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Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma.

ABSTRACT: Circulating tumor-derived exosomes (TEX) interact with a variety of cells in cancer-bearing hosts, leading to cellular reprogramming which promotes disease progression. To study TEX effects on the development of solid tumors, immunosuppressive exosomes carrying PD-L1 and FasL were isolated from supernatants of murine or human HNSCC cell lines. TEX were delivered (IV) to immunocompetent C57BL/6 mice bearing premalignant oral/esophageal lesions induced by the carcinogen, 4-nitroquinoline 1-oxide (4NQO). Progression of the premalignant oropharyngeal lesions to malignant tumors was monitored. A single TEX injection increased the number of developing tumors (6.2 versus 3.2 in control mice injected with phosphate-buffered saline; P < 0.0002) and overall tumor burden per mouse (P < 0.037). The numbers of CD4+ and CD8+ T lymphocytes infiltrating the developing tumors were coordinately reduced (P < 0.01) in mice injected with SCCVII-derived TEX relative to controls. Notably, TEX isolated from mouse or human tumors had similar effects on tumor development and immune cells. A single IV injection of TEX was sufficient to condition mice harboring premalignant OSCC lesions for accelerated tumor progression in concert with reduced immune cell migration to the tumor.

SUBMITTER: Razzo BM

PROVIDER: S-EPMC7350555 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma.

Razzo Beatrice M BM Ludwig Nils N Hong Chang-Sook CS Sharma Priyanka P Fabian Kellsye P KP Fecek Ronald J RJ Storkus Walter J WJ Whiteside Theresa L TL

Carcinogenesis 20200701 5

Circulating tumor-derived exosomes (TEX) interact with a variety of cells in cancer-bearing hosts, leading to cellular reprogramming which promotes disease progression. To study TEX effects on the development of solid tumors, immunosuppressive exosomes carrying PD-L1 and FasL were isolated from supernatants of murine or human HNSCC cell lines. TEX were delivered (IV) to immunocompetent C57BL/6 mice bearing premalignant oral/esophageal lesions induced by the carcinogen, 4-nitroquinoline 1-oxide ( ...[more]

PMID: 31245809

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Project description:ObjectiveOur previous study suggested cyclin-dependent kinase-like 3 (CDKL3) acts as a new oncogene in esophageal squamous cell carcinoma (ESCC) cell line TE-1. However, the molecular mechanisms and biological effects of CDKL3 in ESCC remain unknown. In the present study, we aimed to explore the clinical significance of CDKL3 in ESCC and how CDKL3 regulates the malignant behavior of ESCC.MethodsESCC samples were stained by immunohistochemical staining (IHC) and analyzed for the expression of CDKL3. The functions of CDKL3 on proliferation, apoptosis, migration, invasion, and colony formation were investigated by celigo assay, MTT assay, colony formation, caspase 3/7 activity analysis, transwell migration and invasion assay, respectively. A transplanted tumor model was established to study the functions of FLVCR1 on the tumorigenesis of ESCC cells. Microarray analysis was utilized to identify the CDKL3-regulated genes in ESCC cells.ResultsESCC tumor tissues possessed a significantly higher expression of CDKL3 and autophagy-related gene 5 (ATG5) than matched adjacent normal tissues. The high expressions of CDKL3 were positively associated with the tumor-node-metastasis (TNM) stage and Ki67. Upregulated ATG5 expression was positively correlated with male, advanced tumor (T) stage, and TNM stage. Kaplan-Meier analysis showed that ESCC patients with higher expression of CDKL3 or ATG5 had a shorter overall survival. The worst prognosis was recognized in patients with both high manifestations of CDKL3 and ATG5. Time-dependent receiver operating characteristic (ROC) curve was established to reveal that the combination of CDKL3, ATG5, and TNM stage-based model had better prognostic accuracy than TNM stage. Moreover, CDKL3 knockdown markedly repressed cell growth and aggressivity in vitro and in vivo. Mechanistically, ATG5 was confirmed as a downstream gene involved in the pro-oncogenic function of CDKL3.ConclusionCDKL3 can be utilized as an independent poor prognostic marker in ESCC patients. Furthermore, CDKL3 may promote tumor profession, invasion, metastasis, and prohibit tumor apoptosis partly by ATG5 activation.

Project description:The stromal cells in the tumor microenvironment (TME) can influence the progression of multiple types of cancer; however, data on oral squamous cell carcinoma (OSCC) are limited. In the present study, the effects of verrucous squamous cell carcinoma‑associated stromal cells (VSCC‑SCs), squamous cell carcinoma‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts (HDFs) on the tumor nest formation, proliferation, invasion and migration of HSC‑3 cells were examined in vitro using Giemsa staining, MTS, and Transwell (invasion and migration) assays, respectively. The results revealed that both the VSCC‑SCs and SCC‑SCs inhibited the tumor nest formation, and promoted the proliferation, invasion and migration of OSCC cells in vitro. Furthermore, the effects of VSCC‑SCs, SCC‑SCs and HDFs on the differentiation, proliferation, invasion and migration of OSCC cells in vivo were evaluated by hematoxylin and eosin staining, tartrate‑resistant acid phosphatase staining, immunohistochemistry and double‑fluorescent immunohistochemical staining, respectively. The results demonstrated that the VSCC‑SCs promoted the differentiation, proliferation, invasion and migration of OSCC cells, while the SCC‑SCs inhibited the differentiation, and promoted the proliferation, invasion and migration of OSCC cells in vivo. Finally, microarray data were used to predict genes in VSCC‑SCs and SCC‑SCs that may influence the progression of OSCC, and those with potential to influence the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. It was found that C‑X‑C motif chemokine ligand (CXCL)8, mitogen‑activated protein kinase 3 (MAPK3), phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA), C-X-C motif chemokine ligand 1 (CXCL1) and C‑C motif chemokine ligand 2 (CCL2) may be involved in the crosstalk between VSCC‑SCs, SCC‑SCs and OSCC cells, which regulates the progression of OSCC. Intercellular adhesion molecule 1 (ICAM1), interleukin (IL)1B, Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), bone morphogenetic protein 4 (BMP4), insulin (INS) and nerve growth factor (NGF) may be responsible for the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. On the whole, the present study demonstrates that both VSCC‑SCs and SCC‑SCs may promote the progression of OSCC, and SCC‑SCs were found to exert a more prominent promoting effect; this may represent a potential regulatory mechanism for the progression of OSCC.

Project description:Rationale: High neutrophil infiltration in hepatocellular carcinoma (HCC) is associated with a poor prognosis in patients with HCC. Tumor-derived exosomes (TDEs) have been proven to be important in the reprogramming of tumor-associated neutrophils (TANs), but the roles and mechanisms have not been fully clarified. Methods: The roles of HCC-exosome-reprogrammed neutrophils on tumor progression were evaluated in the DEN/CCl4-induced HCC mouse model by blocking neutrophil infiltration, depleting neutrophil, and neutrophil adoptive transfer. Transcriptome sequencing and flow cytometry were performed to investigate the effects of HCC exosomes on the phenotype and function of neutrophils. The mobilization and apoptosis of neutrophils were evaluated by the Transwell experiment and Annexin V/7-AAD staining, respectively. Moreover, we detected the effects of HCC-exosome-reprogrammed neutrophils on T cells by flow cytometry. Next, we used the NF-κB pathway inhibitor JSH-23 and miR-362-5p inhibitor or mimic to determine the molecular mechanisms. Lastly, we constructed the miR-362-5p sponge to validate its targeted therapeutic potential. Results: We found that HCC exosomes induced neutrophil infiltration and T-cell exhaustion in the livers of DEN/CCl4-induced HCC mice and promoted tumor progression. Blocking neutrophil infiltration and depleting neutrophils diminished these promotive effects of HCC exosomes. In addition, HCC exosome-reprogrammed neutrophils display proinflammatory and protumor phenotypes, and can directly induce T-cell exhaustion in vitro. The transfer of HCC exosome-reprogrammed neutrophils exacerbated tumor progression and induced T-cell exhaustion, as evidenced by the downregulation of IFN-γ and TNF-α, and the upregulation of PD-1 and Tim3 in T cells. Mechanistically, we found that HCC exosomes upregulate the expression of miR-362-5p in neutrophils and activate the NF-κB signaling pathway by targeting CYLD, promoting the survival and recruitment of neutrophils. In HCC mice, blocking miR-362-5p suppressed neutrophil infiltration, attenuated T-cell exhaustion, and suppressed HCC progression. Conclusions: This study clarified the roles of HCC exosomes on neutrophil infiltration and reprogramming and identified a potential target miR-362-5p for HCC treatment.

Dataset Information

Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma.

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Tumor-derived exosomes promote carcinogenesis of murine oral squamous cell carcinoma.

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