Rab27B enhances drug resistance in hepatocellular carcinoma by promoting exosome-mediated drug efflux.

Liver cancer is a major threat to human life and health, and chemotherapy has been the standard non-surgical treatment for liver cancer. However, the emergence of drug resistance of liver cancer cells has hindered the therapeutic effect of chemical drugs. The discovery of exosomes has provided new insights into the mechanisms underlying tumour cell resistance. In this study, we aimed to determine the proteins associated with drug resistance in tumour cells and to elucidate the underlying mechanisms. We found that Rab27B expression in drug (5-fluorouracil, 5Fu)-resistant Bel7402 (Bel/5Fu) cells increased significantly compared with that in drug-sensitive Bel7402 cells. In addition, Bel/5Fu cells secreted more exosomes under 5Fu stimulation. The number of exosomes secreted by Bel/5Fu cells significantly reduced after knocking down Rab27B, and the cellular concentration of 5Fu increased, enhancing its therapeutic effect. We also found that the administration of classical drug efflux pump (P-glycoprotein, P-gp) inhibitors together with knockdown of Rab27B further improved the therapeutic effects of chemotherapy drugs. In conclusion, our findings suggest that Rab27B could be a new therapeutic target in liver cancer.

The critical role of exosomes in tumor biology.

Exosomes are a type of extracellular vesicles (diameter, 30-160 nm), which contain multiple proteins, nucleic acids, lipid molecules, and other substances. Most types of cells can secrete exosomes, although the biogenesis, composition, and function is specific to different cell types. Recently, many studies have demonstrated that exosomes play a critical role in tumor development. In this review, we briefly summarize the biogenesis, composition, and function of exosomes. We also discuss the recent advances in the critical role of exosomes in tumor biology with a special focus on their application in tumor diagnosis and treatment.

Multipotent mesenchymal stromal cells play critical roles in hepatocellular carcinoma initiation, progression and therapy.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity, relapse and mortality rates. Multipotent mesenchymal stromal cells (MSCs) can be recruited to and become integral components of the HCC microenvironment and can influence tumor progression. This review discusses MSC migration to liver fibrosis and the HCC microenvironment, MSC involvement in HCC initiation and progression and the widespread application of MSCs in HCC-targeted therapy, thus clarifying the critical roles of MSCs in HCC.

Endothelial-to-mesenchymal transition in tumour progression and its potential roles in tumour therapy.

Tumour-associated endothelial cells (TECs) are a critical stromal cell type in the tumour microenvironment and play central roles in tumour angiogenesis. Notably, TECs have phenotypic plasticity, as they have the potential to transdifferentiate into cells with a mesenchymal phenotype through a process termed endothelial-to-mesenchymal transition (EndoMT). Many studies have reported that EndoMT influences multiple malignant biological properties of tumours, such as abnormal angiogenesis and tumour metabolism, growth, metastasis and therapeutic resistance. Thus, the value of targeting EndoMT in tumour treatment has received increased attention. In this review, we comprehensively explore the phenomenon of EndoMT in the tumour microenvironment and identify influencing factors and molecular mechanisms responsible for EndoMT induction. Furthermore, the pathological functions of EndoMT in tumour progression and potential therapeutic strategies for targeting EndoMT in tumour treatment are also discussed to highlight the pivotal roles of EndoMT in tumour progression and therapy.

This review comprehensively summarizes and discusses the phenotypic plasticity of TECs, the critical influence of EndoMT in tumour progression and therapy and potential EndoMT-targeted therapeutic strategies to highlight and connect the gaps in knowledge and therapeutic opportunities.

The potential applications of artificially modified exosomes derived from mesenchymal stem cells in tumor therapy.

Mesenchymal stem cells (MSCs) have tumor-homing ability and play critical roles in tumor treatment, but their dual influences on tumor progression limit their therapeutic applications. Exosomes derived from MSCs (MSC-exosomes) exhibit great potential in targeted tumor treatment due to their advantages of high stability, low immunogenicity, good biocompatibility, long circulation time and homing characteristics. Furthermore, the artificial modification of MSC-exosomes could amplify their advantages and their inhibitory effect on tumors and could overcome the limit of tumor-promoting effect. In this review, we summarize the latest therapeutic strategies involving artificially modified MSC-exosomes in tumor treatment, including employing these exosomes as nanomaterials to carry noncoding RNAs or their inhibitors and anticancer drugs, and genetic engineering modification of MSC-exosomes. We also discuss the feasibility of utilizing artificially modified MSC-exosomes as an emerging cell-free method for tumor treatment and related challenges.

Lipid-related FABP5 activation of tumor-associated monocytes fosters immune privilege via PD-L1 expression on Treg cells in hepatocellular carcinoma.

Monocytes/macrophages, a plastic and heterogeneous cell population of the tumor microenvironment (TME), can constitute a major component of most solid tumors. Under the pressure of rapid proliferation of the tumor, monocytes/macrophages can be educated and foster immune tolerance via metabolic reprogramming. Our studies have shown that the activation of FABP5, a lipid-binding protein, decreases the rate of ß-oxidation causing the accumulation of lipid droplets in monocytes. We found that hepatocellular carcinoma cells (HCC) increased IL-10 secretion by monocytes, which depended on the expression of FABP5 and suppressing of the PPARα pathway. Moreover, the elevated level of IL-10 promotes PD-L1 expression on Treg cells via the JNK-STAT3 pathway activation. We also observed that elevation of FABP5 in monocytes was negatively related to HCC patients' overall survival time. Thus, FABP5 promotes monocyte/macrophage lipid accumulation, fosters immune tolerance formation, and might represent itself as a therapeutic target in both tumor-associated monocytes (TAMs) and cancer cells.

Identifying potential prognostic biomarkers in head and neck cancer based on the analysis of microRNA expression profiles in TCGA database.

The present study aimed to identify sensitive, specific and independent prognostic biomarkers in head and neck cancer (HNC) based on microRNA expression profiles and other high­throughput sequencing data in The Cancer Genome Atlas (TCGA) database. Identification of such prognostic biomarkers could provide insight into HNC diagnosis and treatment. The differential expression profiles of microRNAs between HNC tissues and adjacent cancer tissues in the TCGA database were analyzed (log fold­change >2; P<0.01). Univariate and multivariate Cox regression analyses of the differentially expressed microRNAs were performed to determine those significantly related to the survival of patients with HNC. The identified microRNAs were verified by survival and receiver operating characteristic curve analyses. To better predict prognosis, a combined prognostic model (risk equation) was established based on the risk coefficient of each microRNA, calculated by a multivariate Cox regression analysis, and the risk score was calculated. To explore the signaling pathways related to prognosis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed on the differentially expressed genes between the high­risk and low­risk groups, grouped according to the median risk score. A total of 89 differentially expressed microRNAs between HNC and adjacent cancer tissues were screened, 11 of which were identified as risk factors related to HNC survival by the univariate Cox regression analysis (P<0.05). The multivariate Cox regression analysis showed that three of the 11 microRNAs, hsa­miR­99a, hsa­miR­499a and hsa­miR­1911 (all P<0.01), were identified as independent risk factors significantly related to patient survival. The risk equation used was as follows: Risk score=(­0.1597 x hsa­miR­99a) + (0.1871 x hsa­miR­499a) + (0.1033 x hsa­miR­1911). KEGG and GO analyses showed that the JAK­STAT signaling pathway and some metabolic pathways were associated with HNC prognosis. The present study suggested that hsa­miR­99a, hsa­miR­499a and hsa­miR­1911 may serve as potential prognostic biomarkers in HNC.

Exosome-derived ENO1 regulates integrin α6ß4 expression and promotes hepatocellular carcinoma growth and metastasis.

Alpha-enolase (ENO1) has been found to be dysregulated in several human malignancies, including hepatocellular carcinoma (HCC). Although the role of ENO1 as a glycolytic enzyme in HCC cells has been well characterized, little is known about the other roles of ENO1, especially exosome-derived ENO1, in regulating HCC progression. Here, we demonstrated that ENO1 is frequently upregulated in HCC cells or tissues, with even higher expression in highly metastatic HCC cells or metastatic tissues as well as in exosomes derived from highly metastatic sources. Moreover, ENO1 expression is associated with the tumor-node-metastasis (TNM) stage, differentiation grade and poor prognosis in HCC patients. Surprisingly, ENO1 can be transferred between HCC cells via exosome-mediated crosstalk, exhibiting an effect similar to that of ENO1 overexpression in HCC cells, which promoted the growth and metastasis of HCC cells with low ENO1 expression by upregulating integrin α6ß4 expression and activating the FAK/Src-p38MAPK pathway. In summary, our data suggest that exosome-derived ENO1 is essential to promoting HCC growth, metastasis, and further patient deterioration. The findings from this study implicate a novel biomarker for the clinical evaluation of HCC progression, especially the prediction of HCC metastatic risk.

Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal disease, and recurrence and metastasis are the major causes of death in HCC patients. Cancer-associated fibroblasts (CAFs), a major stromal cell type in the HCC microenvironment, promote HCC progression, and have gradually become a hot research topic in HCC-targeted therapy. This review comprehensively describes and discusses the heterogeneous tissue distribution, cellular origin, phenotype, and biological functions of HCC-associated fibroblasts. Furthermore, the possible use of CAFs for predicting HCC prognosis and in targeted therapeutic strategies is discussed, highlighting the critical roles of CAFs in HCC progression, diagnosis, and therapy.