Chitosan-grafted phenolic acids as an efficient biopolymer for food packaging films/coatings.

Abstract Background Exosome is crucial mediator and play an important role in tumor angiogenesis. Tip cell formation is a prerequisite for persistent tumor angiogenesis which causes tumor metastasis. However, the functions and underlying mechanisms of tumor cell-derived exosomes in angiogenesis and tip cell formation remain less understood. Methods Exosomes derived from serum of colorectal cancer (CRC) patients with metastasis/non-metastasis and CRC cells were isolated by ultracentrifugation. CircRNAs in these exosomes were analyzed by circRNA microarray. Then, exosomal circTUBGCP4 was identified and verified by quantitative real-time PCR (qRT–PCR) and in situ hybridization (ISH). Loss- and gain-of-function assays were performed to explore the effect of exosomal circTUBGCP4 on vascular endothelial cell tipping and colorectal cancer metastasis in vitro and in vivo. Mechanically, bioinformatics analysis, biotin-labeled circTUBGCP4/ miR-146b-3p RNA pulldown, RNA immunoprecipitation (RIP), and luciferase reporter assay were used to confirm the interaction among circTUBGCP4, miR-146b-3p, and PDK2. Results Here, we showed that exosomes derived from CRC cells enhanced vascular endothelial cell migration and tube formation via inducing filopodia formation and endothelial cell tipping. We further screened the upregulated circTUBGCP4 in serum of CRC patients with metastasis compared to non-metastasis. Silencing circTUBGCP4 expression in CRC cell-derived exosomes (CRC-CDEs) inhibited endothelial cell migration, tube formation, tip cell formation, and CRC metastasis. Overexpression of circTUBGCP4 had opposite results in vitro and in vivo. Mechanically, circTUBGCP4 upregulated PDK2 to activate Akt signaling pathway by sponging miR-146b-3p. Moreover, we found that miR-146b-3p could be a key regulator for vascular endothelial cell dysfunction. Exosomal circTUBGCP4 promoted tip cell formation and activated the Akt signaling pathway by inhibiting miR-146b-3p. Conclusions Our results suggest that colorectal cancer cells generate exosomal circTUBGCP4, which causes vascular endothelial cell tipping to promote angiogenesis and tumor metastasis by activating Akt signaling pathway. 

/pdf/exosomal-circtubgcp4-promotes-vascular-endothelial-cell-14egvsre.pdf

Exosomal circTUBGCP4 promotes vascular endothelial cell tipping and colorectal cancer metastasis by activating Akt signaling pathway

Abstract Background Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, contribute to an immunosuppressive tumor microenvironment (TME) through the induction and functional polarization of protumoral macrophages. We have herein investigated the contribution of CAFs to monocyte recruitment and macrophage polarization. We also sought to identify a possible paracrine mechanism by which CAF-educated monocytes affect breast cancer (BC) cell progression. Methods Monocytes were educated by primary CAFs and normal fibroblast (NF); the phenotypic alterations of CAF- or NF-educated monocytes were measured by flow cytometry. Exosomes isolated from the cultured conditioned media of the educated monocytes were characterized. An in vivo experiment using a subcutaneous transplantation tumor model in athymic nude mice was conducted to uncover the effect of exosomes derived from CAF- or NF-educated monocytes on breast tumor growth. Gain- and loss-of-function experiments were performed to explore the role of miR-181a in BC progression with the involvement of the AKT signaling pathway. Western blotting, enzyme-linked immunosorbent assay, RT-qPCR, flow cytometry staining, migration assay, immunohistochemical staining, and bioinformatics analysis were performed to reveal the underlying mechanisms. Results We illustrated that primary CAFs recruited monocytes and established pro-tumoral M2 macrophages. CAF may also differentiate human monocyte THP-1 cells into anti-inflammatory M2 macrophages. Besides, we revealed that CAFs increased reactive oxygen species (ROS) generation in THP-1 monocytes, as differentiating into M2 macrophages requires a level of ROS for proper polarization. Importantly, T-cell proliferation was suppressed by CAF-educated monocytes and their exosomes, resulting in an immunosuppressive TME. Interestingly, CAF-activated, polarized monocytes lost their tumoricidal abilities, and their derived exosomes promoted BC cell proliferation and migration. In turn, CAF-educated monocyte exosomes exhibited a significant promoting effect on BC tumorigenicity in vivo. Of clinical significance, we observed that up-regulation of circulating miR-181a in BC was positively correlated with tumor aggressiveness and found a high level of this miRNA in CAF-educated monocytes and their exosomes. We further clarified that the pro-oncogenic effect of CAF-educated monocytes may depend in part on the exosomal transfer of miR-181a through modulating the PTEN/Akt signaling axis in BC cells. Conclusions Our findings established a connection between tumor stromal communication and tumor progression and demonstrated an inductive function for CAF-educated monocytes in BC cell progression. We also proposed a supporting model in which exosomal transfer of miR-181a from CAF-educated monocytes activates AKT signaling by regulating PTEN in BC cells. 

/pdf/monocytes-educated-by-cancer-associated-fibroblasts-secrete-1x34c8lt.pdf

Monocytes educated by cancer-associated fibroblasts secrete exosomal miR-181a to activate AKT signaling in breast cancer cells

Abstract Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis. 

Pre-metastatic niche: formation, characteristics and therapeutic implication

Gastric cancer (GC) with peritoneal metastases and malignant ascites continues to have poor prognosis. Exosomes mediate intercellular communication during cancer progression and promote therapeutic resistance. Here, we report the significance of exosomes derived from malignant ascites (EXOAscites) in cancer progression and use modified exosomes as resources for cancer therapy. EXOAscites from patients with GC stimulated invasiveness and angiogenesis in an ex vivo three-dimensional autologous tumor spheroid microfluidic system. EXOAscites concentration increased invasiveness, and blockade of their secretion suppressed tumor progression. In MET-amplified GC, EXOAscites contain abundant MET; their selective delivery to tumor cells enhanced angiogenesis and invasiveness. Exosomal MET depletion substantially reduced invasiveness; an additive therapeutic effect was induced when combined with MET and/or VEGFR2 inhibition in a patient-derived MET-amplified GC model. Allogeneic MET-harboring exosome delivery induced invasion and angiogenesis in a MET non-amplified GC model. MET-amplified patient tissues showed higher exosome concentration than their adjacent normal tissues. Manipulating exosome content and production may be a promising complementary strategy against GC.

Patient-derived exosomes facilitate therapeutic targeting of oncogenic MET in advanced gastric cancer

Exosomes are produced by the majority of eukaryotic cells and are capable of transporting a variety of substances, including non-coding RNAs, between cells. Metastasis is a significant cause of death from cancer. Numerous studies have established an important role for exosomal non-coding RNAs in tumor metastasis. Exosomal non-coding RNAs from a variety of cells have been shown to affect tumor metastasis via several mechanisms. Exosomes transmit non-coding RNAs between tumor cells, fibroblasts, endothelial cells, and immune cells within the tumor microenvironment. Exosomal non-coding RNAs also have an effect on epithelial-mesenchymal transition, angiogenesis, and lymphangiogenesis. Exosomes derived from tumor cells have the ability to transport non-coding RNAs to distant organs, thereby facilitating the formation of the metastatic niche. Due to their role in tumor metastasis, exosomal non-coding RNAs have the potential to serve as diagnostic or prognostic markers as well as therapeutic targets for tumors. The purpose of this paper is to review and discuss the mechanisms of exosomal non-coding RNAs, their role in tumor metastasis, and their clinical utility, aiming to establish new directions for tumor metastasis, diagnosis, and treatment research. 

Exosomal non-coding RNAs have a significant effect on tumor metastasis

Acute inflammation and hyperuricemia are associated with gouty arthritis. As an edible and therapeutic mushroom, Sanghuangporus vaninii (SV) has an inhibitory effect on tumorigenesis, and Inonotus hispidus (IH) exhibits anti-tumor, anti-inflammatory, and antioxidant properties. In this study, uric acid (UA) and xanthine oxidase (XOD) levels in hyperuricemic mice were examined to determine the regulatory effects of SV and IH. SV and IH reversed the pathogenic state of elevated UA levels in the serum and reduced levels of XOD in the serum and liver of mice with hyperuricemia. SV and IH affected the inflammatory response in rats with acute gouty arthritis. Compared to vehicle-treated rats, monosodium urate crystals (MSU) increased the swelling ratio of the right ankle joints. SV and IH administration significantly reduced swelling and inflammatory cell infiltration. SV reduced the levels of interleukin-8 (IL-8) and chemokine ligand-2 (CCL-2), whereas IH reduced the levels of matrix metalloproteinase-9 (MMP-9), CCL-2, and tumor necrosis factor-α (TNF-α), which were confirmed in articular soft tissues by immunohistochemistry. In summary, our data provide experimental evidence for the applicability of SV and IH in gouty arthritis and hyperuricemia treatment.

/pdf/anti-gouty-arthritis-and-anti-hyperuricemia-properties-of-3dobk3sm.pdf

Anti-Gouty Arthritis and Anti-Hyperuricemia Properties of Sanghuangporus vaninii and Inonotus hispidus in Rodent Models

Invasion and metastasis are the leading causes of death of patients with CRC. 5‐Fluorouracil is widely used in clinic practice as the basic chemotherapy drug for CRC. However, it is inefficient in inhibiting tumor metastasis. MicroRNA‐10b is uninvolved in regulating the growth of primary tumors; however, it could induce early tumor metastases and is a key regulator of chemotherapeutic resistance to 5‐FU. A multifunctional nanovehicle that can carry small molecule drugs not only through the hydrophobic pockets of conjugated β‐cyclodextrin but also through electrostatic interaction between the conjugated peptides and siRNA to target functional genes is previously developed. In this study, a nanovehicle, named GCD, with epithelium growth factor receptor (EGFR)‐targeted characteristics to simultaneously deliver chemotherapeutic and nucleotide drugs to distinct targets in CRC, is employed. These data show that co‐delivery of 5‐FU and anti‐miR‐10b can be effectively applied to targeted therapy of EGFR‐overexpressed CRC, particularly inhibiting the metastasis of CRC. Furthermore, the therapeutic effect of this combination on tumor xenograft models derived from patients with CRC is evaluated. Taken together, this study may provide insights into the inhibition of tumor growth and metastasis simultaneously.

Enhancing the Management of Metastatic Tumors by Robust Co‐Delivery of 5‐Fluorouracil/MicroRNA‐10b Inhibitor Using EGFR‐Targeted Nanovehicles

[This corrects the article DOI: 10.7150/thno.52076.].

Co-delivery of 5-fluorouracil and miRNA-34a mimics by host-guest self-assembly nanocarriers for efficacious targeted therapy in colorectal cancer patient-derived tumor xenografts: Erratum

Thermal-assisted synthesis of ferulic acid-chitosan complex in water and its application as safe antioxidant.

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