Exosomes carry and transmit signaling molecules used for intercellular communication. The generation and secretion of exosomes is a multistep interlocking process that allows simultaneous control of multiple regulatory sites. Protein molecules, mainly RAB GTPases, cytoskeletal proteins and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE), are specifically regulated in response to pathological conditions such as altered cellular microenvironment, stimulation by pathogenic factors, or gene mutation. This interferes with the smooth functioning of endocytosis, translocation, degradation, docking and fusion processes, leading to changes in the secretion of exosomes. Large numbers of secreted exosomes are disseminated by the flow of body fluids and absorbed by the recipient cells. By transmitting characteristic functional proteins and genetic information produced under disease conditions, exosomes can change the physiological state of the recipient cells and their microenvironment. The microenvironment, in turn, affects the occurrence and development of disease. Therefore, this review will discuss the mechanism by which exosome secretion is regulated in cells following the formation of mature secretory multivesicular bodies (MVBs). The overall aim is to find ways to eliminate disease-derived exosomes at their source, thereby providing an important new basis for the clinical treatment of disease.

Abstract Background At present, the clinical diagnosis and treatment of pancreatic cancer (PC) are challenging, and there are still in gaps in the knowledge about its malignant progression. In particular, there is not enough information about the mechanism by which exosomes released by PC cells are significantly increased and involved in promoting malignant progression. Results In the present study, the expression of the metalloproteinase ADAM10 on cell membranes was found to be increased significantly in PC tissues and cell lines. Further, PC cells with high ADAM10 expression had stronger migration and invasion ability and were able to release more exosomes. Moreover, ADAM10 was found to affect the expression of RAB GTPase, a key regulatory molecule involved in the production of exosomes in cells, especially RAB5, which is associated with the formation of early endosomes. Further analysis indicated that ADAM10 may upregulate the transcription level of RAB5 by increasing the Notch2 signal intensity in PC cells, thus promoting the generation and secretion of exosomes in PC cells and further regulating the occurrence and development of PC. Conclusions These results reveal that ADAM10 plays a key role in regulating exosome secretion and may have potential as a therapeutic target for the clinical treatment of PC.

Objective:To investigate the effects of poly adenosine diphosphate ribose polymerase-1(PARP-1) inhibitor fluzoparib on proliferation, apoptosis and migration of pancreatic cancer PANC1 cells.Methods:PANC1 cells cultured in conventional culture medium were used as control group, and PANC1 cells cultured in the medium containing fluzoparib were used as fluzoparib group. The effects of fluzoparib with different concentrations on the proliferation of PANC1 cells were detected by CCK8 method, and the half inhibitory concentration (IC 50) of fluzoparib on PANC1 cells was calculated. The effect of fluzoparib on apoptosis and cell cycle of PANC1 cells was detected by flow cytometry, and the migration ability of PANC1 cells was detected by cell scratch test and Transwell chamber. Results:Compared with control group, with the increase of fluzoparib concentration and the prolongation of the action time, the cell proliferation activity of PANC1 in fluzoparib group was significantly decreased, and the differences were statistically significant (all P values <0.05). IC 50 of fluzoparib on PANC1 cells cultured for 24 h was 0.03 mmol/L. After 24 h culture, the IC 50 apoptosis rate of fluzoparib group was (32.19±2.48)%, and the apoptosis rate of control group was (21.99±6.30)%. The former was greatly higher than the latter, and the difference was statistically significant ( P<0.05). The proportion of cells in G 2/M phase was (16.28±0.62)% in the fluzoparib group and (11.64±0.88)% in the control group, and the difference between the two groups was statistically significant ( P<0.05). The migration rates of PANC1 cells in IC 50 fluzoparib group in 12 h and 24 h culture were (2.59±1.46)% and (19.76±7.84)%; and those in control group were (27.08±2.17)% and (45.92±3.61)%, respectively. The number of transmembrane cells was (348±19) cells/10 visual field in the fluzoparib group and (587±14) cells/10 visual field in the control group. The migration ability of PANC1 cells in fluzoparib group was significantly lower than that in control group ( P<0.05). Conclusions:Fluzoparib can inhibit the proliferation and migration of PANC1 cells and promote the apoptosis of PANC1 in vitro, which may be an effective drug for the treatment of pancreatic cancer.

Pancreatic cancer is one of the most lethal neoplasms with high metastatic potential and is resistant to almost all current therapies. Epalrestat is an aldo-keto reductase family 1 member B1 (AKR1B1) inhibitor for the treatment of diabetic neuropathy, but its potential application in cancer treatment and the underlying mechanism are largely unknown. Here, we found that AKR1B1 is upregulated in pancreatic cancer and is positively associated with metastasis. Upregulated AKR1B1 promoted exosome secretion, accelerating cell migration in pancreatic cancer cells. Further analysis indicated that AKR1B1 negatively regulated lysosomal function and multivesicular body (MVB) degradation in lysosomes. However, AKR1B1 had a minimal role in the generation of MVBs. Transcription factor EB (TFEB) and MVB-expressed RAB7A were two molecular targets that are negatively regulated by AKR1B1. These results uncovered a critical role for AKR1B1 in the regulation of lysosomal function and exosome secretion. Pharmacological targeting of AKR1B1 by clinically used medicines, such as Epalrestat, might represent an efficient way to inhibit pancreatic growth and metastasis.

Galectin-3 plays an important role in cell-cell adhesion, macrophage activation, angiogenesis, metastasis and apoptosis and is overexpressed in pancreatic cancer. We explored the importance of galectin-3 in the screening, early diagnosis, prognosis and therapeutic effect evaluation of pancreatic cancer. A time-resolved fluorescence immunoassay was performed to detect serum galectin-3 level. Serum samples were collected from healthy controls and patients with pancreatic cancer before and after different treatments, and the relationships between galectin-3 level and clinical parameters were analysed. Among the healthy controls, one individual with an abnormally high concentration of galectin-3 (9.85 μg/L) was diagnosed with pancreatic cancer. Compared to the pre-operative level, galectin-3 concentration significantly decreased in patients with radical excision 1 month after surgery (P < .05), but showed no obvious change in patients who underwent palliative resection. Additionally, among patients with radical excision, carcinoma recurrence rate was significantly higher in those with increased or unchanged galectin-3 level. Retrospective analysis revealed the extraordinarily high value and high specificity of galectin-3 for predicting 3-year survival (P < .001). Thus, galectin-3 may serve as a potential biomarker for the screening and early diagnosis of pancreatic cancer and as an independent prognostic indicator in patients with pancreatic cancer.