Cholangiocarcinoma (CCA), a common primary malignant tumor of bile duct epithelia, is highly prevalent in Asian countries and unresponsive to chemotherapeutic drugs. Thus, a newly recognized biological entity for early diagnosis and treatment is highly needed. Exosomes are small membrane bound vesicles found in body fluids and released by most cell types including cancer cells. The vesicles contain specific subset of proteins and nucleic acids corresponding to cell types and play essential roles in pathophysiological processes. The present study aimed to assess the protein profiles of CCA-derived exosomes and their potential roles. We have isolated exosomes from CCA cells namely KKU-M213 and KKU-100 derived from Thai patients and their roles were investigated by incubation with normal human cholangiocyte (H69) cells. Exosomes were internalized into H69 cells and had no effects on viability or proliferation of the host cells. Interestingly, the exosomes from KKU-M213 cells only induced migration and invasion of H69 cells. Proteomic analysis of the exosomes from KKU-M213 cells disclosed multiple cancer related proteins that are not present in H69 exosomes. Consistent with the protein profile, treatment with KKU-M213 exosomes induced β-catenin and reduced E-cadherin expressions in H69 cells. Collectively, our results suggest that a direct cell-to-cell transfer of oncogenic proteins via exosomal pathway may be a novel mechanism for CCA progression and metastasis.

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Extracellular vesicles (EVs) released from non-small cell lung cancer (NSCLC) cells are known to promote cancer progression. However, it remains unclear how EVs from various NSCLC cells differ in their secretion profile and their ability to promote phenotypic changes in non-tumorigenic cells. Here, we performed a comparative analysis of EV release from non-tumorigenic cells (HBEC/BEAS-2B) and several NSCLC cell lines (A549, H460, H358, SKMES, and Calu6) and evaluated the potential impact of NSCLC EVs, including EV-encapsulated RNA (EV-RNA), in driving invasion and epithelial barrier impairment in HBEC/BEAS-2B cells. Secretion analysis revealed that cancer cells vary in their secretion level, with some cell lines having relatively low secretion rates. Differential uptake of NSCLC EVs was also observed, with uptake of A549 and SKMES EVs being the highest. Phenotypically, EVs derived from Calu6 and H358 cells significantly enhanced invasion, disrupted an epithelial barrier, and increased barrier permeability through downregulation of E-cadherin and ZO-1. EV-RNA was a key contributing factor in mediating these phenotypes. More nuanced analysis suggests a potential correlation between the aggressiveness of NSCLC subtypes and the ability of their respective EVs to induce cancerous phenotypes.

Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low.

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