Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

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Preclinical Quantification of Prostate Cancer-Associated Vascular Alterations in the Bone Microenvironment in vivo

European Surgical Research ◽

10.1159/000514224 ◽

2020 ◽

Vol 61 (6) ◽

pp. 188-200

Author(s):

Malte Schroeder ◽

Lennart Viezens ◽

Jördis Sündermann ◽

Svenja Hettenhausen ◽

Gerrit Hauenherm ◽

...

Keyword(s):

Prostate Cancer ◽

Blood Flow ◽

Flow Velocity ◽

Cell Lines ◽

Blood Flow Velocity ◽

Tumour Growth ◽

Prostate Cancer Cell ◽

Bone Microenvironment ◽

Prostate Cancer Cell Lines

Introduction: Prostate cancer has a special predilection to form bone metastases. Despite the known impact of the microvascular network on tumour growth and its dependence on the organ-specific microenvironment, the characteristics of the tumour vasculature in bone remain unknown. Methods: The cell lines LNCaP, DU145, and PC3 were implanted into the femurs of NSG mice to examine the microvascular properties of prostate cancer in bone. Tumour growth and the functional and morphological alterations of the microvasculature were analysed for 21 days in vivo using a transparent bone chamber and fluorescence microscopy. Results: Vascular density was significantly lower in tumour-bearing bone than in non-tumour-bearing bone, with a marked loss of small vessels. Accelerated blood flow velocity led to increased volumetric blood flow per vessel, but overall perfusion was not affected. All of the prostate cancer cell lines had similar vascular patterns, with more pronounced alterations in rapidly growing tumours. Despite minor differences between the prostate cancer cell lines associated with individual growth behaviours, the same overall pattern was observed and showed strong similarity to that of tumours growing in soft tissue. Discussion: The increase in blood flow velocity could be a specific characteristic of prostate cancer or the bone microenvironment.

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Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Angiogenesis ◽

10.1007/s10456-021-09776-8 ◽

2021 ◽

Author(s):

Delphine M. Lees ◽

Louise E. Reynolds ◽

Ana Rita Pedrosa ◽

Marina Roy-Luzarraga ◽

Kairbaan M. Hodivala-Dilke

Keyword(s):

Blood Vessel ◽

Tumour Growth ◽

Vascular Endothelial Cell ◽

Vessel Density ◽

In Vivo Studies ◽

Blood Vessel Density ◽

Tumour Vessel ◽

Vessel Regression ◽

Tumour Blood

AbstractFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrβCre + ;FAKWT/WT, PdgfrβCre + ;FAKY397F/Y397F and PdgfrβCre + ;FAKY861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrβCre + ;FAKY861F/Y861F but not PdgfrβCre + ;FAKY397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of pericyte derived signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

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Prostaglandin E 3 attenuates macrophage‐associated inflammation and prostate tumour growth by modulating polarization

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16570 ◽

2021 ◽

Author(s):

Jing Cui ◽

Kai Shan ◽

Qin Yang ◽

Yumin Qi ◽

Hongyan Qu ◽

...

Keyword(s):

Tumour Growth ◽

Prostaglandin E ◽

Prostate Tumour

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Antitumoural hydroxyapatite nanoparticles-mediated hepatoma-targeted trans-arterial embolization gene therapy: in vitro and in vivo studies

Liver International ◽

10.1111/j.1478-3231.2012.02761.x ◽

2012 ◽

Vol 32 (6) ◽

pp. 998-1007 ◽

Cited By ~ 12

Author(s):

Gaopeng Li ◽

Lu Ye ◽

Jingsheng Pan ◽

Miaoyun Long ◽

Zizhuo Zhao ◽

...

Keyword(s):

Gene Therapy ◽

Arterial Embolization ◽

In Vivo Studies ◽

Hydroxyapatite Nanoparticles

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Increased tumour extracellular pH induced by Bafilomycin A1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics

European Journal of Cancer ◽

10.1016/s0959-8049(02)00671-8 ◽

2003 ◽

Vol 39 (4) ◽

pp. 532-540 ◽

Cited By ~ 24

Author(s):

P.M.J. McSheehy ◽

H. Troy ◽

L.R. Kelland ◽

I.R. Judson ◽

M.O. Leach ◽

...

Keyword(s):

Tumour Growth ◽

Extracellular Ph ◽

Bafilomycin A1

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Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽

10.1136/gutjnl-2018-317570 ◽

2018 ◽

Vol 68 (4) ◽

pp. 693-707 ◽

Cited By ~ 18

Author(s):

Delphine Goehrig ◽

Jérémy Nigri ◽

Rémi Samain ◽

Zhichong Wu ◽

Paola Cappello ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumour Growth ◽

Matrix Protein ◽

Immune Escape ◽

Interaction Mechanism ◽

Tumour Microenvironment ◽

Extracellular Matrix Protein ◽

Ductal Adenocarcinoma ◽

The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

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STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

Endocrine Related Cancer ◽

10.1530/erc-12-0231 ◽

2012 ◽

Vol 20 (1) ◽

pp. 53-64 ◽

Cited By ~ 10

Author(s):

Joanna M Day ◽

Paul A Foster ◽

Helena J Tutill ◽

Fabien Schmidlin ◽

Christopher M Sharland ◽

...

Keyword(s):

Prostate Cancer ◽

Tumour Growth ◽

Plasma Testosterone ◽

Prostate Hyperplasia ◽

Testosterone Levels ◽

Concept Model ◽

Body Weights ◽

Type 3

17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17β-HSD type 3 (17β-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17β-HSD3 inhibitor with an IC50 of ∼200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17β-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17β-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1×107 cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17β-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17β-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.

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The Inhibitory Effect of KIAA1456 on the Proliferation and Metastasis of Epithelial Ovarian Cancer Through SSX1 and AKT Signaling Pathway

10.21203/rs.3.rs-950951/v1 ◽

2021 ◽

Author(s):

Yingfeng Zhang ◽

Yanhong Gao ◽

Congcong Sun ◽

Yanhua Mao ◽

Benyuan Wu ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Tumour Growth ◽

Molecular Mechanisms ◽

Signalling Pathway ◽

Migration And Invasion ◽

Ovarian Tumours ◽

Proliferation And Metastasis ◽

Epithelial Ovarian Tumours

Abstract Background: KIAA1456 is effective in the inhibition of tumorigenesis. We previously confirmed that KIAA1456 inhibits cell proliferation and metastasis in epithelial ovarian tumours. In the current study, the specific molecular mechanisms and clinical significance of KIAA1456 underlying the repression of epithelial ovarian cancer were investigated.Methods: Immunohistochemistry was used to evaluate the protein expression of KIAA1456 and SSX1 in epithelial ovarian tumours and normal ovarian tissues. The relationship of KIAA1456 and SSX1 with overall survival of patients with epithelial ovarian cancer was analysed with Kaplan–Meier survival curve and log-rank tests. KIAA1456 was overexpressed and silenced in HO8910PM cells with a lentivirus. The anticancer activity of KIAA1456 was tested by CCK8, plate clone formation assay, flow cytometry, wound healing assay and Transwell invasion assay. Xenograft tumour models were used to investigate the effects of KIAA1456 on tumour growth in vivo. Bioinformatics analyses of microarray profiling indicated that SSX1 and the PI3K/AKT signalling pathway were differentially expressed in KIAA1456-overexpressing and control cells. Therefore, the biological function of HO8910PM cotransfected with KIAA1456- and SSX1-overexpressing cells was detected to validate the rescue effect of SSX1. The downstream factors of PI3K/AKT that are related to cell growth and apoptosis, including p-AKT, PCNA, MMP9, CyclinD1 and Bcl-2, were detected by Western blot analysis.Results: KIAA1456 expression was lower in epithelial ovarian tumours than in normal ovarian tissues. Its expression level negatively correlated with pathological grade. Pearson’s correlation analysis showed that KIAA1456 negatively correlated with SSX1 expression. The overexpression of KIAA1456 in HO8910PM cells inhibited proliferation, migration and invasion and promoted apoptosis. By contrast, the silencing of KIAA1456 resulted in the opposite behaviour. A xenograft tumour experiment showed that KIAA1456 overexpression inhibited tumour growth in vivo. Mechanistically, the overexpression of KIAA1456 inhibited SSX1 expression and AKT phosphorylation in HO8910PM cells, causing the inactivation of the AKT signalling pathway and eventually reducing the expression of PCNA, CyclinD1, MMP9 and Bcl2. Similarly, the silencing of KIAA1456 resulted in the opposite behaviour. Finally, SSX1 overexpression could partially reverse the KIAA1456-induced biological effect.Conclusion: KIAA1456 may serve as a tumour suppressor via the inactivation of SSX1 and the AKT pathway, providing a promising therapeutic target for epithelial ovarian cancers.

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Microvessel Chaste: An Open Library for Spatial Modelling of Vascularized Tissues

10.1101/105692 ◽

2017 ◽

Cited By ~ 2

Author(s):

J.A. Grogan ◽

A.J. Connor ◽

B. Markelc ◽

R.J. Muschel ◽

P.K. Maini ◽

...

Keyword(s):

Open Source ◽

Tumour Growth ◽

Spatial Models ◽

3D Models ◽

Tissue Growth ◽

Coronary Perfusion ◽

Analysis Model ◽

User Friendly

AbstractSpatial models of vascularized tissues are widely used in computational physiology, to study for example, tumour growth, angiogenesis, osteogenesis, coronary perfusion and oxygen delivery. Composition of such models is time-consuming, with many researchers writing custom software for this purpose. Recent advances in imaging have produced detailed three-dimensional (3D) datasets of vascularized tissues at the scale of individual cells. To fully exploit such data there is an increasing need for software that allows user-friendly composition of efficient, 3D models of vascularized tissue growth, and comparison of predictions with in vivo or in vitro experiments and other models. Microvessel Chaste is a new open-source library for building spatial models of vascularized tissue growth. It can be used to simulate vessel growth and adaptation in response to mechanical and chemical stimuli, intra- and extra-vascular transport of nutrient, growth factor and drugs, and cell proliferation in complex 3D geometries. The library provides a comprehensive Python interface to solvers implemented in C++, allowing user-friendly model composition, and integration with experimental data. Such integration is facilitated by interoperability with a growing collection of scientific Python software for image processing, statistical analysis, model annotation and visualization. The library is available under an open-source Berkeley Software Distribution (BSD) licence at https://jmsgrogan.github.io/MicrovesselChaste. This article links to two reproducible example problems, showing how the library can be used to model tumour growth and angiogenesis with realistic vessel networks.

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