Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma
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ABSTRACT:
SUBMITTER: Wang Z
PROVIDER: S-EPMC10950582 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Project description:PurposeChronic gastroesophageal reflux disease (GERD) causes the abnormal reflux of acid and bile salts, which would induce Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EGFR, as one of main components of the exosome, plays an important role in cancer progression. Here, we investigated the role of acidic bile salts (ABS)-induced exosomal EGFR in EAC cell proliferation.MethodsElectronic microscopic examination and Western blot were used to identify exosomes. Western blot, siRNA transfection, enzyme-linked immunosorbent assay, qRT-PCR, cell viability detection, mouse xenograft tumor models, and immunohistochemical staining were performed to study the function of ABS-induced exosomal EGFR in cell proliferation.ResultsWe found that ABS improved the exosomal EGFR level of normal human esophageal epithelial cells, BE cells, and BE-associated adenocarcinoma cells. The results were confirmed in the serum-derived exosomes from healthy persons and patients suffering from GERD, BE with or without GERD, and EAC with or without GERD. Moreover, cell line-derived exosomal EGFR was found to promote macrophage M2 polarization through the PI3K-AKT pathway. The co-incubation medium of macrophages and exosomes improved cell proliferation and tumor growth, which depended on the exosomal EGFR level. CCL18 was identified as the most effective component of the co-incubation medium to promote EAC cell proliferation by binding to its receptor PITPNM3 in vitro and in vivo.ConclusionOur findings demonstrate that ABS-induced exosomal EGFR regulates macrophage M2 polarization to promote EAC proliferation. This study provides an important insight into the role of ABS in EAC development.
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Project description:Macrophages are key participants in melanoma growth and survival. In general, macrophages can be classified as M1 or M2 activation phenotypes. Increasing evidence demonstrates that melanoma exosomes also facilitate tumor survival and metastasis. However, the role of melanoma exosomes in directly influencing macrophage function is poorly understood. Herein, we investigated the hypothesis that natural melanoma exosomes might directly influence macrophage polarization. To explore this hypothesis, ELISA, RT-qPCR, and macrophage functional studies were performed in vitro using an established source of melanoma exosomes (B16-F10). ELISA results for melanoma exosome induction of common M1 and M2 cytokines in RAW 264.7 macrophages, revealed that melanoma exosomes do not polarize macrophages exclusively in the M1 or M2 direction. Melanoma exosomes induced the M1 and M2 representative cytokines TNF-α and IL-10 respectively. Further assessment, using an RT-qPCR array with RAW 264.7 and primary macrophages, confirmed and extended the ELISA findings. Upregulation of markers common to both M1 and M2 polarization phenotypes included CCL22, IL-12B, IL-1β, IL-6, i-NOS, and TNF-α. The M2 cytokine TGF-β was upregulated in primary but not RAW 264.7 macrophages. Pro-tumor functions have been attributed to each of these markers. Macrophage functional assays demonstrated a trend toward increased i-NOS (M1) to arginase (M2) activity. Collectively, the results provide the first evidence that melanoma exosomes can induce a mixed M1 and M2 pro-tumor macrophage activation phenotype.
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Project description:Pueraria lobata (known as Gegen) is an edible and medicinal herb that is a nutritious medicine food homology plant in China. Previous studies indicated that P. lobata plays an essential role in controlling cytokines. However, the exact mechanism of the inflammation response is still unknown. In this study, we observed the uptake of P. lobata-derived exosomes (Exos) in isolated mouse macrophages. Our results show that P. lobata-derived Exos shift M1 macrophages toward the M2. These data present that P. lobata and puerarin might exert and enhance anti-inflammatory effects through the activation of exosomes and shifts in macrophage polarization, providing strong evidence for the application of P. lobata as novel an anti-inflammatory therapeutic biomaterial.
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Project description:Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer.
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Project description:Osteoporosis is characterized by reduced bone mass due to imbalanced bone metabolism. Exosomes derived from bone mesenchymal stem cells (BMSCs) have been shown to play roles in various diseases. This study aimed to clarify the regulatory function and molecular mechanism of BMSCs-derived exosomes in osteogenic differentiation and their potential therapeutic effects on osteoporosis. Exosomes were extracted from BMSCs. Bone marrow-derived macrophages (BMDMs) were cultured and internalized with BMSCs-derived exosomes. Real-time quantitative PCR was used to detect the expression of macrophage surface markers and tripartite motif (TRIM) family genes. BMDMs were co-cultured with human osteoblasts to assess osteogenic differentiation. Western blot was performed to analyze the ubiquitination of triggering receptor expressed on myeloid cell 1 (TREM1) mediated by TRIM25. An ovariectomized mice model was established to evaluate the role of TRIM25 and exosomes in osteoporosis. Exosomes were successfully isolated from BMSCs. BMSCs-derived exosomes upregulated TRIM25 expression, promoting M2 macrophage polarization and osteogenic differentiation. TRIM25 facilitated the ubiquitination and degradation of TREM1. Overexpression of TREM1 reversed the enhanced M2 macrophage polarization and osteogenic differentiation caused by TRIM25 overexpression. TRIM25 enhanced the protective effect of BMSCs-derived exosomes against bone loss in mice. These findings suggested that BMSCs-derived exosomes promoted osteogenic differentiation by regulating M2 macrophage polarization through TRIM25-mediated ubiquitination and degradation of TREM1. This mechanism might provide a novel approach for treating osteoporosis.
| S-EPMC11577737 | biostudies-literature
Project description:M2 macrophages promote adipose tissue thermogenesis which dissipates energy in the form of heat to combat obesity. However, the regulation of M2 macrophages by thermogenic adipocytes is unclear. Here, it is identified magnesium (Mg) as a thermogenic adipocyte-secreted factor to promote M2 macrophage polarization. Mg transporter Cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) induced by ADRB3-PKA-CREB signaling in thermogenic adipocytes during cold exposure mediates Mg efflux and Mg in turn binds to the DFG motif in mTOR to facilitate mTORC2 activation and M2 polarization in macrophages. In obesity, downregulation of CNNM4 expression inhibits Mg secretion from thermogenic adipocytes, which leads to decreased M2 macrophage polarization and thermogenesis. As a result, CNNM4 overexpression in adipocytes or Mg supplementation in adipose tissue ameliorates obesity by promoting thermogenesis. Importantly, an Mg wire implantation (AMI) approach is introduced to achieve adipose tissue-specific long-term Mg supplement. AMI promotes M2 macrophage polarization and thermogenesis and ameliorates obesity in mice. Taken together, a reciprocal regulation of thermogenic adipocytes and M2 macrophages important for thermogenesis is identified, and AMI is offered as a promising strategy against obesity.
| S-EPMC11653670 | biostudies-literature
Project description:Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage polarization remains unknown. In this study, we compared the capacities of MSCs from normal cervix (NCx) and CeCa to promote M2 macrophage polarization in a coculture system. Our results demonstrated that CeCa-MSCs, in contrast to NCx-MSCs, significantly decreased M1 macrophage cell surface marker expression (HLA-DR, CD80, CD86) and increased M2 macrophage expression (CD14, CD163, CD206, Arg1) in cytokine-induced CD14+ monocytes toward M1- or M2-polarized macrophages. Interestingly, compared with NCx-MSCs, in M2 macrophages generated from CeCa-MSC cocultures, we observed an increase in the percentage of phagocytic cells, in the intracellular production of IL-10 and IDO, the capacity to decrease T cell proliferation and for the generation of CD4+CD25+FoxP3+ Tregs. Importantly, this capacity to promote M2 macrophage polarization was correlated with the intracellular expression of macrophage colony-stimulating factor (M-CSF) and upregulation of IL-10 in CeCa-MSCs. Furthermore, the presence of M2 macrophages was correlated with the increased production of IL-10 and IL-1RA anti-inflammatory molecules. Our in vitro results indicate that CeCa-MSCs, in contrast to NCx-MSCs, display an increased M2-macrophage polarization potential and suggest a role of CeCa-MSCs in antitumor immunity.
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Project description:Background: Tumor-associated macrophages (TAMs) are one of the most prominent tumor-infiltrating immune cells in the tumor microenvironment (TME) of CRC and play a vital role in the progression of CRC. BST2 was predicted to be associated with the infiltration of TAMs. However, its potential function by which CRC cells and TAMs interact with each other still needs further investigation. Methods: The target genes in CRC were selected by bioinformatics screening. The level of bone marrow stromal cell antigen 2 (BST2) in CRC cells and tissues was determined by qRT‒PCR, Western blotting, and immunohistochemistry staining. In vitro and in vivo assays were applied to clarify the function of BST2. Results: In this study, according to bioinformatics analysis, a nomogram based on the risk score (constructed by BST2 and CAV1 (caveolin-1)) and clinical features was built and displayed satisfactory prognostic value. Upregulated BST2 was significantly related to Braf mutation, dMMR/MSI-H, CMS1 subtype, and immune response and was a potential biomarker for predicting immune checkpoint blockade therapy. Silencing BST2 in CRC obviously restrained CRC progression and M2 TAM polarization. The infiltration of TAMs was positively correlated with the high expression of BST2, and depletion of TAMs alleviated the protumoural effect of BST2 in CRC in vivo. In vitro experiments revealed that a reduction in BST2 in CRC inhibited CRC proliferation and migration and also M2 polarization. Conclusion: These findings indicated that BST2 played a vital role in CRC progression and might be a predictable marker for immunotherapy.
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Project description:Alveolar macrophages (AMs) play an essential role in ventilator‑induced lung injury (VILI). Exosomes and their cargo, including microRNAs (miRNAs/miRs) serve as regulators of the intercellular communications between macrophages and epithelial cells (ECs), and are involved in maintaining homeostasis in lung tissue. The present study found that exosomes released by ECs subjected to cyclic stretching promoted M2 macrophage polarization. It was demonstrated that miR‑21a‑5p, upregulated in epithelial‑derived exosomes, increased the percentage of M2 macrophages by suppressing the expression of Notch2 and the suppressor of cytokine signaling 1 (SOCS1). The overexpression of Notch2 decreased the percentage of M2 macrophages. However, these effects were reversed by the downregulation of SOCS1. The percentage of M2 macrophages was increased in both short‑term high‑ and low‑tidal‑volume mechanical ventilation, and the administration of exosomes‑derived from cyclically stretched ECs had the same function. However, the administration of miR‑21a‑5p antagomir decreased M2 macrophage activation induced by cyclically stretched ECs or ventilation. Thus, the present study demonstrates that the intercellular transferring of exosomes from ECs to AMs promotes M2 macrophage polarization. Exosomes may prove to be a novel treatment for VILI.
| S-EPMC9170191 | biostudies-literature
Project description:BackgroundImmunotherapy has brought new hope to gastric cancer (GC) patients. Exploring the immune infiltration pattern in GC and the key molecules is critical for optimizing the efficacy of immunotherapy. Aldo-keto reductase family 1 member B10 (AKR1B10) is an inflammatory regulator and is closely related to the prognosis of patients with GC. However, the function of AKR1B10 in GC remains unclear.MethodsIn the present study, the CIBERSORT algorithm was used to analyze the immune infiltration pattern in 373 samples in the Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were seared by combing the TCGA database and the Gene Expression Omnibus (GEO) database, and the key molecule AKR1B10 was identified by weighted gene coexpression network analysis (WGCNA). The biological functions of AKR1B10 in stomach adenocarcinoma (STAD) were investigated in vitro.ResultsMacrophage polarization was the main immune infiltration pattern in GC, and the state of macrophage polarization was closely related to the pathological grading of GC and the clinical stage of patients. AKR1B10, MUC5AC, TFF2, GKN1, and PGC were significantly down-regulated in GC tissues. Low AKR1B10 expression induced M2 macrophage polarization and promoted the malignant phenotype of GC.ConclusionM2 macrophage polarization is the main immune infiltration pattern in GC. Low AKR1B10 expression induces M2 macrophage polarization and promotes the malignant transformation of GC.
| S-EPMC10545534 | biostudies-literature