Tumor-secreted exosomal Wnt2B activates fibroblasts to promote cervical cancer progression.
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ABSTRACT:
SUBMITTER: Liang LJ
PROVIDER: S-EPMC7969781 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumour‑associated macrophages (TAMs) compose a major component of the tumour microenvironment and form in this microenvironment prior to cancer metastasis. However, the detailed mechanisms of TAM remodelling in the context of bladder cancer have not been clearly defined. The present study collected exosomes from the conditioned medium of human bladder T24 cancer cells. The effects of macrophages treated with exosomes derived from T24 cells on bladder cancer cell migration and invasion were analysed by Transwell assays. The expression levels of endogenous and exosomal microRNA‑21 (miR‑21) were examined by reverse transcription‑quantitative PCR, while the expression level of the target protein was analysed by western blot analysis. Luciferase reporter plasmids and mutants were used to confirm direct targeting. The effects of miR‑21 on bladder cancer cell migration and invasion were analysed by Transwell and Matrigel assays following miR‑21 transfection. It was identified that exosomes derived from bladder cancer cells polarized THP‑1 cell‑derived macrophages into the M2 phenotype, and TAM‑mediated pro‑migratory and pro‑invasive activity was determined. Moreover, it was found that miR‑21 was highly expressed in exosomes derived from bladder cancer cells as well as in macrophages treated with exosomes. In addition, macrophages transfected with miR‑21 exhibited M2 polarization and promoted T24 cell migratory and invasive ability. Mechanistically, exosomal miR‑21 derived from bladder cancer cells inhibited phosphatase and tensin homolog activation of the PI3K/AKT signalling pathway in macrophages and enhanced STAT3 expression to promote M2 phenotypic polarization. The present results suggest that exosomal miR‑21 can promote cancer progression by polarizing TAMs.
| S-EPMC6910194 | biostudies-literature
Project description:UNLABELLED:Cancer-associated fibroblasts enhance cancer progression when activated by tumor cells through mechanisms not yet fully understood. Blocking mammary tumor cell-derived lysyl oxidase-like 2 (LOXL2) significantly inhibited mammary tumor cell invasion and metastasis in transgenic and orthotopic mouse models. Here, we discovered that tumor-derived LOXL2 directly activated stromal fibroblasts in the tumor microenvironment. Genetic manipulation or antibody inhibition of LOXL2 in orthotopically grown mammary tumors reduced the expression of ?-smooth muscle actin (?-SMA). Using a marker for reticular fibroblasts, it was determined that expression of ?-SMA was localized to fibroblasts recruited from the host tissue. This marker also revealed that the matrix present in tumors with reduced levels of LOXL2 was more scattered compared with control tumors which exhibited matrices with dense, parallel alignments. Importantly, in vitro assays revealed that tumor-derived LOXL2 and a recombinant LOXL2 protein induced fibroblast branching on collagen matrices, as well as increased fibroblast-mediated collagen contraction and invasion of fibroblasts through extracellular matrix. Moreover, LOXL2 induced the expression of ?-SMA in fibroblasts grown on collagen matrices. Mechanistically, it was determined that LOXL2 activated fibroblasts through integrin-mediated focal adhesion kinase activation. These results indicate that inhibition of LOXL2 in tumors not only reduces tumor cell invasion but also attenuates the activation of host cells in the tumor microenvironment. IMPLICATIONS:These findings reveal new insight into the mechanisms of fibroblast activation, a novel function of LOXL2, and further highlight the importance of generating LOXL2-targeted therapies for the prevention of tumor progression and metastasis.
| S-EPMC3833835 | biostudies-literature
Project description:This study investigated the exosomal circular RNAs (CircRNAs) produced by tumor-associated macrophages and delivered into the microenvironment of cholangiocarcinoma cells in order to use them as molecular targets for clinical therapy. Tumor-associated M2 macrophages (TAMs) were induced from THP-1 cells and identified by flow cytometry. The TAM-secreted exosomes were isolated from conditioned medium and a CircRNA microarray assay was performed to identify CircRNAs that were uniquely expressed in the isolated exosomes. Circ_0020256 was especially identified based on having the highest differential expression level among all of the CircRNA candidates. In vitro and in vivo experiments were performed to assess the effects of TAMs, exosomes, and Circ_0020256 on the growth and migration of cholangiocarcinoma (CCA) cells. The induced TAMs promoted the proliferation, migration, and invasion of CCA cells and those effects were mediated by exosomes secreted by the TAMs. In CCA cells (RBE and HCCC-9810), Circ_0020256 significantly promoted cellular activity by interacting with its intra-cellular microRNA target, miR-432-5p. In contrast, overexpression of transcription factor E2F3 in CCA cells restored the CCA cellular activities that were inhibited by miR-432-5p. On the other hand, treatment with small interference RNA (siRNA) for Circ_0020256 inhibited CCA cell proliferation, migration, and invasion both in vitro and in vivo. In conclusion, Circ_0020256 in TAM-secreted exosomes promoted the proliferation, migration, and invasion of CCA cells, and that promotional activity was regulated via a Circ_0020256/miR-432-5p/E2F3 axis.
| S-EPMC8799724 | biostudies-literature
Project description:Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression.
| S-EPMC5309924 | biostudies-literature
Project description:BackgroundCancer-associated fibroblasts, comprised of activated fibroblasts or myofibroblasts, are found in the stroma surrounding solid tumors. These myofibroblasts promote invasion and metastasis of cancer cells. Mechanisms regulating the activation of the fibroblasts and the initiation of invasive tumorigenesis are of great interest. Upregulation of the cytoskeletal protein, palladin, has been detected in the stromal myofibroblasts surrounding many solid cancers and in expression screens for genes involved in invasion. Using a pancreatic cancer model, we investigated the functional consequence of overexpression of exogenous palladin in normal fibroblasts in vitro and its effect on the early stages of tumor invasion.Principal findingsPalladin expression in stromal fibroblasts occurs very early in tumorigenesis. In vivo, concordant expression of palladin and the myofibroblast marker, alpha smooth muscle actin (?-SMA), occurs early at the dysplastic stages in peri-tumoral stroma and progressively increases in pancreatic tumorigenesis. In vitro introduction of exogenous 90 kD palladin into normal human dermal fibroblasts (HDFs) induces activation of stromal fibroblasts into myofibroblasts as marked by induction of ?-SMA and vimentin, and through the physical change of cell morphology. Moreover, palladin expression in the fibroblasts enhances cellular migration, invasion through the extracellular matrix, and creation of tunnels through which cancer cells can follow. The fibroblast invasion and creation of tunnels results from the development of invadopodia-like cellular protrusions which express invadopodia proteins and proteolytic enzymes. Palladin expression in fibroblasts is triggered by the co-culture of normal fibroblasts with k-ras-expressing epithelial cells.ConclusionsOverall, palladin expression can impart myofibroblast properties, in turn promoting the invasive potential of these peri-tumoral cells with invadopodia-driven degradation of extracellular matrix. Palladin expression in fibroblasts can be triggered by k-ras expression in adjacent epithelial cells. This data supports a model whereby palladin-activated fibroblasts facilitate stromal-dependent metastasis and outgrowth of tumorigenic epithelium.
| S-EPMC3264580 | biostudies-literature
Project description:The mechanisms underlying the effects of cancer-associated fibroblasts (CAFs) on cancer stemness and tumor progression in renal cell carcinoma (RCC) have not been elucidated yet. In the present study, we found that the enrichment of CAFs was positively associated with tumor progression and cancer stemness in RCC. Further investigation revealed that CAFs could enhance cancer stemness through delivering exosomes to RCC cells, and miR-181d-5p was identified as the critical exosomal miRNA in CAF-secreted exosomes by small RNA sequencing and subsequent screening assays. Mechanistically, exosomal miR-181d-5p transferred from CAFs to RCC cells directly suppressed the expression of ring finger protein 43 (RNF43) and activated Wnt/β-catenin signaling pathway, thus promoted cancer stemness and tumor progression. Overexpression of RNF43 strongly suppressed stemness properties and the effects could be reverted by miR-181d-5p. Overall, our findings revealed a crucial mechanism by which CAF-secreted exosomal miRNAs to enhance cancer stemness and thus promote RCC progression, suggesting a new avenue based on CAF-secreted miRNAs for more effective targeted therapies.
| S-EPMC9626570 | biostudies-literature
Project description:Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen super family, is a pleiotropic cytokine that impacts diverse cellular functions. Previous studies have shown that tumor cell-derived Fgl2 promotes tumorigenesis and metastasis in immune-deficient mice, and it also functions as an immune-suppressive modulator in glioblastoma multiform (GMB). This study aimed to evaluate whether and how tumor stroma-derived Fgl2 affects tumorigenesis and tumor progression. We established the syngeneic transplantable Lewis lung carcinoma (LLC) model in Fgl2-knock-out (Fgl2-KO) mice and we found that deficiency of host Fgl2 is associated with reduced growth of syngeneic LLC tumors. Furthermore, we confirmed that host Fgl2 deficiency significantly decreased the accumulation of myeloid-derived suppressor cells (MDSCs) through down-regulation of chemokine (C-X-C motif) ligand 12 (CXCL12) expression. More importantly, we demonstrated that Fgl2 induced an activated and pro-tumorigenic phenotype of cancer-associated fibroblasts (CAFs) which are the principal source of CXCL12 in the tumor microenvironment (TME). Our results present a novel role of stroma-derived Fgl2 in CAF activation and function, suggesting that Fgl2 is an effective therapeutic target for treating lung cancer.
| S-EPMC5485635 | biostudies-literature
Project description:The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer-associated fibroblasts, play a pivotal role. TP53-deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53-deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell-derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53-WT colon cancer, HCT116; TP53-mutant colon cancer, HT29; and fibroblasts, CCD-18Co and WI-38) and an immune-deficient nude mouse xenograft model. HCT116 (HCT116sh p53 ) cells deficient in TP53 accelerated cocultured fibroblast proliferation compared to TP53-WT HCT116 (HCT116sh control ) cells in vitro. Exosomes from HCT116sh p53 cells suppressed TP53 expression of fibroblasts and promoted their proliferation. Xenografts of HCT116sh p53 cells grew significantly faster than those of HCT116sh control cells in the presence of co-injected fibroblasts, but this difference was diminished by CDE inhibition. Microarray analysis identified upregulation of several microRNAs (miR-1249-5p, miR-6737-5p, and miR-6819-5p) in TP53-deficient CDEs, which were functionally proven to suppress TP53 expression in fibroblasts. Exosomes derived from TP53-mutant HT29 cells also suppressed TP53 expression in fibroblasts and accelerated their growth. The proliferative effect of HT29 on cocultured fibroblasts was diminished by inhibition of these miRNAs in fibroblasts. Our results suggest that CDEs play a pivotal role in tumor progression by fibroblast modification. Cancer cell-derived exosomes might, therefore, represent a novel therapeutic target in colon cancer.
| S-EPMC6676271 | biostudies-literature
Project description:Background: Cancer-associated fibroblasts (CAFs) promote tumor progression through extracellular matrix (ECM) remodeling and extensive communication with other cells in tumor microenvironment. However, most CAF-targeting strategies failed in clinical trials due to the heterogeneity of CAFs. Hence, we aimed to identify the cluster of tumor-promoting CAFs, elucidate their function and determine their specific membrane markers to ensure precise targeting. Methods: We integrated multiple single-cell RNA sequencing (scRNA-seq) datasets across different tumors and adjacent normal tissues to identify the tumor-promoting CAF cluster. We analyzed the origin of these CAFs by pseudotime analysis, and tried to elucidate the function of these CAFs by gene regulatory network analysis and cell-cell communication analysis. We also performed cell-type deconvolution analysis to examine the association between the proportion of these CAFs and patients' prognosis in TCGA cancer cohorts, and validated that through IHC staining in clinical tumor tissues. In addition, we analyzed the membrane molecules in different fibroblast clusters, trying to identify the membrane molecules that were specifically expressed on these CAFs. Results: We found that COL11A1+ fibroblasts specifically exist in tumor tissues but not in normal tissues and named them cancer-specific fibroblasts (CSFs). We revealed that these CSFs were transformed from normal fibroblasts. CSFs represented a more activated CAF cluster and may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. High CSF proportion was associated with poor prognosis in bladder cancer (BCa) and lung adenocarcinoma (LUAD), and IHC staining of COL11A1 confirmed their specific expression in tumor stroma in clinical BCa samples. We also identified that CSFs specifically express the membrane molecules LRRC15, ITGA11, SPHK1 and FAP, which could distinguish CSFs from other fibroblasts. Conclusion: We identified that CSFs is a tumor specific cluster of fibroblasts, which are in active state, may promote tumor progression through the regulation on ECM remodeling and antitumor immune responses. Membrane molecules LRRC15, ITGA11, SPHK1 and FAP could be used as therapeutic targets for CSF-targeting cancer treatment.
| S-EPMC9894880 | biostudies-literature
Project description:Tumor budding (TB) is considered a histomorphological marker of poor prognosis in patients with breast cancer (BC). Tumor vasculature is disordered and unstable in BC, which causes restricted drug delivery, hypoxia, and tumor metastasis. Traditional anti-angiogenic treatments cause extreme hypoxia, increased invasion, metastasis, and drug resistance due to blood vessel rarefaction or regression. Therefore, the application of anti-angiogenic strategies for vascular normalization in tumors is crucial to improve therapeutic efficacy in BC. In the present study, we found that transgelin (TAGLN) promoted the normalization of tumor vessels by regulating the structure and function of endothelial cells, and knockout of TAGLN in tumor-bearing mice resulted in tumor vessel abnormalization, an increase in epithelial-mesenchymal transition characteristics of tumor cells, and promotion of TB. Moreover, BC cells secrete exosomal miR-22-3p that mediates tumor vessel abnormalization by inhibiting TAGLN. We demonstrated for the first time that TAGLN plays an essential role in tumor vessel normalization, and thus it impairs TB and metastasis. Additionally, the findings of this study indicate that exosomal miR-22-3p is a potential therapeutic target for BC.
| S-EPMC8178443 | biostudies-literature