scholarly journals Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ute Jungwirth ◽  
Antoinette van Weverwijk ◽  
Rachel J. Evans ◽  
Liam Jenkins ◽  
David Vicente ◽  
...  
Keyword(s):  
Normal Mouse ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Phenotypic Heterogeneity ◽  
Cancer Associated Fibroblasts ◽  
Cancer Associated Fibroblast ◽  
Functional Characterisation ◽  
Genetic Deletion ◽  
Insight Into

AbstractProfiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.

scholarly journals Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

2020 ◽  
Author(s):  
Ute Jungwirth ◽  
Antoinette van Weverwijk ◽  
Liam Jenkins ◽  
John Alexander ◽  
David Vicente ◽  
...  
Keyword(s):  
Normal Mouse ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Phenotypic Heterogeneity ◽  
Cancer Associated Fibroblasts ◽  
Cancer Associated Fibroblast ◽  
Functional Characterisation ◽  
Genetic Deletion ◽  
Insight Into

AbstractProfiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability which, coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.

scholarly journals Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 693-707 ◽  
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.

scholarly journals Regulation of Extracellular Matrix Production in Activated Fibroblasts: Roles of Amino Acid Metabolism in Collagen Synthesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Emily J. Kay ◽  
Grigorios Koulouras ◽  
Sara Zanivan
Keyword(s):  
Extracellular Matrix ◽  
Tumour Growth ◽  
Acid Metabolism ◽  
Tumour Progression ◽  
Tumour Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Secretory Phenotype ◽  
Matrix Production ◽  
Activated Fibroblasts ◽  
Translational Level

Cancer associated fibroblasts (CAFs) are a major component of the tumour microenvironment in most tumours, and are key mediators of the response to tissue damage caused by tumour growth and invasion, contributing to the observation that tumours behave as ‘wounds that do not heal’. CAFs have been shown to play a supporting role in all stages of tumour progression, and this is dependent on the highly secretory phenotype CAFs develop upon activation, of which extracellular matrix (ECM) production is a key element. A collagen rich, stromal ECM has been shown to influence tumour growth and metastasis, exclude immune cells and impede drug delivery, and is associated with poor prognosis in many cancers. CAFs also extensively remodel their metabolism to support cancer cells, however, it is becoming clear that metabolic rewiring also supports intrinsic functions of activated fibroblasts, such as increased ECM production. In this review, we summarise how fibroblasts metabolically regulate ECM production, focussing on collagen production, at the transcriptional, translational and post-translational level, and discuss how this can provide possible strategies for effectively targeting CAF activation and formation of a tumour-promoting stroma.

scholarly journals Textures of the tumour microenvironment

2019 ◽  
Vol 63 (5) ◽  
pp. 619-629 ◽  
Author(s):  
Julie S Di Martino ◽  
Chandrani Mondal ◽  
Jose Javier Bravo-Cordero
Keyword(s):  
Intravital Microscopy ◽  
Tumour Growth ◽  
Dimensional Space ◽  
Three Dimensional ◽  
Tumour Microenvironment ◽  
Dynamic Nature ◽  
Structural Details ◽  
Shed Light ◽  
Three Dimensional Space

Abstract In this review, we present recent findings on the dynamic nature of the tumour microenvironment (TME) and how intravital microscopy studies have defined TME components in a spatiotemporal manner. Intravital microscopy has shed light into the nature of the TME, revealing structural details of both tumour cells and other TME co-habitants in vivo, how these cells communicate with each other, and how they are organized in three-dimensional space to orchestrate tumour growth, invasion, dissemination and metastasis. We will review different imaging tools, imaging reporters and fate-mapping strategies that have begun to uncover the complexity of the TME in vivo.

scholarly journals Core–shell nanoparticles suppress metastasis and modify the tumour-supportive activity of cancer-associated fibroblasts

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Dávid Kovács ◽  
Nóra Igaz ◽  
Annamária Marton ◽  
Andrea Rónavári ◽  
Péter Bélteky ◽  
...  
Keyword(s):  
Tumour Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Malignant Cells ◽  
Tumour Stroma ◽  
Shell Nanoparticles ◽  
Stromal Fibroblasts ◽  
Metastatic Dissemination ◽  
Gold Core ◽  
Silver Shell

Abstract Background Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. Results We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. Conclusions Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.

scholarly journals Lysine demethylase 2A expression in cancer-associated fibroblasts promotes breast tumour growth

2020 ◽  
Author(s):  
Jing-Yi Chen ◽  
Chien-Feng Li ◽  
You-Syuan Lai ◽  
Wen-Chun Hung
Keyword(s):  
Breast Cancer ◽  
Transcriptional Activation ◽  
Tumour Growth ◽  
Breast Tumour ◽  
Cancer Associated Fibroblasts ◽  
Cancer Cell Proliferation ◽  
Breast Cancer Patients ◽  
Programmed Death ◽  
Lysine Demethylase

Abstract Background Our previous study demonstrated that lysine demethylase 2A (KDM2A) enhances stemness in breast cancer cells. This demethylase is also highly expressed in cancer-associated fibroblasts (CAFs). However, its clinical significance is unclear. Methods The expression of KDM2A in CAFs was studied using immunohistochemical staining and its association with clinicopathological features and patient’s survival was tested. Overexpression and knockdown strategies were used to investigate KDM2A-regulated genes in fibroblasts. Senescent cells were detected by using β-galactosidase staining. The in vivo tumour-promoting activity of stromal KDM2A was confirmed by animal study. Results Increase of stromal KDM2A is associated with advanced tumour stage and poor clinical outcome in breast cancer patients. Cancer-derived cytokines stimulated KDM2A expression in normal fibroblasts and transformed them into CAFs. Upregulation of KDM2A induced p53-dependent senescence in fibroblasts and enhanced the release of cytokines, which reciprocally promoted cancer cell proliferation. Additionally, KDM2A upregulated programmed death-ligand 1 (PD-L1) expression via transcriptional activation in fibroblasts. Knockdown of KDM2A completely abolished the tumour-promoting activity of CAFs on breast tumour growth in vivo and diminished PD-L1 expression in the stroma of tumour tissues. Conclusions Stromal KDM2A plays an oncogenic role in breast cancer and inhibition of KDM2A reduces fibroblast senescence and suppresses tumour growth.

scholarly journals Sophoridine Inhibits the Tumour Growth of Non-Small Lung Cancer by Inducing Macrophages M1 Polarisation via MAPK-Mediated Inflammatory Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Bei Zhao ◽  
Xiaodan Hui ◽  
Hairong Zeng ◽  
Yinan Yin ◽  
Jian Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Tumour Growth ◽  
Therapeutic Potential ◽  
Tumour Microenvironment ◽  
Lung Cancer Cells ◽  
Mice Model ◽  
Lewis Lung Cancer

Lung cancer is one of the most common and lethal neoplasms for which very few efficacious treatments are currently available. M1-like polarised tumour-associated macrophages (TAMs) are key mediators to modulate the tumour microenvironment, which play a key role in inhibiting cancer cell growth. Sophoridine, a naturally occurring alkaloid, exerts multiple pharmacological activities including anti-tumour and anti-inflammatory activities, but it has not been characterised as a regulator of tumour microenvironment towards NSCLC. Herein, the regulatory effects of sophoridine on the polarisation of THP-1 cells into TAMs and the anti-tumour effects of sophoridine-stimulated M1 polarised macrophages towards lung cancer cells were carefully investigated both in vitro and in vivo. The results showed that sophoridine could significantly promote M1 polarisation of RAW264.7 and THP-1-derived macrophages, leading to increased expression of pro-inflammatory cytokines and the M1 surface markers CD86 via activating MAPKs signaling pathway. Further investigations showed that sophoridine-stimulated RAW264.7 and THP-1-derived M1 macrophages effectively induced cell apoptosis as well as inhibited the cell colony formation and cell proliferation in both H460 and Lewis lung cancer cells. In Lewis-bearing mice model, sophoridine (15 or 25 mg/kg) significantly inhibited the tumour growth and up-regulated the expression of CD86/F4/80 in tumour tissues. Collectively, the findings clearly demonstrate that sophoridine promoted M1-like polarisation in vitro and in vivo, suggesting that sophoridine held a great therapeutic potential for treating lung cancer.

Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

1992 ◽  
Vol 67 (01) ◽  
pp. 111-116 ◽  
Author(s):  
Marcel Levi ◽  
Jan Paul de Boer ◽  
Dorina Roem ◽  
Jan Wouter ten Cate ◽  
C Erik Hack
Keyword(s):  
Monoclonal Antibodies ◽  
Plasminogen Activator ◽  
Plasma Levels ◽  
Fold Increase ◽  
Fibrinolytic System ◽  
Plasminogen Activation ◽  
Plasminogen Activator Activity ◽  
Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

scholarly journals Plant-Derived Extracellular Vesicles: Current Findings,Challenges, and Future Applications

Membranes ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 411
Author(s):  
Nader Kameli ◽  
Anya Dragojlovic-Kerkache ◽  
Paul Savelkoul ◽  
Frank R. Stassen
Keyword(s):  
Human Health ◽  
Extracellular Vesicles ◽  
Preliminary Results ◽  
In Vivo Experiments ◽  
Health And Disease ◽  
Conducting Research ◽  
Protocol Standardization ◽  
Insight Into

In recent years, plant-derived extracellular vesicles (PDEVs) have gained the interest of many experts in fields such as microbiology and immunology, and research in this field has exponentially increased. These nano-sized particles have provided researchers with a number of interesting findings, making their application in human health and disease very promising. Both in vitro and in vivo experiments have shown that PDEVs can exhibit a multitude of effects, suggesting that these vesicles may have many potential future applications, including therapeutics and nano-delivery of compounds. While the preliminary results are promising, there are still some challenges to face, such as a lack of protocol standardization, as well as knowledge gaps that need to be filled. This review aims to discuss various aspects of PDEV knowledge, including their preliminary findings, challenges, and future uses, giving insight into the complexity of conducting research in this field.

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