Co-administration of a clinically relevant dexamethasone dosage with ablative radiotherapy reduces peripheral lymphocytes but does not alter in vivo intratumoral lymphocyte phenotype or inhibit efficacy of radiotherapy in a murine colorectal tumor model

2021 ◽  
Author(s):  
Nicholas G. Battaglia ◽  
Taylor P. Uccello ◽  
Angie Hughson ◽  
Jesse Garrett-Larsen ◽  
Johnathan J. Caldon ◽  
...  
Keyword(s):  
Tumor Model ◽  
Colorectal Tumor ◽  
Peripheral Lymphocytes ◽  
Lymphocyte Phenotype

Long Non-Coding RNA ARAP1-AS1 Facilitates the Progression of Cervical Cancer by Regulating miR-149-3p and POU2F2

Pathobiology ◽  
2021 ◽  
pp. 1-12
Author(s):  
Ling Zhou ◽  
Xiao-li Xu
Keyword(s):  
Cervical Cancer ◽  
Tumor Model ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Non Coding Rna ◽  
Injection Model ◽  
Rna Immunoprecipitation ◽  
Long Non Coding Rna

<b><i>Background:</i></b> Emerging research has demonstrated that long non-coding RNAs (lncRNAs) attach great importance to the progression of cervical cancer (CC). LncRNA ARAP1-AS1 was involved in the development of several cancers; however, its role in CC is far from being elucidated. <b><i>Methods:</i></b> Real-time PCR (RT-PCR) was employed to detect ARAP1-AS1 and miR-149-3p expression in CC samples. CC cell lines (HeLa and C33A cells) were regarded as the cell models. The biological effect of ARAP1-AS1 on cancer cells was measured using CCK-8 assay, colony formation assay, flow cytometry, Transwell assay and wound healing assay in vitro, and subcutaneous xenotransplanted tumor model and tail vein injection model in vivo. Furthermore, interactions between ARAP1-AS1 and miR-149-3p, miR-149-3p and POU class 2 homeobox 2 (POU2F2) were determined by bioinformatics analysis, qRT-PCR, Western blot, luciferase reporter and RNA immunoprecipitation assay, respectively. <b><i>Results:</i></b> The expression of ARAP1-AS1 was enhanced in CC samples, while miR-149-3p was markedly suppressed. Additionally, ARAP1-AS1 overexpression enhanced the viability, migration, and invasion of CC cells. ARAP1-AS1 downregulated miR-149-3p via sponging it. ARAP1-AS1 and miR-149-3p exhibited a negative correlation in CC samples. On the other hand, ARAP1-AS1 enhanced the expression of POU2F2, which was validated as a target gene of miR-149-3p. <b><i>Conclusion:</i></b> ARAP1-AS1 was abnormally upregulated in CC tissues and indirectly modulated the POU2F2 expression via reducing miR-149-3p expression. Our study identified a novel axis, ARAP1-AS1/miR-149-3p/POU2F2, in CC tumorigenesis.

scholarly journals Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jingjing Yang ◽  
Yulu Zhou ◽  
Shuduo Xie ◽  
Ji Wang ◽  
Zhaoqing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Morphological Changes ◽  
Tumor Model ◽  
Independent Manner ◽  
Regulated Cell Death ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Approved Drugs

Abstract Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc− inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

scholarly journals Mannan-Based Nanodiagnostic Agents for Targeting Sentinel Lymph Nodes and Tumors

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 146
Author(s):  
Markéta Jirátová ◽  
Andrea Gálisová ◽  
Maria Rabyk ◽  
Eva Sticová ◽  
Martin Hrubý ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Intraoperative Imaging ◽  
Tumor Model ◽  
Intercellular Adhesion Molecule ◽  
Internal Organs ◽  
Polymer Carriers ◽  
Polymer Conjugates ◽  
Imaging Tool ◽  
Imaging Probes

Early detection of metastasis is crucial for successful cancer treatment. Sentinel lymph node (SLN) biopsies are used to detect possible pathways of metastasis spread. We present a unique non-invasive diagnostic alternative to biopsy along with an intraoperative imaging tool for surgery proven on an in vivo animal tumor model. Our approach is based on mannan-based copolymers synergistically targeting: (1) SLNs and macrophage-infiltrated solid tumor areas via the high-affinity DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) receptors and (2) tumors via the enhanced permeability and retention (EPR) effect. The polymer conjugates were modified with the imaging probes for visualization with magnetic resonance (MR) and fluorescence imaging, respectively, and with poly(2-methyl-2-oxazoline) (POX) to lower unwanted accumulation in internal organs and to slow down the biodegradation rate. We demonstrated that these polymer conjugates were successfully accumulated in tumors, SLNs and other lymph nodes. Modification with POX resulted in lower accumulation not only in internal organs, but also in lymph nodes and tumors. Importantly, we have shown that mannan-based polymer carriers are non-toxic and, when applied to an in vivo murine cancer model, and offer promising potential as the versatile imaging agents.

scholarly journals Molecular imaging of orthotopic prostate cancer with nanobubble ultrasound contrast agents targeted to PSMA

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Wang ◽  
Al Christopher De Leon ◽  
Reshani Perera ◽  
Eric Abenojar ◽  
Ramamurthy Gopalakrishnan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ultrasound Imaging ◽  
Prostate Gland ◽  
Ultrasound Contrast Agent ◽  
Tumor Model ◽  
Focal Therapy ◽  
Ultrasound Contrast Agents ◽  
Time Intensity Curve ◽  
Ultrasound Contrast

AbstractUltrasound imaging is routinely used to guide prostate biopsies, yet delineation of tumors within the prostate gland is extremely challenging, even with microbubble (MB) contrast. A more effective ultrasound protocol is needed that can effectively localize malignancies for targeted biopsy or aid in patient selection and treatment planning for organ-sparing focal therapy. This study focused on evaluating the application of a novel nanobubble ultrasound contrast agent targeted to the prostate specific membrane antigen (PSMA-targeted NBs) in ultrasound imaging of prostate cancer (PCa) in vivo using a clinically relevant orthotopic tumor model in nude mice. Our results demonstrated that PSMA-targeted NBs had increased extravasation and retention in PSMA-expressing orthotopic mouse tumors. These processes are reflected in significantly different time intensity curve (TIC) and several kinetic parameters for targeted versus non-targeted NBs or LUMASON MBs. These, may in turn, lead to improved image-based detection and diagnosis of PCa in the future.

scholarly journals 708 Application of a novel mSENS drug delivery technology for mRNA therapeutics

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A750-A750
Author(s):  
Sojin Lee ◽  
Joon Young Park ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Minhyuk Yun ◽  
...  
Keyword(s):  
Particle Size ◽  
Protein Expression ◽  
Cancer Vaccine ◽  
Encapsulation Efficiency ◽  
Tumor Model ◽  
Cell Responses ◽  
Delivery Platform ◽  
Mrna Therapeutics

BackgroundSuccessful clinical translation of mRNA therapeutics requires an appropriate delivery strategy to overcome instability of mRNA and facilitate cellular uptake into the cells.1 Several lipid based nanoparticle approaches that encapsulate mRNA, notably lipid nanoparticle (LNP), have been developed, but their efficiency for delivery to certain target tissues and toxicity profiles still have room for improvement. The application of a novel polymer based nanoparticle technology platform, so called Stability Enhanced Nano Shells (SENS) for mRNA (mSENS) as a mRNA delivery platform for a cancer vaccine was demonstrated.MethodsThe physicochemical properties of mSENS formulation, particle size and encapsulation efficiency, were characterized using dynamic light scattering (DLS) and gel retardation assay. Using luciferase-encoding mRNA, the protein expression levels in vitro and in vivo were evaluated by luciferase assay or bioluminescence imaging (BLI), respectively. For cancer vaccine studies, antigen (tyrosinase-related protein 2 (Trp-2))-specific T cell responses were assessed by immunophenotyping mouse splenocytes using flow cytometry and by the enzyme-linked immunosorbent spot (ELISPOT) assay. The anti-tumor efficacy was studied in B16F10 lung tumor model in C57BL/6 mice. Liver and systemic toxicity of mSENS treated mice was evaluated through blood chemistry and complete blood count (CBC) tests.ResultsA library of mSENS formulations complexed with luciferase-encoding mRNA, were characterized for their particle size, surface charge, encapsulation efficiency, colloidal stability, and in vitro and in vivo luciferase protein expression level. Upon systemic administration in mice, varying biodistribution profiles were observed, implicating the potential for tailored delivery to target tissues. Particularly, cancer vaccine application was further developed leveraging the formulation with preferential spleen delivery. Following vaccination with Trp-2 mRNA encapsulated with mSENS (Trp-2 mRNA-mSENS) in B16F10 tumor bearing mice, strong Trp-2 antigen-specific IFN-γ T-cell responses were observed. Generated anti-tumor immunity also marked suppression of B16F10 lung tumors were observed in Trp-2-mSENS immunized mice compared to non-immunized controls, demonstrating the potential of mSENS as a mRNA delivery platform for the application for vaccine.ConclusionsProprietary biodegradable polymer based-mSENS platform offers an attractive delivery strategy for mRNA by tailoring to specific therapeutic applications. Depending on the application, whether it’s a vaccine or protein replacement, a rationally designed mSENS formulation can efficiently distribute mRNA to specific tissues. In particular, application of a splenic mSENS formulation for a cancer vaccine has been demonstrated in murine tumor model. In summary, mRNA delivery through mSENS platform is expected to provide significant opportunities in clinical development for mRNA therapeutics.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals’ IACUC (Institutional Animal Care and Use Committee), approval number SYAU-2027.ReferencePiotr S. Kowalski, Arnab Rudra, Lei Miao, and Daniel G. Anderson, delivering the messenger: advances in technologies for therapeutic mRNA delivery. Molecular Therapy Vol. 27 No 4 April 2019.

scholarly journals Cirsiliol targets tyrosine kinase 2 to inhibit esophageal squamous cell carcinoma growth in vitro and in vivo

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xuechao Jia ◽  
Chuntian Huang ◽  
Yamei Hu ◽  
Qiong Wu ◽  
Fangfang Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Tumor Model ◽  
Kinase Assay ◽  
Tyrosine Kinase 2

Abstract Background Esophageal squamous cell carcinoma (ESCC) is an aggressive and lethal cancer with a low 5 year survival rate. Identification of new therapeutic targets and its inhibitors remain essential for ESCC prevention and treatment. Methods TYK2 protein levels were checked by immunohistochemistry. The function of TYK2 in cell proliferation was investigated by MTT [(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and anchorage-independent cell growth. Computer docking, pull-down assay, surface plasmon resonance, and kinase assay were used to confirm the binding and inhibition of TYK2 by cirsiliol. Cell proliferation, western blot and patient-derived xenograft tumor model were used to determine the inhibitory effects and mechanism of cirsiliol in ESCC. Results TYK2 was overexpressed and served as an oncogene in ESCC. Cirsiliol could bind with TYK2 and inhibit its activity, thereby decreasing dimer formation and nucleus localization of signal transducer and activator of transcription 3 (STAT3). Cirsiliol could inhibit ESCC growth in vitro and in vivo. Conclusions TYK2 is a potential target in ESCC, and cirsiliol could inhibit ESCC by suppression of TYK2.

Detection of early primary colorectal cancer with upconversion luminescent NP-based molecular probes

Nanoscale ◽  
2016 ◽  
Vol 8 (25) ◽  
pp. 12579-12587 ◽  
Author(s):  
Chunyan Liu ◽  
Yifei Qi ◽  
Ruirui Qiao ◽  
Yi Hou ◽  
Kaying Chan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Model ◽  
Molecular Probes ◽  
Colorectal Tumor ◽  
Primary Colorectal Cancer ◽  
Early Primary

A primary mice colorectal tumor model was established and carefully studied for achieving sensitive imaging with specific upconversion nanoprobes.

scholarly journals Implantable NMR Microcoils in Rats: A New Tool for Exploring Tumor Metabolism at Sub-Microliter Scale?

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 176
Author(s):  
Justine Deborne ◽  
Noël Pinaud ◽  
Yannick Crémillieux
Keyword(s):  
Magnetic Resonance ◽  
Tumor Model ◽  
Surface Coil ◽  
Regions Of Interest ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Volume Coil ◽  
Detection Volume ◽  
The Right

The aim of this study was to evaluate the potential of a miniaturized implantable nuclear magnetic resonance (NMR) coil to acquire in vivo proton NMR spectra in sub-microliter regions of interest and to obtain metabolic information using magnetic resonance spectroscopy (MRS) in these small volumes. For this purpose, the NMR microcoils were implanted in the right cortex of healthy rats and in C6 glioma-bearing rats. The dimensions of the microcoil were 450 micrometers wide and 3 mm long. The MRS acquisitions were performed at 7 Tesla using volume coil for RF excitation and microcoil for signal reception. The detection volume of the microcoil was measured equal to 450 nL. A gain in sensitivity equal to 76 was found in favor of implanted microcoil as compared to external surface coil. Nine resonances from metabolites were assigned in the spectra acquired in healthy rats (n = 5) and in glioma-bearing rat (n = 1). The differences in relative amplitude of choline, lactate and creatine resonances observed in glioma-bearing animal were in agreement with published findings on this tumor model. In conclusion, the designed implantable microcoil is suitable for in vivo MRS and can be used for probing the metabolism in localized and very small regions of interest in a tumor.

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