Cancer-associated fibroblasts-derived exosomal miR-3656 promotes the development and progression of esophageal squamous cell carcinoma via the ACAP2/PI3K-AKT signaling pathway

Qiu

et al. 2022

Preprint

Self Cite

Background: Cancer-associated fibroblast (CAF) is an ideal target for cancer treatment. Recent studies have focused on eliminating CAFs and their effects by targeting their markers or blocking individual CAF-secreted factors. However, these strategies have been limited by their specificity for targeting CAFs and effectiveness in blocking widespread influence of CAFs. Here, we aimed to explore the molecular mechanisms of CAF generation and optimize CAF-targeted therapeutic strategies.Methods: Using FGFR2 as a tracing marker, we identified a novel origin of CAFs in esophageal squamous cell carcinoma (ESCC). Furthermore, we successfully isolated CAF precursors from peripheral blood of ESCC patients and explored the mechanisms underlying their expansion, recruitment and differentiation via RNA-sequencing and bioinformatics analysis.Results: We found that FGFR2+ hematopoietic stem cell (HSC)-derived fibrocytes could be induced by ESCC cells, homing into tumor xenografts, and differentiate into functional CAFs. They could be mobilized by cancer-secreted FGF2 and recruited into tumor sites via the CXCL12/CXCR4 axis. Moreover, they differentiate into CAFs through the activation of YAP-TEAD complex which is trigger by directly contract with tumor cells. FGF2 and CXCR4 neutralizing antibodies could effectively block the mobilization and recruitment process of FGFR2+ CAFs. The YAP-TEAD complex-based mechanism can be used to locally activate the production of genetically encoded therapeutic payloads in tumor sites.Conclusion: We identified a novel CAF origin and systematically studied the process of mobilization, recruitment, and maturation of CAFs in ESCC under the guidance of tumor cells. These findings give rise to new approaches that target CAFs before their incorporation into tumor stroma and use CAF- precursors as cellular vehicles to target cancer cells.

Section: Introductionmentioning

confidence: 80%

Hematopoietic stem cell-derived fibrocytes as targets and tools for cancer therapy: mechanisms and therapeutic implications

Qiu

et al. 2022

Preprint

Self Cite

“… 4 , 5 It was reported that CAFs-derived exosomes could affect cell proliferation, migration and invasion of cancer cells. 6 , 7 CAFs-derived exosomes enhanced drug resistance in CRC through priming cancer stem cells. 8 LncRNAs, miRNAs and circular RNAs (circRNAs) participate in the crosstalks between CAFs and cancer cells, thereby accelerating tumor progression, which are enriched in exosomes.…”

Section: Introductionmentioning

confidence: 99%

CAFs-derived small extracellular vesicles circN4BP2L2 promotes proliferation and metastasis of colorectal cancer via miR-664b-3p/HMGB3 pathway

Yang

Cancer Biology & Therapy

Luo

et al. 2022

Our previous research has demonstrated that colorectal cancer (CRC) progression was promoted by circN4BP2L2. This study aimed to further explore the mechanism of circN4BP2L2 in the development of CRC from the perspective of small extracellular vesicles (sEVs). Cancer-associated fibroblasts cell (CAFs) and normal fibroblasts cell (NFs) were isolated from CRC tissues and adjacent tissues, respectively. The ultra-centrifugation was used for extraction of their related sEVs. Cell proliferation and apoptosis were analyzed using CCK-8 and flow cytometry, respectively. Transwell assay was conducted to measure cell migration. The tube formation ability was assessed by tube formation assay. The target relationships between circN4BP2L2 and miR-664b-3p, and miR-664b-3p and HMGB3 were validated by dual-luciferase reporter detection. The effect of CAFs-derived sEV (CAFs-sEVs) circN4BP2L2 on CRC was further studied in nude mice. CAFs-exo promoted cell proliferation, migration, tube formation ability, and inhibited apoptosis of CRC cells. CAFs-sEV circN4BP2L2 knockdown reversed the above results. CircN4BP2L2 directly targeted miR-664b-3p, and HMGB3 was targeted by miR-664b-3p. Moreover, subcutaneous tumorigenesis and liver metastasis of nude mice with CRC were repressed by CAFs-sEV circN4BP2L2 knockdown. CAFs-sEV circN4BP2L2 knockdown restrained CRC cell proliferation and migration by regulating miR-664b-3p/HMGB3 pathway.

“…Extracellular vesicles (EVs) are extracellular membrane particles’ component with diameters of 40–1,000 nm, whose outer layer is a bilayer lipid membrane while the inside encapsulates different proportions of DNA, RNA, and protein components ( Jin et al, 2021 ). Numerous reports indicate that EVs are usually existing in body fluids, including cerebrospinal fluid, blood, urine, saliva, pleural effusion, and ascites ( Caivano et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle-Derived miR-105-5p Promotes Malignant Phenotypes of Esophageal Squamous Cell Carcinoma by Targeting SPARCL1 via FAK/AKT Signaling Pathway

Han

et al. 2022

Front. Genet.

Objective: Esophageal squamous cell carcinoma (ESCC) presents high morbidity and mortality. It was demonstrated that blood-derived vesicles can facilitate ESCC development and transmit regulating signals. However, the molecular mechanism of vesicle miRNA secreted by tumor cells affecting ESCC progression has not been explored.Methods: The mRNA-related signaling pathways and differentially expressed genes were screened out in TCGA dataset. The levels of miRNA-105-5p and SPARCL1 were determined by qRT-PCR. Protein level determination was processed using Western blot. The interaction between the two genes was verified with the dual-luciferase method. A transmission electron microscope was utilized to further identify extracellular vesicles (EVs), and co-culture assay was performed to validate the intake of EVs. In vitro experiments were conducted to evaluate cell function changes in ESCC. A mice tumor formation experiment was carried out to observe tumor growth in vivo.Results: MiRNA-105-5p expression was increased in ESCC, while SPARCL1 was less expressed. MiRNA-105-5p facilitated cell behaviors in ESCC through targeting SPARCL1 and regulating the focal adhesion kinase (FAK)/Akt signaling pathway. Blood-derived external vesicles containing miRNA-105-5p and EVs could be internalized by ESCC cells. Then, miRNA-105-5p could be transferred to ESCC cells to foster tumorigenesis as well as cell behaviors.Conclusion: EV-carried miRNA-105-5p entered ESCC cells and promoted tumor-relevant functions by mediating SPARCL1 and the FAK/Akt signaling pathway, which indicated that the treatment of ESCC via serum EVs might be a novel therapy and that miRNA-105-5p can be a molecular target for ESCC therapy.