Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune‐associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

Antidiabetic medication may modify the incidence of hepatocellular carcinoma (HCC). We aimed to compare the use of different antidiabetic strategies and the incidence of HCC. PubMed, Embase.com and Cochrane Library databases were searched up to 31 October 2015 and randomized controlled trials (RCTs), cohort studies or case-control studies were included for our analyses. A total of thirteen studies enrolling 481358 participants with 240678 HCC cases who received at least two different strategies were retrieved in this analysis. Direct comparisons showed that use of metformin (risk ratio [RR] 0.49, 95% CI 0.25–0.97) was associated with a significant risk reduction of HCC, while insulin (RR = 2.44, 95% CI 1.10- 5.56) may significantly increase the risk. Indirect evidence also suggested that insulin (RR = 2.37, 95% CI 1.21–4.75) was associated with a significantly increased risk of HCC. Additionally, metformin was effective in reducing the risk of HCC when compared with sulphonylurea (RR = 0.45, 95% CI 0.27–0.74) and insulin (RR = 0.28, 95% CI 0.17–0.47). Notably, metformin was hierarchically the best when compared with other antidiabetic therapies for the prevention of HCC. In summary, available evidence suggests that metformin was the most effective strategy to reduce HCC risk when compared with other antidiabetic interventions.

Lifestyle interventions remain the first-line therapy for nonalcoholic fatty liver disease (NAFLD). This study aims to evaluate the individual impact of exercise and/or dietary interventions on the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), homeostasis model of assessment for insulin resistance index (HOMA-IR), and BMI. Randomized-controlled trials from patients diagnosed with NAFLD were included in the meta-analysis if they reported the associations between changes in ALT, AST, HOMA-IR, or BMI and types of lifestyle interventions. Nineteen eligible articles were included. Compared with observation, aerobic exercise training (AEx) plus diet [weighted mean difference (WMD)=-25.85; 95% confidence interval (CI): -43.90 to -7.80], AEx (WMD=-8.81; 95% CI: -20.22-2.60) and diet (WMD=-11.85; 95% CI: -47.65-24.95) showed significant efficacy in the improvement of ALT levels. Also AST, AEx plus diet showed a significant tendency to reduce AST levels. In addition, progressive resistance training (WMD=-1.70; 95% CI: -5.61-2.21) led to the most obvious reduction in HOMA-IR compared with observation, but appeared to show no significant effect in BMI (WMD=0.27; 95% CI: -0.48 to -0.07), whereas AEx plus diet (WMD=-0.96; 95% CI: -1.54 to -0.38 and WMD=-1.96; 95% CI: -2.79 to -1.12) showed great efficacy both in the improvement of HOMA-IR and BMI. AEx plus diet is the most effective intervention in the management of patients with NAFLD. Dietary intervention may be more effective in the improvements of aminotransferases, whereas exercise shows superiority in improving insulin sensitivity and reduction of BMI.

Intercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

Although several risk factors for metabolic syndrome (MetS) have been reported, there are few clinical scores that predict its incidence. Therefore, we created and validated a risk score for prediction of 3-year risk for MetS. Three-year follow-up data of 4395 initially MetS-free subjects, enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. Subjects at enrollment were randomly divided into the training and the validation cohort. Univariate and multivariate logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. The predictive performance of the model was tested by computing the area under the receiver operating characteristic curve (AUROC). Four independent predictors were chosen to construct the MetS risk score, including BMI (HR=1.906, 95% CI: 1.040-1.155), FPG (HR=1.507, 95% CI: 1.305-1.741), DBP (HR=1.061, 95% CI: 1.002-1.031), HDL-C (HR=0.539, 95% CI: 0.303-0.959). The model was created as -1.5 to 4 points, which demonstrated a considerable discrimination both in the training cohort (AUROC=0.674) and validation cohort (AUROC=0.690). Comparison of the observed with the estimated incidence of MetS revealed satisfactory precision. We developed and validated the MetS risk score with 4 risk factors to predict 3-year risk of MetS, useful for assessing the individual risk for MetS in medical practice.

Backgrounds and Aims: Previous studies have investigated that sarcopenia is associated with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis, and fibrosis in NAFLD. The study aims to investigate the risk for NAFLD, especially NAFLD-related significant fibrosis among subjects with sarcopenia. Methods: We searched electronic databases until 30, September 2017 and reviewed literature extensively. Effect estimates were pooled using random effect models regarding the risk for NAFLD and fixed effect models concerning the risk for significant fibrosis among sarcopenia patients. Sensitivity analysis was performed for the risk of NAFLD. Results: We identified 6 studies. Our results showed that subjects with sarcopenia exhibited an increased risk for NAFLD compared to those without sarcopenia (OR 1.29, 95% CI 1.12–1.49) with heterogeneity among the individual studies (I² = 61%). And the risk for NAFLD-related significant fibrosis appeared to be more pronounced in sarcopenia patients (OR 1.57, 95% CI 1.29–1.90) with an I² of 0%. Sensitivity analysis revealed that neither the direction nor the magnitude of the estimated pooled results for NAFLD was obviously affected. Furthermore, the pooled ORs were both close to initial analysis when omitting the study by Hong et al. [Hepatology 2014; 59: 1772–1778] (OR 1.24, 95% CI 1.11–1.39, I² = 47%) or by Hashimoto et al. [Endocr J 2016; 63: 877–884] (OR 1.33, 95% CI 1.11–1.59, I² = 67%), which were considered sources of heterogeneity. Conclusions: Our analysis demonstrated that sarcopenia served not only as a risk factor for the onset of NAFLD but also related to the progression of NAFLD-related significant fibrosis.

Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating epidermal growth factor receptor (EGFR) and stimulating the EGFR-STAT3-ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft-dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR-STAT3-ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease.