scholarly journals Organ-Specific Uptake of Extracellular Vesicles Secreted by Urological Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4937
Author(s):  
Johannes Linxweiler ◽  
Anja Kolbinger ◽  
Dirk Himbert ◽  
Philip Zeuschner ◽  
Matthias Saar ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Urological Cancer ◽  
Immunodeficient Mice ◽  
Organ Systems ◽  
Organ Specific ◽  
Distant Organ ◽  
Specific Uptake ◽  
Bladder Cells

Extracellular vesicles (EVs) secreted by cancer cells have been shown to take a pivotal part in the process of local and systemic tumor progression by promoting the formation of a supportive local tumor microenvironment and preparing premetastatic niches in distant organ systems. In this study, we analyzed the organ-specific uptake of EVs secreted by urological cancer cells using an innovative in-vivo approach. EVs from benign and malignant prostate, kidney, and bladder cells were isolated using ultracentrifugation, fluorescence-labeled and injected intravenously in immunodeficient mice. After 12 or 24 h, the animals were sacrificed, their organs were harvested and analyzed for the presence of EVs by high-resolution fluorescence microscopy. Across all entities, EVs were taken up fast (12 h > 24 h), and EVs from malignant cells were taken up more efficiently than EVs from benign cells. Though not entirely organ-specific, EVs were incorporated in different amounts, depending on the entity (prostate: lung > liver > brain; kidney: brain > lung > liver; bladder: lung > liver > brain). EV uptake in other organs than lung, liver, brain, and spleen was not observed. Our results suggest a role of EVs in the formation of premetastatic niches and an organotropism in EV uptake, which have to be examined in more detail in further studies.

scholarly journals Organ-specific uptake of extracellular vesicles secreted by urological cancer cells

2021 ◽  
Vol 79 ◽  
pp. S735
Author(s):  
J. Linxweiler ◽  
A. Kolbinger ◽  
M. Saar ◽  
M. Stöckle ◽  
K. Junker
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Urological Cancer ◽  
Organ Specific ◽  
Specific Uptake

scholarly journals Snail Overexpression Alters the microRNA Content of Extracellular Vesicles Released from HT29 Colorectal Cancer Cells and Activates Pro-Inflammatory State In Vivo

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 172
Author(s):  
Izabela Papiewska-Pająk ◽  
Patrycja Przygodzka ◽  
Damian Krzyżanowski ◽  
Kamila Soboska ◽  
Izabela Szulc-Kiełbik ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Colorectal Cancer Cells ◽  
Microrna Profile ◽  
Inflammatory State ◽  
Metastatic Process

During metastasis, cancer cells undergo phenotype changes in the epithelial-mesenchymal transition (EMT) process. Extracellular vesicles (EVs) released by cancer cells are the mediators of intercellular communication and play a role in metastatic process. Knowledge of factors that influence the modifications of the pre-metastatic niche for the migrating carcinoma cells is important for prevention of metastasis. We focus here on how cancer progression is affected by EVs released from either epithelial-like HT29-cells or from cells that are in early EMT stage triggered by Snail transcription factor (HT29-Snail). We found that EVs released from HT29-Snail, as compared to HT29-pcDNA cells, have a different microRNA profile. We observed the presence of interstitial pneumonias in the lungs of mice injected with HT29-Snail cells and the percent of mice with lung inflammation was higher after injection of HT29-Snail-EVs. Incorporation of EVs released from HT29-pcDNA, but not released from HT29-Snail, leads to the increased secretion of IL-8 from macrophages. We conclude that Snail modifications of CRC cells towards more invasive phenotype also alter the microRNA cargo of released EVs. The content of cell-released EVs may serve as a biomarker that denotes the stage of CRC and EVs-specific microRNAs may be a target to prevent cancer progression.

TAMI-73. GLIOBLASTOMA CELL POPULATIONS WITH DISTINCT ONCOGENIC PROGRAMS RELEASE PODOPLANIN AS PROCOAGULANT EXTRACELLULAR VESICLES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi213-vi213
Author(s):  
Nadim Tawil ◽  
Rayhaan Bassawon ◽  
Brian Meehan ◽  
Laura Montermini ◽  
Ali Nehme ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Extracellular Vesicles ◽  
Glioblastoma Cell ◽  
Activation Markers ◽  
Increased Risk ◽  
Gradient Fractionation ◽  
D Dimer

Abstract BACKGROUND Vascular anomalies, including thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of dysregulated cancer cell genome and epigenome. Up-regulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk of venous thromboembolism in glioblastoma patients. Thus, regulation of this platelet activating protein by transforming events and release from cancer cells is of considerable interest. AIMS I. Investigate the pattern of PDPN expression and characterize PDPN-expressing cellular populations in GBM. II. Evaluate the contribution of oncogenic drivers to PDPN expression in GBM models. III. Investigate the potential involvement of extracellular vesicles (EVs) as a mechanism for systemic dissemination of PDPN and tissue factor (TF). IV. Examine the role of PDPN in intratumoral and systemic thrombosis. METHODS Bioinformatics (single-cell and bulk transcriptome data mining), GBM cell lines and stem cell lines, xenograft models in mice, ELISA assays for PDPN and TF, platelet (PF4) and clotting activation markers (D-dimer), EV electron microscopy, density gradient fractionation, and nano-flow cytometry. RESULTS PDPN is expressed by distinct glioblastoma cell subpopulations (mesenchymal) and downregulated by oncogenic mutations of EGFR and IDH1 genes, via changes in chromatin modifications (EZH2) and DNA methylation, respectively. GBM cells exteriorize PDPN and/or TF as cargo of exosome-like EVs shed both in vitro and in vivo. Injection of glioma PDPN-EVs activates platelets. Increase of platelet activation (PF4) or coagulation markers (D-dimer) occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Co-expression of PDPN and TF by GBM cells cooperatively increases tumor microthrombosis. CONCLUSION Distinct cellular subsets drive multiple facets of GBM-associated thrombosis and may represent targets for diagnosis and intervention. We suggest that the preponderance of PDPN expression as a risk factor in glioblastoma and the involvement of platelets may merit investigating anti-platelets for potential inclusion in thrombosis management in GBM.

scholarly journals Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

2021 ◽  
Vol 5 (6) ◽  
pp. 1682-1694
Author(s):  
Nadim Tawil ◽  
Rayhaan Bassawon ◽  
Brian Meehan ◽  
Ali Nehme ◽  
Laura Montermini ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Coagulation System ◽  
Platelet Factor ◽  
Increased Risk ◽  
Cell Subpopulations ◽  
Cancer Associated Thrombosis

Abstract Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type–based diagnosis and antithrombotic intervention.

scholarly journals Zinc-Phthalocyanine-Loaded Extracellular Vesicles Increase Efficacy and Selectivity of Photodynamic Therapy in Co-Culture and Preclinical Models of Colon Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1547
Author(s):  
Pablo Lara ◽  
Ruben V. Huis in ‘t Veld ◽  
Carla Jorquera-Cordero ◽  
Alan B. Chan ◽  
Ferry Ossendorp ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Malignant Tumors ◽  
Intratumoral Injection ◽  
Zinc Phthalocyanine ◽  
Tumor Cell Death ◽  
Culture Models

Photodynamic therapy (PDT) is a promising and clinically approved method for the treatment of cancer. However, the efficacy of PDT is often limited by the poor selectivity and distribution of the photosensitizers (PS) toward the malignant tumors, resulting in prolonged periods of skin photosensitivity. In this work, we present a simple and straightforward strategy to increase the tumor distribution, selectivity, and efficacy of lipophilic PS zinc phthalocyanine (ZnPc) in colon cancer by their stabilization in purified, naturally secreted extracellular vesicles (EVs). The PS ZnPc was incorporated in EVs (EV-ZnPc) by a direct incubation strategy that did not affect size distribution or surface charge. By using co-culture models simulating a tumor microenvironment, we determined the preferential uptake of EV-ZnPc toward colon cancer cells when compared with macrophages and dendritic cells. We observed that PDT promoted total tumor cell death in normal and immune cells, but showed selectivity against cancer cells in co-culture models. In vivo assays showed that after a single intravenous or intratumoral injection, EV-ZnPc were able to target the tumor cells and strongly reduce tumor growth over 15 days. These data expose opportunities to enhance the potential and efficacy of PDT using simple non-synthetic strategies that might facilitate translation into clinical practice.

scholarly journals Chemotherapeutic drugs stimulate the release and recycling of extracellular vesicles to assist cancer cells in developing an urgent chemoresistance

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaokun Wang ◽  
Dongjuan Qiao ◽  
Likun Chen ◽  
Meng Xu ◽  
Shupeng Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Small Cell Lung Carcinoma ◽  
Underlying Mechanism ◽  
Chemotherapeutic Agents ◽  
Chemotherapeutic Drugs ◽  
Xenograft Tumor ◽  
Tumor Models ◽  
Cell Lung Carcinoma

Abstract Background Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. Methods Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. Results Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. Conclusions Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.

scholarly journals Extracellular Vesicles in Prostate Cancer: New Future Clinical Strategies?

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Ilaria Giusti ◽  
Vincenza Dolo
Keyword(s):  
Prostate Cancer ◽  
Extracellular Vesicles ◽  
Specific Antigen ◽  
Specific Marker ◽  
Cellular Origin ◽  
Organ Specific ◽  
Potential Use

Prostate cancer (PCa) is the most common cancer—excluding skin tumors—in men older than 50 years of age. Over time, the ability to diagnose PCa has improved considerably, mainly due to the introduction of prostate-specific antigen (PSA) in the clinical routine. However, it is important to take into account that although PSA is a highly organ-specific marker, it is not cancer-specific. This shortcoming suggests the need to find new and more specific molecular markers. Several emerging PCa biomarkers have been evaluated or are being assessed for their potential use. There is increasing interest in the prospective use of extracellular vesicles as specific markers; it is well known that the content of vesicles is dependent on their cellular origin and is strongly related to the stimulus that triggers the release of the vesicles. Consequently, the identification of a disease-specific molecule (protein, lipid or RNA) associated with vesicles could facilitate their use as novel biological markers. The present review describes severalin vitrostudies that demonstrate the role of vesicles in PCa progression and severalin vivostudies that highlight the potential use of vesicles as PCa biomarkers.

scholarly journals Activation of iCaspase-9 in Neovessels Inhibits Oral Tumor Progression

2006 ◽  
Vol 85 (5) ◽  
pp. 436-441 ◽  
Author(s):  
M.S. Pinsky ◽  
W. Song ◽  
Z. Dong ◽  
K. Warner ◽  
B. Zeitlin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Oral Cancer ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Immunodeficient Mice ◽  
Oral Tumor ◽  
Biodegradable Scaffolds ◽  
Oral Tumors ◽  
Oral Cancer Cells

Tumors of the oral cavity are highly vascularized malignancies. Disruption of neovascular networks was shown to limit the access of nutrients and oxygen to tumor cells and inhibit tumor progression. Here, we evaluated the effect of the activation of an artificial death switch (iCaspase-9) expressed in neovascular endothelial cells on the progression of oral tumors. We used biodegradable scaffolds to co-implant human dermal microvascular endothelial cells stably expressing iCaspase-9 (HDMEC-iCasp9) with oral cancer cells expressing luciferase (OSCC3-luc or UM-SCC-17B-luc) in immunodeficient mice. Alternatively, untransduced HDMEC were co-implanted with oral cancer cells, and a transcriptionaly targeted adenovirus (Ad-VEGFR2-iCasp-9) was injected locally to deliver iCaspase-9 to neovascular endothelial cells. In vivo bioluminescence demonstrated that tumor progression was inhibited, and immunohistochemistry showed that microvessel density was decreased, when iCaspase-9 was activated in tumor-associated microvessels. We conclude that activation of iCaspase-9 in neovascular endothelial cells is sufficient to inhibit the progression of xenografted oral tumors.

scholarly journals Sulfisoxazole does not inhibit the secretion of small extracellular vesicles

2020 ◽  
Author(s):  
Pamali Fonseka ◽  
Sai V Chitti ◽  
Rahul Sanwlani ◽  
Suresh Mathivanan
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Drug Repurposing ◽  
Tumor Burden ◽  
Immunocompetent Mouse ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractRecently, the study by Im et al. focused on blocking the release of extracellular vesicles (EVs) by cancer cells, as a strategy to block metastasis, by deploying a drug repurposing screen. Upon screening the library of FDA approved drugs in breast cancer cells in vitro, the authors reported the ability of the antibiotic Sulfisoxazole (SFX) in inhibiting EV biogenesis and secretion. SFX was also effective in reducing breast primary tumor burden and blocking metastasis in immunocompromised and immunocompetent mouse models. As we seek a compound to block EV biogenesis and secretion in our current in vivo studies, we intended to use SFX and hence performed in vitro characterization as the first step. However, treatment of two cancer cells with SFX did not reduce the amount of EVs as reported by the authors.

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