Mesenchymal Stem Cells Target Gastric Cancer and Deliver Epirubicin via Tunneling Nanotubes for Enhanced Chemotherapy.

BACKGROUND: A reduced effective local concentration significantly contributes to the unsatisfactory therapeutic results of epirubicin in gastric cancer. Mesenchymal stem cells exhibit targeted chemotaxis towards solid tumors and form tunneling nanotubes with tumor cells, facilitating the delivery of various substances. This study demonstrates the novelty of mesenchymal stem cells in releasing epirubicin into gastric cancer cells through tunneling nanotubes. OBJECTIVE: Epirubicin delivery to gastric cancer cells using mesenchymal stem cells Methods: In vitro transwell migration assays, live cell tracking, and in vivo targeting assays were used to demonstrate the chemotaxis of mesenchymal stem cells towards gastric cancer. We verified the targeted chemotaxis of mesenchymal stem cells towards gastric cancer cells and the epirubicin loading ability using a high-content imaging system (Equipment type:Operetta CLS). Additionally, tunneling nanotube formation and the targeted release of epirubicin-loaded mesenchymal stem cells co-cultured with gastric cancer cells through mesenchymal stem cell-tunneling nanotubes into gastric cancer cells was observed using Operetta CLS. RESULTS: Mesenchymal stem cells demonstrated targeted chemotaxis towards gastric cancer, with effective epirubicin loading and tolerance. Co-culturing induced tunneling nanotube formation between these cells. Epirubicin-loaded mesenchymal stem cells were released into gastric cancer cells through tunneling nanotubes, significantly increasing their non-viability compared to the negative control group (p < 0.05). CONCLUSIONS: We identified a novel approach for precisely targeting epirubicin release in gastric cancer cells. Therefore, mesenchymal stem cell-tunneling nanotubes could serve as a potential tool for targeted delivery of drugs, enhancing their chemotherapeutic effects in cancer cells.

A Novel Classification of Glioma Subgroup, Which Is Highly Correlated With the Clinical Characteristics and Tumor Tissue Characteristics, Based on the Expression Levels of Gß and Gγ Genes.

PURPOSE: Glioma is a classical type of primary brain tumors that is most common seen in adults, and its high heterogeneity used to be a reference standard for subgroup classification. Glioma has been diagnosed based on histopathology, grade, and molecular markers including IDH mutation, chromosome 1p/19q loss, and H3K27M mutation. This subgroup classification cannot fully meet the current needs of clinicians and researchers. We, therefore, present a new subgroup classification for glioma based on the expression levels of Gß and Gγ genes to complement studies on glioma and Gßγ subunits, and to support clinicians to assess a patient's tumor status. METHODS: Glioma samples retrieved from the CGGA database and the TCGA database. We clustered the gliomas into different groups by using expression values of Gß and Gγ genes extracted from RNA sequencing data. The Kaplan-Meier method with a two-sided log-rank test was adopted to compare the OS of the patients between GNB2 group and non-GNB2 group. Univariate Cox regression analysis was referred to in order to investigate the prognostic role of each Gß and Gγ genes. KEGG and ssGSEA analysis were applied to identify highly activated pathways. The "estimate" package, "GSVA" package, and the online analytical tools CIBERSORTx were employed to evaluate immune cell infiltration in glioma samples. RESULTS: Three subgroups were identified. Each subgroup had its own specific pathway activation pattern and other biological characteristics. High M2 cell infiltration was observed in the GNB2 subgroup. Different subgroups displayed different sensitivities to chemotherapeutics. GNB2 subgroup predicted poor survival in patients with gliomas, especially in patients with LGG with mutation IDH and non-codeleted 1p19q. CONCLUSION: The subgroup classification we proposed has great application value. It can be used to select chemotherapeutic drugs and the prognosis of patients with target gliomas. The unique relationships between subgroups and tumor-related pathways are worthy of further investigation to identify therapeutic Gßγ heterodimer targets.

Liposomal honokiol promotes hair growth via activating Wnt3a/ß-catenin signaling pathway and down regulating TGF-ß1 in C57BL/6N mice.

Liposomal honokiol isolated from the genus Magnolia has been found to have antiangiogenic, anti-inflammatory and antitumor properties. However, there has no report on its role in hair growth. Hair follicles are life-long cycled organelles that go through from anagen, catagen and telogen stages and are regulated by diverse signaling pathways, including Wnt/ß-catenin, Notch, Epidermal growth factor (EGF) and Sonic hegehog (SHH). Wnt signals are essential for the initiation of hair follicle placode development and a new potential target of hair loss treatment. This study was designed to investigate the effect of liposomal honokiol (Lip-honokiol) on inducing hair anagen. We identified the hair grew out in advance in the shaving area of C57BL/6N mice after the treatment of liposomal honokiol (Lip-honokiol) by daily abdominal injection. We first demonstrated that Lip-Honokiol activated the Wnt3a/ß-catenin pathway and downregulated the transforming growth factor-ß1 (TGF-ß1) to promote hair growth in mice via immunohistochemistry and immunofluorescence staining. These findings suggest that Lip-honokiol activated the Wnt/ß-catenin pathway and accelerated the transfer from the telogen to anagen stage and finally promoted the hair growth.

Liposomal honokiol inhibits glioblastoma growth through regulating macrophage polarization.

BACKGROUND: Glioblastoma is a type of aggressive brain tumor-related to infiltrating microglia/macrophages. Various studies have identified antitumor properties of a bioactive plant compound named honokiol, originating from the Magnolia species. This beneficial characteristic of honokiol has been discovered in many malignant tumors. METHODS: We investigated the molecular mechanisms behind the anti-glioma effects of liposomal honokiol (Lip-HNK) using qRT-PCR, Western blot, co-culture, and in vivo animal experiments. RESULTS: It was discovered that the expression of M1 markers such as CD11c, inducible nitric oxide synthase (iNOS), and major histocompatibility complex (MHC) II (IA/IE subregions) induced by lipopolysaccharide (LPS)/IFN-γ was increased by Lip-HNK, and M2 markers Arg1 and CD206 induced by interleukin (IL)-4 had reduced expression, thus inhibiting tumor cell growth through co-culture experiments. After Lip-HNK treatment, a considerable increase in signal transducer and activator of transcription 1 (STAT1) activation was observed, and in contrast, STAT6 activation was suppressed. STAT1 and STAT6 are the key signaling molecules mediating M1 and M2 polarization, respectively. Furthermore, the percentage of CD11c-positive M1 macrophages was increased by Lip-HNK in G422 xenograft mice, while Lip-HNK treatment reduced the CD206-positive M2 macrophage distribution in tumor tissues. These findings are consistent with the decline in tumor volume seen in mice treated with Lip-HNK. CONCLUSIONS: Lip-HNK inhibits the growth of glioblastoma by upregulating M1 macrophages and limiting M2 phenotypic macrophages.

Identification of Chaetocin as a Potent non-ROS-mediated Anticancer Drug Candidate for Gastric Cancer.

Chaetocin, a natural product extracted from Chaetomium species, possesses anticancer effects in several kinds of tumors. However, it remains unclear whether the potential indication for chaetocin could also include human gastric cancer. We found here that chaetocin induced caspase-dependent and -independent apoptosis in human gastric cancer cell lines, which greatly depended on BID-mediated AIF translocation. Despite not increasing the intercellular ROS levels in gastric cancer cells, chaetocin did cause a reduction in mitochondrial membrane potential probably through its regulation on the expression of Bcl-2 and BAX. Chaetocin could also induce autophagy in gastric cancer cells; blocking autophagy by chloroquine enhanced the cytotoxicity of chaetocin. Chaetocin was further found to suppress the growth of gastric cancer xenograft in nude mice. Therefore, our study provides first evidence that chaetocin has an anticancer efficacy against gastric cancer and the combined use of chaetocin with autophagy inhibitors may enhance the therapeutic effect for gastric cancer. As chronic and exorbitant ROS levels instigate drug resistance, chaetocin, which eradicates gastric cancer cells without increasing ROS levels, may initiate a new line of non-ROS-mediated anti-tumor strategy.

Exo70 is an independent prognostic factor in colon cancer.

Exo70, a key component of the Exocyst complex, plays important roles in human cancer progression beyond exocytosis. However, the expression of Exo70 and its prognostic value for patients with colon cancer has not been well investigated to date. In this study, we observed that the mRNA and protein levels of Exo70 were upregulated in 11 of 13 colon cancer tissues, compared with their normal counterparts, which was validated by immunohistochemical analysis in a tissue microarray containing 89 pairs of colon cancer tissues and the matched adjacent normal tissues. Statistical analysis revealed that Exo70 expression is positively correlated with tumor size, invasion depth, TNM stage and distant metastasis. Kaplan-Meier survival analysis showed that colon cancer patients with higher Exo70 expression have a poorer clinical outcome than those with lower Exo70 expression. Multivariate Cox regression analysis revealed that Exo70, age and distant metastasis were there independent prognostic factors for overall survival rate of colon cancer patients. Through gain- and loss of Exo70 in colon cancer cells, we found that Exo70 could enhance the migration ability of colon cancer cells. Taken together, our studies revealed that Exo70 might be a promising negative prognostic factor and a potential therapeutic target for colon cancer.