free Ag NPs makes it a promising tool for cancer therapy.
The gap junction (GJ) protein connexin-43 (Cx43) is considered as a tumour suppressor protein for its role in reversing the phenotype of the cancer cells. In this study, we exploited the antitumor property of Cx43 in conjunction with the artesunate (ART), a plant-based active anti-malarial compound. The reactive oxygen species (ROS) generated by ART resulted in DNA damage, which in turn led to DNA damage response by activation of DNA damage repair proteins. GJ deficient MCF-7 cells transfected with Cx43 gene showed an increased sensitivity towards dose-dependent ART treatment and required a significantly lower dose of ART to attain its IC50, as compared to parental cells. This would ultimately result in reduced dose-dependent side effects of ART. The Co-culture experiments involving GJ intercellular communication (GJIC) deficient and GJIC enabled cells, established the transfer of ROS to the neighbouring cancer cells not exposed to ART. The ROS accumulated in the ART-treated cells induced the oxidative damage in neighbouring cells, leading to bystander cell death and inhibition of bystander cell proliferation. Thus, our study revealed that expression of Cx43 helped in reducing the dose-dependent cytotoxicity of ART as well as enhanced the bystander apoptosis of the neighbouring cells.
Nonlinear evolution of shear waves into shocks in incompressible elastic materials is investigated using the framework of large deformation elastodynamics, for a family of loadings and commonly used hyperelastic material models. Closed form expressions for the shock formation distance are derived and used to construct non-dimensional phase maps that determine regimes in which a shock can be realized. These maps reveal the sensitivity of shock evolution to the amplitude, shape, and ramp time of the loading, and to the elastic material parameters. In light of a recent study (Espindola et al., 2017), which hypothesizes that shear shock formation could play a significant role in Traumatic Brain Injury (TBI), application to brain tissue is considered and it is shown that the size matters in TBI research. Namely, for realistic loadings, smaller brains are less susceptible to formation of shear shocks. Furthermore, given the observed sensitivity to the imparted waveform and the constitutive properties, it is suggested that the non-dimensional maps can guide the design of protective structures by determining the combination of loading parameters, material dimensions, and elastic properties that can avoid shock formation.
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