Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

The effects of traditional Chinese medicine and dietary compounds on digestive cancer immunotherapy and gut microbiota modulation: A review.

Digestive tract-related cancers account for four of the top ten high-risk cancers worldwide. In recent years, cancer immunotherapy, which exploits the innate immune system to attack tumors, has led to a paradigm shifts in cancer treatment. Gut microbiota modification has been widely used to regulate cancer immunotherapy. Dietary compounds and traditional Chinese medicine (TCM) can alter the gut microbiota and its influence on toxic metabolite production, such as the effect of iprindole on lipopolysaccharide (LPS), and involvement in various metabolic pathways that are closely associated with immune reactions. Therefore, it is an effective strategy to explore new immunotherapies for gastrointestinal cancer to clarify the immunoregulatory effects of different dietary compounds/TCMs on intestinal microbiota. In this review, we have summarized recent progress regarding the effects of dietary compounds/TCMs on gut microbiota and their metabolites, as well as the relationship between digestive cancer immunotherapy and gut microbiota. We hope that this review will act as reference, providing a theoretical basis for the clinical immunotherapy of digestive cancer via gut microbiota modulation.

Tumor-Targeted Polydopamine-Based Nanoparticles for Multimodal Mapping Following Photothermal Therapy of Metastatic Lymph Nodes.

Purpose: Lymphadenectomy with lymph node (LN) mapping is essential for surgical removal of solid tumors. Existing agents do not provide accurate multimodal mapping and antitumor therapy for metastatic LNs; therefore, we fabricated a polydopamine (PDA) nanoparticle (NP)-based tumor-targeted LN mapping agent capable of multimodal mapping and guided photothermal therapy (PTT) for metastatic LNs. Materials and Methods: PDA NPs modified with polyethylene glycol (PEG) were obtained by polymerization under alkaline conditions. The PEG-PDA NPs were loaded with the circular tripeptide Arg-Gly-Asp (cRGD) to achieve tumor-targeting capacity and with the fluorescent dye IR820 and magnetic resonance imaging (MRI) contrast Gd(NH2)2 for in situ detection. The resulting cRGD-PEG-PDA@IR820/Gd(NH2)2 (cRGD-PPIG) NPs were tested for their biosafety and metastatic LN mapping ability. They were drained specifically into LNs and selectively taken up by gastric MKN45 cells via αvß3 integrin-mediated endocytosis. Results: This phenomenon enabled MR/optical/near-infrared fluorescence multimodal metastatic LN mapping, guiding the creation of accurate and highly efficient PTT for gastric cancer metastatic LNs in mice. Conclusion: In summary, we fabricated tumor-targeted cRGD-PPIG NPs with MR/optical/near-infrared fluorescence multimodal metastatic LN mapping capacity for surgery and efficient PTT guidance post-surgery.

Graphene oxide (GO)-based nanosheets with combined chemo/photothermal/photodynamic therapy to overcome gastric cancer (GC) paclitaxel resistance by reducing mitochondria-derived adenosine-triphosphate (ATP).

BACKGROUND: Paclitaxel (PTX) has been suggested to be a promising front-line drug for gastric cancer (GC), while P-glycoprotein (P-gp) could lead to drug resistance by pumping PTX out of GC cells. Consequently, it might be a hopeful way to combat drug resistance by inhibiting the out-pumping function of P-gp. RESULTS: In this study, we developed a drug delivery system incorporating PTX onto polyethylene glycol (PEG)-modified and oxidized sodium alginate (OSA)-functionalized graphene oxide (GO) nanosheets (NSs), called PTX@GO-PEG-OSA. Owing to pH/thermal-sensitive drug release properties, PTX@GO-PEG-OSA could induced more obvious antitumor effects on GC, compared to free PTX. With near infrared (NIR)-irradiation, PTX@GO-PEG-OSA could generate excessive reactive oxygen species (ROS), attack mitochondrial respiratory chain complex enzyme, reduce adenosine-triphosphate (ATP) supplement for P-gp, and effectively inhibit P-gp's efflux pump function. Since that, PTX@GO-PEG-OSA achieved better therapeutic effect on PTX-resistant GC without evident toxicity. CONCLUSIONS: In conclusion, PTX@GO-PEG-OSA could serve as a desirable strategy to reverse PTX's resistance, combined with chemo/photothermal/photodynamic therapy.

Biodegradable hollow mesoporous organosilica nanotheranostics (HMON) for multi-mode imaging and mild photo-therapeutic-induced mitochondrial damage on gastric cancer.

BACKGROUND: CuS-modified hollow mesoporous organosilica nanoparticles (HMON@CuS) have been preferred as non-invasive treatment for cancer, as near infrared (NIR)-induced photo-thermal effect (PTT) and/or photo-dynamic effect (PDT) could increase cancer cells' apoptosis. However, the certain role of HMON@CuS-produced-PTT&PDT inducing gastric cancer (GC) cells' mitochondrial damage, remained unclear. Moreover, theranostic efficiency of HMON@CuS might be well improved by applying multi-modal imaging, which could offer an optimal therapeutic region and time window. Herein, new nanotheranostics agents were reported by Gd doped HMON decorated by CuS nanocrystals (called HMON@CuS/Gd). RESULTS: HMON@CuS/Gd exhibited appropriate size distribution, good biocompatibility, L-Glutathione (GSH) responsive degradable properties, high photo-thermal conversion efficiency (82.4%) and a simultaneous reactive oxygen species (ROS) generation effect. Meanwhile, HMON@CuS/Gd could efficiently enter GC cells, induce combined mild PTT (43-45 °C) and PDT under mild NIR power density (0.8 W/cm2). Surprisingly, it was found that PTT might not be the only factor of cell apoptosis, as ROS induced by PDT also seemed playing an essential role. The NIR-induced ROS could attack mitochondrial transmembrane potentials (MTPs), then promote mitochondrial reactive oxygen species (mitoROS) production. Meanwhile, mitochondrial damage dramatically changed the expression of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax). Since that, mitochondrial permeability transition pore (mPTP) was opened, followed by inducing more cytochrome c (Cyto C) releasing from mitochondria into cytosol, and finally activated caspase-9/caspase-3-depended cell apoptosis pathway. Our in vivo data also showed that HMON@CuS/Gd exhibited good fluorescence (FL) imaging (wrapping fluorescent agent), enhanced T1 imaging under magnetic resonance imaging (MRI) and infrared thermal (IRT) imaging capacities. Guided by FL/MRI/IRT trimodal imaging, HMON@CuS/Gd could selectively cause mild photo-therapy at cancer region, efficiently inhibit the growth of GC cells without evident systemic toxicity in vivo. CONCLUSION: HMON@CuS/Gd could serve as a promising multifunctional nanotheranostic platform and as a cancer photo-therapy agent through inducing mitochondrial dysfunction on GC.

Hydrophobic IR780 loaded sericin nanomicelles for phototherapy with enhanced antitumor efficiency.

The near-infrared dye, IR780 iodide, has been utilized in photodynamic therapy (PDT) and photothermal therapy (PTT). However, the hydrophobicity and photosensitivity of IR780 limit its further applications in biomedical fields. Herein, the hydrophilic sericin was modified with hydrophobic cholesterol to form an amphiphilic macromolecular conjugate (Ser-Chol). The tumor-targeting agent, folic acid (FA), was further linked to the conjugate (FA-Ser-Chol). The IR780 could be encapsulated into such amphiphilic macromolecule to form stable micelles (FA-Ser-Chol/IR780) by self-assembly, and the solubility and photo-stability of IR780 were greatly improved. The FA-Ser-Chol/IR780 micelles could be efficiently absorbed by FA-positive gastric cancer cells (BGC-823) through FA receptors, while the uptake micelles showed remarkable PDT and PTT cytotoxicity towards BGC-823 cells under laser irradiation of 808 nm. Therefore, FA-Ser-Chol micelles may serve as a promising IR780 carrier for PDT and PTT therapy.

[Progress in prophylatic hyperthermic intraperitoneal chemotherapy for advanced gastric carcinoma].

Advanced gastric cancer (AGC) has a high recurrence rate (especially peritoneal relapse) and a poor prognosis. Systematic chemotherapy or targeted therapy have not been able to significantly reduce the major cause of an unfavorable prognosis, namely the high peritoneal AGC recurrence rate post-surgery. Further studies concerning the application of hyperthermic intraperitoneal chemotherapy (HIPEC) post curative surgery for AGC patients, namely the prophylactic HIPEC (P-HIPEC), have involved a prophylactic approach to prevent peritoneal relapse following curative gastrectomy in high-risk patients. Theoretically, breaking the "plasma-peritoneal barrier" increases cytotoxic chemotherapy activity via a synergistic hyperthermic effect; therefore, HIPEC can eradicate free cancer cells and micro-metastasis within the peritoneal cavity intraoperatively or soon after curative gastrectomy to reduce peritoneal recurrence. Many clinical trials have shown that P-HIPEC can reduce peritoneal recurrence and improve prognosis of AGC patients. However, some studies applying HIPEC at an early stage have revealed a high rate of complications that limited generalizability. This procedure has been increasingly adopted, given the complication rate has now been reduced and safety has been proven. Recently, for assessing the important role of HIPEC, many high-quality prospective randomized controlled clinical trials have been conducted to further investigate the best guidance for P-HIPEC and to demonstrate its effectiveness and safety with a higher grade of evidence. With theory development, the technique, equipment, and management of HIPEC and the role of P-HIPEC for AGC continues to evolve. This study summarizes the progress of P-HIPEC for high-risk AGC patients.

Survival benefit of gastrectomy for gastric cancer with peritoneal carcinomatosis: a propensity score-matched analysis.

Peritoneal carcinomatosis (PC) is the most frequent pattern of metastasis in stage IV gastric cancer (GC). The study aims to investigate the efficacy of gastrectomy in GC with PC. Clinicopathological data of 518 stage IV GC patients were retrospectively collected in Nanfang Hospital. Among all cases, 312 GC patients with PC (without other site of metastasis) were eligible. Univariate and multivariate analyses were performed to identify the independent prognostic factors. Propensity score matching analysis was performed to balance the characteristics and treatment-related factors. There was a significantly improved overall survival in gastrectomy group (148 patients) compared with nonresection group (164 patients) (P < 0.001). The 1-year and 2-year survival rates were 49.8% and 21.5% in gastrectomy group, whereas 28.8% and 9.7% in nonresection group, respectively. Further analysis showed that gastrectomy had also improved survival in P1 (P = 0.017) and P2 stage patients (P < 0.001), but not P3 stage (P = 0.495). The modality of gastrectomy plus chemotherapy plus hyperthermic intraperitoneal chemotherapy (HIPEC) showed an optimum survival. In addition, P3 disease, nongastrectomy, nonchemotherapy, non-HIPEC, and age ≥ 60 years were independently associated with poor survival. The gastrectomy plus chemotherapy plus HIPEC modality showed a significant survival benefit for gastric adenocarcinoma patients, particularly in those with P1 and P2 diseases.

Early generation of nitric oxide contributes to copper tolerance through reducing oxidative stress and cell death in hulless barley roots.

The objective of this study was to investigate the specific role of nitric oxide (NO) in the early response of hulless barley roots to copper (Cu) stress. We used the fluorescent probe diaminofluorescein-FM diacetate to establish NO localization, and hydrogen peroxide (H2O2)-special labeling and histochemical procedures for the detection of reactive oxygen species (ROS) in the root apex. An early production of NO was observed in Cu-treated root tips of hulless barley, but the detection of NO levels was decreased by supplementation with a NO scavenger, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO). Application of sodium nitroprusside (a NO donor) relieved Cu-induced root inhibition, ROS accumulation and oxidative damage, while c-PTIO treatment had a synergistic effect with Cu and further enhanced ROS levels and oxidative stress. In addition, the Cu-dependent increase in activities of superoxide dismutase, peroxidase and ascorbate peroxidase were further enhanced by exogenous NO, but application of c-PTIO decreased the activities of catalase and ascorbate peroxidase in Cu-treated roots. Subsequently, cell death was observed in root tips and was identified as a type of programed cell death (PCD) by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The addition of NO prevented the increase of cell death in root tips, whereas inhibiting NO accumulation further increased the number of cells undergoing PCD. These results revealed that NO production is an early response of hulless barley roots to Cu stress and that NO contributes to Cu tolerance in hulless barley possibly by modulating antioxidant defense, subsequently reducing oxidative stress and PCD in root tips.

Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: Relevance to therapy response.

AIM: To evaluate the epithelial-to-mesenchymal transition (EMT) of circulating tumor cells (CTCs) in gastric cancer patients. METHODS: We detected tumor cells for expression of four epithelial (E(+)) transcripts (keratins 8, 18, and 19 and epithelial cell adhesion molecule) and two mesenchymal (M(+)) transcripts (Vimentin and Twist) by a quantifiable, dual-colorimetric RNA-in situ hybridization assay. Between July 2014 and October 2014, 44 patients with gastric cancer were recruited for CTC evaluation. Blood samples were obtained from selected patients during the treatment course [before surgery, after surgery and at the 6(th) cycle of XELOX based chemotherapy (about 6 mo postoperatively)]. RESULTS: We found the EMT phenomenon in which there were a few biphenotypic E(+)/M(+) cells in primary human gastric cancer specimens. Of the 44 patients, the presence of CTCs was reported in 35 (79.5%) patients at baseline. Five types of cells including from exclusively E(+) CTCs to intermediate CTCs and exclusively M(+) CTCs were identified (4 patients with M(+) CTCs and 10 patients with M(+) or M(+) > E(+) CTCs). Further, a chemotherapy patient having progressive disease showed a proportional increase of mesenchymal CTCs in the post-treatment blood specimens. We used NCI-N87 cells to analyze the linearity and sensitivity of CanPatrol(TM) system and the correlation coefficient (R(2)) was 0.999. CONCLUSION: The findings suggest that the EMT phenomenon was both in a few cells of primary tumors and abundantly in CTCs from the blood of gastric cancer patients, which might be used to monitor therapy response.

Method of reconstruction governs iron metabolism after gastrectomy for patients with gastric cancer.

OBJECTIVE: Anemia after gastrectomy is commonly neglected by clinicians despite being an important and frequent long-term metabolic sequela. We hypothesized that the incidence and timing of the occurrence of iron deficiency after gastrectomy is closely associated with the extent of gastrectomy and the reconstruction method, and we investigated the treatment outcomes of iron supplementation to understand iron metabolism and determine the optimal reconstruction method after gastrectomy. PATIENTS AND METHODS: Using a prospective gastric cancer database, we identified 381 patients with early gastric cancer with complete hematologic parameters who underwent gastrectomy between January 2004 and May 2008. Kaplan-Meier methods, Cox regression, and logistic regression were used to evaluate the associations of the extent of gastrectomy and reconstruction method with iron metabolism. RESULTS: The prevalence of iron deficiency 3 years after gastrectomy was 69.1%, and iron-deficiency anemia was observed in 31.0% of patients. Iron deficiency developed in 64.8% and 90.5% of patients after distal gastrectomy and total gastrectomy within 3 years after surgery (P < 0.0001), respectively. Iron deficiency was significantly more frequent in women than in men (P < 0.0001) and after gastrojejunostomy than after gastroduodenostomy (P < 0.0001). Serum ferritin levels were different according to the extent of gastrectomy and reconstruction method. The proportion of patients treated for iron-deficiency anemia was also significantly different according to the extent of gastrectomy (P = 0.020). CONCLUSIONS: Iron deficiency occurs in most patients with gastric cancer after gastrectomy, and its incidence was different according to the extent of gastrectomy and reconstruction method. To improve iron metabolism after distal gastrectomy, gastroduodenostomy would be the method of reconstruction whenever possible.