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EphA2?enriched exosomes promote cell migration and are a potential diagnostic serum marker in pancreatic cancer.

ABSTRACT: Pancreatic cancer (PC) is the fourth most common cause of cancer?related mortality worldwide and is characterized by high invasiveness and early metastasis. To identify novel diagnostic markers, the present study aimed to understand the mechanism underlying PC progression. The present study demonstrated that exosomes derived from the highly metastatic Panc?1 PC cell line were internalized by a low metastatic cell line, resulting in increased migration of the latter. Proteomics analysis further revealed that the receptor tyrosine kinase Eph receptor A2 (EphA2) was overexpressed in the Panc?1 exosomes, and these Exo_EphA2 had the ability to transfer metastatic potential to recipient cells. Consistent with this, circulating Exo_EphA2 levels were higher in patients with PC compared with healthy controls. Taken together, these results indicated that Exo_EphA2 acts an oncogene in PC and is a potential tumor maker for PC diagnosis.

SUBMITTER: Wei Q

PROVIDER: S-EPMC7466360 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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EphA2‑enriched exosomes promote cell migration and are a potential diagnostic serum marker in pancreatic cancer.

Wei Qian Q Wei Lijuan L Zhang Jingya J Li Ze Z Feng Honglei H Ren Li L

Molecular medicine reports 20200728 4

Pancreatic cancer (PC) is the fourth most common cause of cancer‑related mortality worldwide and is characterized by high invasiveness and early metastasis. To identify novel diagnostic markers, the present study aimed to understand the mechanism underlying PC progression. The present study demonstrated that exosomes derived from the highly metastatic Panc‑1 PC cell line were internalized by a low metastatic cell line, resulting in increased migration of the latter. Proteomics analysis further r ...[more]

PMID: 32945400

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Project description:ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm with rising incidence worldwide. Gremlin 1 (GREM1), a regulator of bone morphogenetic protein (BMP) signaling, fine-tunes extensive biological processes, including organ morphology, cellular metabolism, and multiple pathological developments. The roles of GREM1 in PDAC remain unknown.MethodsVarieties of public databases and online software were employed to analyze the expressions at transcription and protein levels of GREM1 in multiple malignant neoplasms including PDAC, and in addition, its potential pro-tumoral functions in PDAC were further evaluated. A total of 340 serum samples of pancreatic disease, including PDAC, low-grade malignant pancreatic neoplasm, benign pancreatic neoplasm, pancreatitis, and 132 healthy controls, were collected to detect GREM1. The roles of serum GREM1 in the diagnosis and prediction of survival of PDAC after radical resection were also analyzed.ResultsBioinformatics analyses revealed that GREM1 was overexpressed in PDAC and predicted a poorer survival in PDAC. A higher protein level of GREM1 in PDAC correlated with stroma formation and immunosuppression by recruiting varieties of immunosuppressive cells, including T regulatory cells (Tregs), M2 macrophages, myeloid-derived suppressor cells (MDSCs), and exhaustion T cells into the tumor microenvironment. A higher level of serum GREM1 was observed in PDAC patients, compared to healthy control (p < 0.001). Serum GREM1 had a good diagnostic value (area under the curve (AUC) = 0.718, p < 0.001), and its combination with carbohydrate antigen 199 (CA199) achieved a better diagnostic efficacy (AUC = 0.914, p < 0.001), compared to CA199 alone. The cutoff value was calculated by receiver operating characteristic (ROC) analysis, and PDAC patients were divided into two groups of low and high GREM1. Logistic analyses showed serum GREM1 positively correlated with tumor size (hazard ratio (HR) = 7.097, p = 0.032) and histopathological grades (HR = 2.898, p = 0.014). High-level serum GREM1 (1,117.8 pg/ml) showed a shorter postoperative survival (p = 0.0394).ConclusionHigher intra-tumoral expression of GREM1 in PDAC contributes to tumor stroma and immunosuppressive tumor microenvironment, presenting its therapeutic potential. High-level serum GREM1 predicts poorer survival after resection. A combination of serum CA199 and GREM1 shows a stronger diagnostic efficacy in PDAC.

Project description:The search for valuable early diagnostic markers for leptospirosis is ongoing. The aim of the present study was to evaluate the diagnostic value of macrophage migration inhibitory factor (MIF) for leptospirosis. MIF is an immunoregulatory cytokine secreted by a variety of cell types involved in immune response and the pathogenesis of various diseases. It was previously described as a severity predictor of diseases. Samples of 142 leptospirosis cases, 101 other febrile cases, and 57 healthy controls were studied. The prevalence of leptospirosis was 47.3%. Autumnalis, Australis, and Canicola were the highly prevalent leptospiral serovars with a microscopic agglutination test (MAT) titer in the range 1:80-1:2,560. Enzyme-linked immunosorbent assay (ELISA) of MIF was carried out to measure the serum MIF levels. We found that the serum MIF levels [median, (interquartile range)] were significantly (p < 0.001) elevated in different clinical forms of leptospirosis, such as febrile illness [7.5 ng/ml (5.32-8.97)], pulmonary hemorrhage [13.2 ng/ml (11.77-16.72)], Weil's syndrome [8.8 ng/ml (7.25-9.95)], and renal failure [8.6 ng/ml (7.18-10.5)], than in healthy controls [0.65n g/ml (0.5-1.1)]. Serum MIF had sensitivity, specificity, positive predictive value, and negative predictive value of 100%, >90%, >90%, and 100%, respectively. Receiver operating characteristic (ROC) analysis revealed that the serum MIF levels between leptospirosis cases and control subjects had an area under the curve (AUC) value of >0.9 (p < 0.0001). In leptospirosis patients, elevation of serum MIF was significantly (p < 0.001) higher in severe cases with organ dysfunction [10 ng/ml (7.8-14.5)] than that in mild febrile cases [7.5 ng/ml (5.32-8.97)], with the difference of 2.5 indicating that serum MIF acts as a predictor of leptospirosis severity. Pearson's correlation test demonstrated that the serum MIF level was strongly correlated (r = 0.75, p < 0.0001) with disease progression. The median lethal dose (LD50) of leptospiral lipopolysaccharide (LPS) in BALB/c mice was determined to be 20 mg/kg, which gave rise to endotoxemia. Leptospiral LPS triggered the upregulation of MIF expression at 24 h post-infection, which reached the peak level at 24 h post-treatment in THP-1 cells and showed elevated MIF expressions in different tissues of BALB/c mice at the early stage of infection. Taken together, MIF is an early-phase cytokine that could serve as a rapid diagnostic marker for leptospirosis.

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EphA2?enriched exosomes promote cell migration and are a potential diagnostic serum marker in pancreatic cancer.

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EphA2‑enriched exosomes promote cell migration and are a potential diagnostic serum marker in pancreatic cancer.

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