Browse
Submit Data
Databases
API
Help

Dataset Information

34 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Colorectal Cancer Cell-Derived Small Extracellular Vesicles Educate Human Fibroblasts to Stimulate Migratory Capacity.

ABSTRACT: Colorectal cancer (CRC) is in the top 10 cancers most prevalent worldwide, affecting equally men and women. Current research on tumor-derived extracellular vesicles (EVs) suggests that these small extracellular vesicles (sEVs) play an important role in mediating cell-to-cell communication and thus potentially affecting cancer progression via multiple pathways. In the present study, we hypothesized that sEVs derived from different CRC cell lines differ in their ability to reprogram normal human fibroblasts through a process called tumor education. The sEVs derived from CRC cell lines (HT29 and HCT116) were isolated by a combination of ultrafiltration and polymeric precipitation, followed by characterization based on morphology, size, and the presence or absence of EV and non-EV markers. It was observed that the HT29 cells displayed a higher concentration of sEVs compared with HCT116 cells. For the first time, we demonstrated that HT29-derived sEVs were positive for low-molecular-weight protein tyrosine phosphatase (Lmwptp). CRC cell-derived sEVs were uptake by human fibroblasts, stimulating migratory ability via Rho-Fak signaling in co-incubated human fibroblasts. Another important finding showed that HT29 cell-derived sEVs are much more efficient in activating human fibroblasts to cancer-associated fibroblasts (CAFs). Indeed, the sEVs produced by the HT29 cells that are less responsive to a cytotoxic agent display higher efficiency in educating normal human fibroblasts by providing them advantages such as activation and migratory ability. In other words, these sEVs have an influence on the CRC microenvironment, in part, due to fibroblasts reprogramming.

SUBMITTER: Clerici SP

PROVIDER: S-EPMC8320664 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Perivascular cell-derived extracellular vesicles stimulate colorectal cancer revascularization after withdrawal of antiangiogenic drugs.

Project description:Antiangiogenic tyrosine kinase inhibitors (AA-TKIs) have become a promising therapeutic strategy for colorectal cancer (CRC). In clinical practice, a significant proportion of cancer patients temporarily discontinue AA-TKI treatment due to recurrent toxicities, economic burden or acquired resistance. However, AA-TKI therapy withdrawal-induced tumour revascularization frequently occurs, hampering the clinical application of AA-TKIs. Here, this study demonstrates that tumour perivascular cells mediate tumour revascularization after withdrawal of AA-TKI therapy. Pharmacological inhibition and genetic ablation of perivascular cells largely attenuate the rebound effect of CRC vascularization in the AA-TKI cessation experimental settings. Mechanistically, tumour perivascular cell-derived extracellular vehicles (TPC-EVs) contain Gas6 that instigates the recruitment of endothelial progenitor cells (EPCs) for tumour revascularization via activating the Axl pathway. Gas6 silence and an Axl inhibitor markedly inhibit tumour revascularization by impairing EPC recruitment. Consequently, combination therapy of regorafenib with the Axl inhibitor improves overall survival in mice metastatic CRC model by inhibiting tumour growth. Together, these data shed new mechanistic insights into perivascular cells in off-AA-TKI-induced tumour revascularization and indicate that blocking the Axl signalling may provide an attractive anticancer approach for sustaining long-lasting angiostatic effects to improve the therapeutic outcomes of antiangiogenic drugs in CRC.

| S-EPMC8138700 | biostudies-literature

CD73-positive pediatric urethral mesenchymal stem-like cell-derived small extracellular vesicles stimulate angiogenesis.

Project description:IntroductionAngiogenesis plays an important role in the repair of urethral injury, and stem cells and their secretomes can promote angiogenesis. We obtained pediatric urethral mesenchymal stem-like cells (PU-MSLCs) in an earlier study. This project studied the pro-angiogenic effect of PU-MSLC-derived small extracellular vesicles (PUMSLC-sEVs) and the underlying mechanisms.Materials and methodsPUMSLCs and PUMSLC-sEVs were cultivated and identified. Then, biological methods such as the ethynyl deoxyuridine (EdU) incorporation assay, Cell Counting Kit-8 (CCK-8) assay, scratch wound assay, Transwell assay, and tube formation assay were used to study the effect of PUMSLC-sEVs on the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). We explored whether the proangiogenic effect of PUMSLC-sEVs is related to CD73 and whether adenosine (ADO, a CD73 metabolite) promoted angiogenesis. GraphPad Prism 8 software was used for data analysis.ResultsWe observed that PUMSLC-sEVs significantly promoted the proliferation, migration, and tube-forming abilities of HUVECs. PUMSLC-sEVs delivered CD73 molecules to HUVECs to promote angiogenesis. The angiogenic ability of HUVECs was enhanced after treatment with extracellular ADO produced by CD73, and PUMSLC-sEVs further promoted angiogenesis by activating Adenosine Receptor A2A (A2AR).ConclusionsThese observations suggest that PUMSLC-sEVs promote angiogenesis, possibly through activation of the CD73/ADO/A2AR signaling axis.

| S-EPMC10727923 | biostudies-literature

Colorectal cancer-derived extracellular vesicles induce transformation of fibroblasts into colon carcinoma cells.

Project description:BackgroundWe reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon.MethodsIn the present study, we exposed BRCA1-KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed.ResultsPhenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models.ConclusionsThese discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material.

| S-EPMC6567673 | biostudies-literature

Astrocytes-Derived Small Extracellular Vesicles Hinder Glioma Growth.

Project description:All cells are capable of secreting extracellular vesicles (EVs), which are not a means to eliminate unneeded cellular compounds but represent a process to exchange material (nucleic acids, lipids and proteins) between different cells. This also happens in the brain, where EVs permit the crosstalk between neuronal and non-neuronal cells, functional to homeostatic processes or cellular responses to pathological stimuli. In brain tumors, EVs are responsible for the bidirectional crosstalk between glioblastoma cells and healthy cells, and among them, astrocytes, that assume a pro-tumoral or antitumoral role depending on the stage of the tumor progression. In this work, we show that astrocyte-derived small EVs (sEVs) exert a defensive mechanism against tumor cell growth and invasion. The effect is mediated by astrocyte-derived EVs (ADEVs) through the transfer to tumor cells of factors that hinder glioma growth. We identified one of these factors, enriched in ADEVs, that is miR124. It reduced both the expression and function of the volume-regulated anion channel (VRAC), that, in turn, decreased the cell migration and invasion of murine glioma GL261 cells.

| S-EPMC9688032 | biostudies-literature

Glioblastoma-Derived Small Extracellular Vesicles: Nanoparticles for Glioma Treatment.

Project description:Glioblastoma (GBM), characterized by fast growth and invasion into adjacent tissue, is the most aggressive cancer of brain origin. Current protocols, which include cytotoxic chemotherapeutic agents, effectively treat localized disease; however, these aggressive therapies present side effects due to the high doses administered. Therefore, more efficient ways of drug delivery have been studied to reduce the therapeutic exposure of the patients. We have isolated and fully characterized small extracellular vesicles (EVs) from seven patient-derived GBM cell lines. After loading them with two different drugs, Temozolomide (TMZ) and EPZ015666, we observed a reduction in the total amount of drugs needed to trigger an effect on tumor cells. Moreover, we observed that GBM-derived small EVs, although with lower target specificity, can induce an effect on pancreatic cancer cell death. These results suggest that GBM-derived small EVs represent a promising drug delivery tool for further preclinical studies and potentially for the clinical development of GBM treatments.

| S-EPMC10054028 | biostudies-literature

Small extracellular vesicles derived from dermal fibroblasts promote fibroblast activity and skin development through carrying miR-218 and ITGBL1.

Project description:Skin thickness is closely related to the appearance of human skin, such as sagging and wrinkling, which primarily depends on the level of collagen I synthesized by dermal fibroblasts (DFs). Small extracellular vesicles (SEVs), especially those derived from human DFs (HDFs), are crucial orchestrators in shaping physiological and pathological development of skin. However, the limited supply of human skin prevents the production of a large amount of HDFs-SEVs, and pig skin is used as a model of human skin. In this study, SEVs derived from DFs of Chenghua pigs (CH-SEVs), considered to have superior skin thickness, and Large White pigs (LW-SEVs) were collected to compare their effects on DFs and skin tissue. Our results showed that, compared with LW-SEVs, CH-SEVs more effectively promoted fibroblast proliferation, migration, collagen synthesis and contraction; in addition, in mouse model injected with both SEVs, compared with LW-SEVs, CH-SEVs increased the skin thickness and collagen I content more effectively. Some differentially expressed miRNAs and proteins were found between CH-SEVs and LW-SEVs by small RNA-seq and LC-MS/MS analysis. Interestingly, we identified that CH-SEVs were enriched in miRNA-218 and ITGBL1 protein, which played important roles in promoting fibroblast activity via activation of the downstream TGFβ1-SMAD2/3 pathway in vitro. Furthermore, overexpression of miRNA-218 and ITGBL1 protein increased the thickness and collagen I content of mouse skin in vivo. These results indicate that CH-SEVs can effectively stimulate fibroblast activity and promote skin development and thus have the potential to protect against and repair skin damage.

| S-EPMC9215004 | biostudies-literature

miR-27a-5p-Abundant Small Extracellular Vesicles Derived From Epimedium-Preconditioned Bone Mesenchymal Stem Cells Stimulate Osteogenesis by Targeting Atg4B-Mediated Autophagy.

Project description:Osteoporosis (OP) is a disease affecting the elderly and is characterized by incremental fractures and bone fragility. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells have been demonstrated to possess potent regeneration potential. In this study, we evaluated the osteogenesis effects of sEVs derived from Epimedium-preconditioned bone mesenchymal stem cells (EPI-sEV) from osteoblasts and ovariectomized (OVX) rats. The underlying mechanism of EPI-sEV-induced osteogenesis was explored by RNA-sequencing and verified by transfection with the corresponding mimic and inhibitor. EPI-sEV stimulated osteogenic differentiation of osteoblasts and moderated both bone mass and microstructure in OVX rats. Sequencing identified a unique enrichment of a set of microRNAs (miRNAs) in EPI-sEV. Overexpression or inhibition in vitro demonstrated that the osteogenesis-inducing potential was primarily attributed to miR-27a-5p, one of the most abundant miRNAs in the EPI-sEV fraction. Dual-luciferase reporter assays showed that miR-27a-5p promoted osteogenesis through direct suppression of Atg4B by targeting its 3' untranslated region. Additional experiments showed that miR-27a-5p suppressed autophagy that was activated in OVX rats. Moreover, osteogenic differentiation was ablated by the intervention with rapamycin in osteoblasts. These data report the regenerative potential of EPI-sEV to induce osteogenic differentiation of osteoblast cells leading to bone formation. This process is achieved by delivering sEV-miR-27a-5p to target Atg4B for further autophagy stimulation.

| S-EPMC8491742 | biostudies-literature

Extracellular Vesicles Derived from Senescent Fibroblasts Attenuate the Dermal Effect on Keratinocyte Differentiation.

Project description:The skin is a multilayered and primary defensive organ. Intimate intercellular communication in the skin is necessary to ensure effective surveillance. Extracellular vesicles (EVs) are being explored for their involvement in intercellular skin communication. The aim of this study was to evaluate how human dermal fibroblasts (HDFs) accelerate EV production during senescence and the effects of senescence-associated EVs on epidermal homeostasis. Replicative senescent HDFs were assessed with senescence-associated β-galactosidase staining and the expression of senescence-related markers. Isolated EVs were characterized by dynamic light scattering and EV marker expression. EVs secreted from untreated young or senescent HDFs, or from those treated with a nSMase inhibitor, antioxidant, and lysosomal activity regulators, were determined by sandwich ELISA for CD81. Human epidermal keratinocytes were treated with young- and senescent HDF-derived EVs. Compared to young HDFs, senescent HDFs produced relatively high levels of EVs due to the increased nSMase activity, oxidative stress, and altered lysosomal activity. The nSMase inhibitor, antioxidant, and agents that recovered lysosomal activity reduced EV secretion in senescent HDFs. Relative to young HDF-derived EVs, senescent HDF-derived EVs were less supportive in keratinocyte differentiation and barrier function but increased proinflammatory cytokine IL-6 levels. Our study suggests that dermis-derived EVs may regulate epidermal homeostasis by reflecting cellular status, which provides insight as to how the dermis communicates with the epidermis and influences skin senescence.

| S-EPMC7037765 | biostudies-literature

Inflammatory pain resolution by mouse serum-derived small extracellular vesicles.

Project description:Chronic pain is a significant public health issue. Current treatments have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs) to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30-150 nm sEVs that can carry RNAs, proteins, and lipid mediators to recipient cells via circulation. Exosomes can be beneficial or harmful depending on their source and contents. To investigate the short and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naïve control or spared nerve injury (SNI) model donor mice were injected intrathecally into naïve recipient mice. Basal mechanical thresholds transiently increased in recipient mice. This effect was mediated by opioid signaling as this outcome was blocked by naltrexone. Mass Spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. A single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice delayed mechanical allodynia in SNI model mice and accelerated recovery from inflammatory pain after complete Freund's adjuvant (CFA) injection. ChipCytometry of spinal cord and dorsal root ganglion (DRG) from sEV treated mice showed that prophylactic sEV treatment reduced the number of natural killer (NK) and NKT cells in spinal cord and increased CD206+ anti-inflammatory macrophages in (DRG) after CFA injection. Further characterization of sEVs showed the presence of immune markers suggesting that sEVs can exert immunomodulatory effects in recipient mice to promote the resolution of inflammatory pain. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.

| S-EPMC10888877 | biostudies-literature

Fibroblast-Derived Extracellular Vesicles Induce Colorectal Cancer Progression by Transmitting Amphiregulin.

Project description:Extracellular vesicles (EV), structures surrounded by a biological membrane, transport biologically active molecules, and represent a recently identified way of intercellular communication. Colorectal cancer (CRC), one of the most common cancer types in the Western countries, is composed of both tumor and stromal cells and the amount of stromal fibroblasts negatively correlates with patient survival. Here we show that normal colon fibroblasts (NCF) release EVs with a characteristic miRNA cargo profile when stimulated with TGFβ, one of the most important activating factors of fibroblasts, without a significant increase in the amount of secreted EVs. Importantly, fibroblast-derived EVs induce cell proliferation in epidermal growth factor (EGF)-dependent patient-derived organoids, one of the best current systems to model the intra-tumoral heterogeneity of human cancers. In contrast, fibroblast-derived EVs have no effect in 3D models where EGF is dispensible. This EV-induced cell proliferation did not depend on whether NCFs or cancer-associated fibroblasts were studied or on the pre-activation by TGFβ, suggesting that TGFβ-induced sorting of specific miRNAs into EVs does not play a major role in enhancing CRC proliferation. Mechanistically, we provide evidence that amphiregulin, transported by EVs, is a major factor in inducing CRC cell proliferation. We found that neutralization of EV-bound amphiregulin blocked the effects of the fibroblast-derived EVs. Collectively, our data suggest a novel mechanism for fibroblast-induced CRC cell proliferation, coupled to EV-associated amphiregulin.

| S-EPMC7381355 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data