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Schematic presentation of exosomes in the TME. The biogenesis of exosomes mainly comprises three stages, which includes (i) the formation of early endosome by cytoplasmic membrane invagination, (ii) the formation of MVBs containing cargos-enriched ILVs, and (iii) the release of ILVs as exosomes after the fusion of MVBs with the plasma membrane
Source publication
To identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endot...
Similar publications
Cancer-associated fibroblasts (CAFs), a class of stromal cells in the tumor microenvironment (TME), play a key role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis, and resistance to chemotherapy. CAFs mediate their activities by secreting soluble chemicals, releasing exosomes, and altering the extracellular matrix...
Citations
... Studies indicated that fibroblasts are the dominant heterogeneous cell type in TME and contribute to tumor development and chemotherapy resistance [28]. Likewise, we observed a correlation between fibroblast infiltration and various adverse outcome parameters, coupled with significantly enhanced signaling associated with fibroblasts. ...
Background
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood.
Methods
To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue.
Results
Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs.
Conclusions
This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.
... However, there still exists a gap in our understanding of the mechanism through which CAFs communicate with other component of the TME, resulting in a change in their fate [62]. The secretion of exosomes represents a crucial mechanism through which CAFs influence the behavior of the TME components [24]. Exosomes released by CAFs can initiate metastasis and confer chemotherapy resistance in CRC [63,64]. ...
Background
Circular RNAs (circRNAs) hold potential as diagnostic markers for colorectal cancer (CRC); however, their functional mechanisms remain incompletely elucidated. This work investigates the clinical implications of a unique set comprising six circRNAs derived from serum in CRC. Furthermore, we delve into the role of exosomal circ_0084043, originating from colorectal cancer-associated fibroblasts (CAFs), with a specific focus on its contribution to endothelial cell angiogenesis.
Methods
The study analyzed circRNA levels in serum samples obtained from both CRC and control groups using qRT-PCR. Additionally, exosomes originating from colorectal CAFs and normal fibroblasts (NFs) were purified and confirmed by electron microscopy and Western blotting techniques. The proangiogenic effects of CAF-derived exosomal circ_0084043 were assessed in endothelial cells through proliferation, migration, and in vitro capillary tube formation assays. Gain- and loss-of-function experiments were employed to clarify the role of the circ_0084043/miR-140–3p/HIF-1α axis in endothelial cell angiogenesis, utilizing luciferase reporter assay, Western blotting, and ELISA for mechanism elucidation.
Results
The candidate circRNAs (circ_0060745, circ_001569, circ_007142, circ_0084043, Circ_BANP, and CiRS-7) exhibited notably elevated expression in CRC patient sera compared to the levels observed in healthy individuals. Except for CiRS-7, all circRNAs showed elevated expression in CRC patients with positive lymph node metastasis and advanced tumor stages. Exosomes released by colorectal CAFs augmented endothelial cell proliferation, migration, and angiogenesis by upregulating VEGF expression and secretion. Circ_0084043 was highly detected in endothelial cells treated with CAF-derived exosomes. Silencing circ_0084043 reduced VEGFA expression and diminished CAF exosome-induced endothelial cell processes, indicating its pivotal role in angiogenesis. Circ_0084043 sponges miR-140–3p, regulating HIF-1α, and a reverse relationship was also identified between miR-140–3p and VEGFA in endothelial cells. Inhibiting miR-140–3p mitigated circ_0084043 knockdown effects in CAF exosome-treated endothelial cells. Co-transfection of si-circ_0084043 and a miR-140–3p inhibitor reversed the inhibited migration and angiogenesis caused by circ_0084043 knockdown in CAF exosome-treated endothelial cells. Inhibiting miR-140–3p rescued reduced VEGFA expression due to circ_0084043 knockdown in endothelial cells exposed to CAF-derived exosomes, indicating modulation of the circ_0084043/miR-140–3p/VEGF signaling in CAF-derived exosome-induced angiogenesis.
Conclusions
This study unveiled a distinctive signature of six serum-derived circular RNAs, indicating their potential as promising diagnostic biomarkers for CRC. Importantly, exosomal circ_0084043 originating from colorectal CAFs was identified as playing a crucial role in endothelial cell angiogenesis, exerting its influence through the modulation of the miR-140–3p/HIF-1α/VEGF signaling axis.
... Exosomes are involved in the regulation of TME and can make tumor cells evade immune surveillance (93,94). On top of that, they also have the ability to induce neoangiogenesis and can provide nutrient access and support tumor cells in their proliferation (95,96). ...
Gynecologic cancers, including ovarian cancer (OC), cervical cancer (CC), and endometrial cancer (EC), pose a serious threat to women’s health and quality of life due to their high incidence and lethality. Therapeutic resistance in tumors refers to reduced sensitivity of tumor cells to therapeutic drugs or radiation, which compromises the efficacy of treatment or renders it ineffective. Therapeutic resistance significantly contributes to treatment failure in gynecologic tumors, although the specific molecular mechanisms remain unclear. Exosomes are nanoscale vesicles released and received by distinct kinds of cells. Exosomes contain proteins, lipids, and RNAs closely linked to their origins and functions. Recent studies have demonstrated that exosomal ncRNAs may be involved in intercellular communication and can modulate the progression of tumorigenesis, aggravation and metastasis, tumor microenvironment (TME), and drug resistance. Besides, exosomal ncRNAs also have the potential to become significant diagnostic and prognostic biomarkers in various of diseases. In this paper, we reviewed the biological roles and mechanisms of exosomal ncRNAs in the drug resistance of gynecologic tumors, as well as explored the potential of exosomal ncRNAs acting as the liquid biopsy molecular markers in gynecologic cancers.
... It has long been recognized that CAFs exhibit many malignant properties when compared with NFs. Numerous publications have shown that pro-tumorigenic factors secreted by CAFs can be transferred into tumor cells through the paracrine signaling [41,42] and the exosome-mediated pathway [43,44], which facilitates cancer cell stemness, proliferation, and migration. As confirmed by in vitro and in vivo experiments, CAFs also stimulate tumor angiogenesis by secreting pro-angiogenic factors, such as VEGFA, CXCL12, FGF2, and PDGFC [45]. ...
Cancer-associated fibroblasts (CAFs), the main stromal component of the tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms of regulated cell death (RCD) in adjacent tumor cells, thus involving cancer proliferation, therapy resistance, and immune exclusion. Here, we present a brief introduction to CAFs and basic knowledge of RCD, including apoptosis, autophagy, ferroptosis, and pyroptosis. In addition, we further summarize the different types of RCD in tumors that are mediated by CAFs, as well as the effects of these modes of RCD on CAFs. This review will deepen our understanding of the interactions between CAFs and RCD and might offer novel therapeutic avenues for future cancer treatments.
... The use of exosomes derived from CAFs as peripheral blood biomarkers for cancer diagnostics, monitoring, and treatment is a rapidly evolving field. These exosomes carry a unique molecular signature, including microRNAs and proteins, that is reflective of the TME [62][63][64]. In a previous study, candidate biomarkers identified by Lei Liu et al. in gastric cancer tumor tissues exhibited similar expression patterns in serum and exosomes, providing valuable biomarkers for non-invasive diagnosis and prognosis of gastric cancer [65]. ...
... 145 CAFs recruit suppressive cells (such as MDSCs) by secreting chemokines and cytokines, containing TGF-β, IL-6, C-X-C chemokine ligand 12 (CXCL12), and prostaglandin E2. 146 Besides, exosomes also participate in the communication of CAFs with other cells. 147 Tumor-secreted exosomes support the proliferation of cancer cells by reprogramming fibroblasts. 148 For example, exosomal miR-146a-5p and miR-155-5p 149 secreted by CRC cells promote tumor growth after activating CAFs. ...
... Although CAFs can also construct tumor-promoting TME by modulating other immune cells, the function of exosomes in this process is still unclear. 147 This is a promising research direction for the subsequent study of new immunotherapy targets. ...
Exosomes are indispensable for intercellular communications. Tumor microenvironment (TME) is the living environment of tumor cells, which is composed of various components, including immune cells. Based on TME, immunotherapy has been recently developed for eradicating cancer cells by reactivating antitumor effect of immune cells. The communications between tumor cells and TME are crucial for tumor development, metastasis, and drug resistance. Exosomes play an important role in mediating these communications and regulating the reprogramming of TME, which affects the sensitivity of immunotherapy. Therefore, it is imperative to investigate the role of exosomes in TME reprogramming and the impact of exosomes on immunotherapy. Here, we review the communication role of exosomes in regulating TME remodeling and the efficacy of immunotherapy, as well as summarize the underlying mechanisms. Furthermore, we also introduce the potential application of the artificially modified exosomes as the delivery systems of antitumor drugs. Further efforts in this field will provide new insights on the roles of exosomes in intercellular communications of TME and cancer progression, thus helping us to uncover effective strategies for cancer treatment.
... CAF, as a prominent component of the TME, plays a crucial role in promoting tumor progression by releasing an array of soluble factors or structurally remodeling the extracellular matrix [39]. Additionally, these stromal cells can induce a more malignant activity of tumor cells through the release of exosomes that eventually promote tumor progression [40]. The impact of exosomes on CRC progression has been extensively documented. ...
Background
This study evaluated the clinical relevance of a set of five serum-derived circulating microRNAs (miRNAs) in colorectal cancer (CRC). Additionally, we investigated the role of miR-20a-5p released by exosomes derived from cancer-associated fibroblasts (CAFs) in the context of CRC.
Methods
The expression levels of five circulating serum-derived miRNAs (miR-20a-5p, miR-122-5p, miR-139-3p, miR-143-5p, and miR-193a-5p) were quantified by real-time quantitative PCR (RT-qPCR), and their associations with clinicopathological characteristics in CRC patients were assessed. The diagnostic accuracy of these miRNAs was determined through Receiver Operating Characteristic (ROC) curve analysis. CAFs and normal fibroblasts (NFs) were isolated from tissue samples, and subsequently, exosomes derived from these cells were isolated and meticulously characterized using electron microscopy and Western blotting. The cellular internalization of fluorescent-labeled exosomes was visualized by confocal microscopy. Gain- and loss-of-function experiments were conducted to elucidate the oncogenic role of miR-20a-5p transferred by exosomes derived from CAFs in CRC progression. The underlying mechanisms were uncovered through luciferase reporter assay, Western blotting, enzyme-linked immunosorbent assays, as well as proliferation and migration assays.
Results
The expression levels of serum-derived circulating miR-20a-5p and miR-122-5p were significantly higher in CRC and were positively correlated with advanced stages of tumorigenesis and lymph node metastasis (LNM). In contrast, circulating miR-139-3p, miR-143-5p, and miR-193a-5p were down-regulated in CRC and associated with early tumorigenesis. Except for miR-139-3p, they showed a negative correlation with LNM status. Among the candidate miRNAs, significantly elevated levels of miR-20a-5p were observed in both cellular and exosomal fractions of CAFs. Our findings indicated that miR-20a-5p induces the expression of EMT markers, partly by targeting PTEN. Exosomal miR-20a secreted by CAFs emerged as a key factor enhancing the proliferation and migration of CRC cells. The inhibition of miR-20a impaired the proliferative and migratory potential of CAF-derived exosomes in SW480 CRC cells, suggesting that the oncogenic effects of CAF-derived exosomes are mediated through the exosomal transfer of miR-20a. Furthermore, exosomes originating from CAFs induced increased nuclear translocation of the NF-kB p65 transcription factor in SW480 CRC cells, leading to increased interleukin-6 (IL-6) production.
Conclusions
We established a set of five circulating miRNAs as a non-invasive biomarker for CRC diagnosis. Additionally, our findings shed light on the intricate mechanisms underpinning the oncogenic impacts of CAF-derived exosomes and underscore the pivotal role of miR-20a-5p in CRC progression.
... The role of natural exosomes in tumor therapy relies on the substances they contain, such as nucleic acids and proteins (117,118). For these reasons, researchers have attempted to enhance the therapeutic capabilities of exosomes by altering their composition. ...
The discovery and use of exosomes ushered in a new era of cell-free therapy. Exosomes are a subgroup of extracellular vesicles that show great potential in disease treatment. Engineered exosomes. with their improved functions have attracted intense interests of their application in translational medicine research. However, the technology of engineering exosomes still faces many challenges which have been the great limitation for their clinical application. This review summarizes the current status of research on engineered exosomes and the difficulties encountered in recent years, with a view to providing new approaches and ideas for future exosome modification and new drug development.
... They provide raw materials for cancer cells, participate in cancer cell proliferation, migration, and invasion, and induce metabolic reprogramming. Additionally, intake of CAFs-derived exosomes by cancer cells enhances their ability to evade immune cell attacks [126]. Thus, during OSCC development, CAFs maintain bidirectional crosstalk with cancer cells by secreting exosomes, thereby creating a supportive niche. ...
Oral squamous cell carcinoma (OSCC) is a prevalent cancer that needs new therapeutic targets due to the poor postoperative prognosis in patients. Exosomes are currently one of important research areas owing to their unique properties. Exosomes are capable of acting as drug transporters, as well as facilitating interactions between OSCC and normal cells. Exosomes can be detected in body fluids such as blood, urine, cerebrospinal fluid, and bile. When exosomes are released from donor cells, they can carry various bioactive molecules to recipient cells, where these molecules participate in biological processes. This review highlights the mechanisms of exosome transfer between normal and OSCC cells. Exosomes isolated from donor OSCC cells can carry circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) and play a role in signaling processes in the recipient OSCC cells, human umbilical vein endothelial cells, and macrophages. Exosomes secreted by carcinoma-associated fibroblasts, macrophages, and stem cells can also enter the recipient OSCC cells and modulate signaling events in these cells. Exosomes isolated from OSCC plasma, serum, and saliva are also associated with OSCC prognosis. Furthermore, while exosomes were shown to be associated with chemotherapy resistance in OSCC, they can also be used for drug delivery during OSCC treatment. In this paper, we reviewed the molecular mechanisms and functions of exosomes from different cell sources in OSCC cells, providing a basis for diagnosis and prognosis prediction in OSCC patients, and offering guidance for the design of molecular targets carried by exosomes in OSCC.
... Numerous studies have shown that its pathogenesis suggesting that changes in TME in cancer may serve as a new predictive biomarker [5][6][7][8]. The TME includes the surrounding microenvironment in which tumor cells exist, comprising surrounding blood vessels, immune cells, fibroblasts, various signaling molecules and extracellular matrix [9][10][11][12]. Immune cells are one of critical importance in the TME, as they can affect tumor survival, such as NK cells [13], DC cells [14], tumor-associated macrophages (TAMs) [15], and tumor infiltrating lymphocytes (TILs) [16]. ...
Background: Head and neck cancer is the sixth most common malignancy worldwide, and oral squamous cell carcinoma (OSCC) is the most common head and neck cancer, being one of the leading causes of cancer morbidity and mortality worldwide. CC Chemokine receptor 7(CCR7) is a multifunctional G protein-coupled trans-membrane chemokine that affects immune cell chemotaxis, migration, and cancer progression through
its interaction with its ligands C-C motif chemokine ligand 19(CCL19) and C-C motif chemokine ligand 21 (CCL21). Numerous studies have demonstrated the involvement of CCR7 in the malignant progression of a variety of cancers, reflecting the pro-cancer properties of CCR7. The Cancer Genome Atlas data suggests CCR7 has elevated expression in oral cancer. Specifically, CCR7 expression in tumor microenvironment (TME) may regulate the ability of some immune cells to engage in anti-tumor immune responses. Since CD8+ T cells have become a key immunotherapeutic target, the role of CCR7 in antitumor immune response of naïve CD8+ T cells in TME has not been thoroughly investigated.
Methods: A CCR7 knockout mouse model was constructed, and the mechanism of ccr7 on the regulation of tumor microenvironment by naïve CD8+ T cells was verified under the guidance of single-cell RNA sequencing combined with in vivo animal experiments and in vitro cell experiments.
Results: CCR7 is knocked out with impaired tumor growth and altered CD8+ T cell profiles, revealing the importance of this protein in OSCC.
Conclusions: Inhibition of CCR7 enhances CD8+ T cell activation, proliferation, and anti-tumor function, suggesting its potential as a therapeutic target.
