Monocarboxylate transporter4 (MCT4) is responsible for the efflux of lactate and high expression of MCT4 is related to poor prognosis in multiple cancers. Herein, Fluvastatin, regarded as a lipid-metabolic regulator, has been screened out as an inhibitor of MCT4 for lung adenocarcinoma (LUAD) treatment. As tumor cell-derived microparticles (TMPs) have advantages in low toxicity, biocompatibility and biological targeting, TMPs serve as a highly efficient drug-delivery system to transport Fluvastatin in a relatively low dosage. TMPs encapsulating Fluvastatin (TMP-F), consistent with antitumor function of Fluvastatin, can impede lactate efflux by inhibiting MCT4 expression, resulting in attenuated LUAD progression. TMP-F provokes reversion of immunosuppressive tumor microenvironment (TME) by appealing to infiltration of NK and CD8+ T cells, polarizing M2-type to M1-type macrophages, and decreasing Treg and myeloid-derived suppressor cells (MDSC). In addition, co-administration of TMP-F and chemotherapy Cisplatin still reinforces the antitumor immune response. Meanwhile, TMP-F improves antitumor efficiency of Cisplatin and curbs lung metastasis. Overall, TMP-F or therapeutic alliance with Cisplatin represents a promising strategy for enhancing therapeutic effect on LUAD.
Background miR-26a plays a critical role in tumorigenesis, either as a tumor suppressor or as an oncogenic miRNA, depending on different tumor types. However, the function of miR-26a in pancreatic cancer has not been clearly elucidated. The present study was designed to determine the roles of miR-26a in pancreatic cancer and its association with the survival of patients with pancreatic cancer. Methods The expression of miR-26a was examined in 15 pairs of pancreatic duct adenocarcinoma (PDAC) and their adjacent benign pancreatic tissues (ABPT), by qRT-PCR. The results were confirmed by in situ hybridization using two panels of 106 PDACs and their ABPT microarray. The association of miR-26a expression with overall survival was determined. The proliferation and cell cycle distribution of Capan-2, SW-1990, and Panc-1 cells, transfected with miR-26a mimics or a miR-26a inhibitor, were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. The cell tumorigenicity was evaluated via murine xenograft experiments. Cyclin D2, E2, EZH2, and PCNA levels were analyzed by Western blot and immunohistochemistry. Results miR-26a was expressed in the cytoplasm of pancreatic ductal epithelial cells, whereas its expression was significantly downregulated in PDAC tissues compared with that of ABPT. Patients with low miR-26a expression had a significantly shorter survival than those with high miR-26a expression. The in vitro and in vivo assays showed that overexpression of miR-26a resulted in cell cycle arrest, inhibited cell proliferation, and decreased tumor growth, which was associated with cyclin E2 downregulation. Conclusions miR-26a is an important suppressor of pancreatic ductal carcinoma, and can prove to be a novel prognostic factor and therapeutic target for pancreatic cancer treatment.
Tumor‐derived microparticles (TMPs) are not only carriers for tumor antigens but also can be used as good delivery platform. Therefore, for such an excellent delivery platform, we considered modifying TMPs with lipopolysaccharide (LPS) and polyethyleneimine (PEI) to synthesize TMPs-PEI-LPS for the delivery of tumor antigen and investigated its delivery efficiency, histocompatibility and anti-tumor effect. We investigated the bioactivity of TMPs-PEI-LPS with dendritic cells and their potential for therapeutic application to treat lung cancer in mice models bearing Lewis lung carcinoma cells. Both in vitro and in vivo assays demonstrated successful TMPs-PEI-LPS induced the uptake and maturity of dendritic cells. TMPs-PEI-LPS exhibited certain immunostimulation activity and anti-tumor effects on inhibiting tumor growth in vivo. Notably, TMPs-PEI-LPS were safe and non-toxic in vivo study. These results indicated that TMPs-PEI-LPS are promising platforms for delivering tumor antigens to enhance immunogenicity.
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