• Artificial intelligence
• Colorectal cancer
• Diagnosis and management
• Immune checkpoint inhibitors
• Immunotherapy
• Signaling pathways

• Humans
• Colorectal Neoplasms/therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/diagnosis
• Animals
• Immunotherapy/methods
• Molecular Targeted Therapy
• Signal Transduction

Metastasis is a complicated process through which tumor cells disseminate to distant organs and adapt to novel tumor microenvironments. This multi-step cascade relies on the accumulation of genetic and epigenetic alterations within the tumor cells as well as the surrounding non-tumor stromal cells. Endothelial cells constitute a major player in promoting metastasis formation either by inducing the growth of tumor cells or by directing them towards dissemination in the blood or lymph. In fact, the direct and indirect interactions between tumor and endothelial cells were shown to activate several mechanisms allowing cancer cells’ invasion and extravasation. On the other side, gastrointestinal cancer development was shown to be associated with the disruption of the gut microbiome. While several proposed mechanisms have been investigated in this regard, gut and tumor-associated microbiota were shown to impact the gut endothelial barrier, increasing the dissemination of bacteria through the systemic circulation. This bacterial dislocation allows the formation of an inflammatory premetastatic niche in the distant organs promoting the metastatic cascade of primary tumors. In this review, we discuss the role of the endothelial cells in the metastatic cascade of tumors. We will focus on the role of the gut vascular barrier in the regulation metastasis. We will also discuss the interaction between this vascular barrier and the gut microbiota enhancing the process of metastasis. In addition, we will try to elucidate the different mechanisms through which this bacterial dislocation prepares the favorable metastatic niche at distant organs allowing the dissemination and successful deposition of tumor cells in the new microenvironments. Finally, and given the promising results of the studies combining immune checkpoint inhibitors with either microbiota alterations or anti-angiogenic therapy in many types of cancer, we will elaborate in this review the complex interaction between these 3 factors and their possible therapeutic combination to optimize response to treatment.

• angiogenesis
• endothelial cells
• gastrointestinal tract
• immunotherapy
• metastasis
• microbiota

• gastric adenocarcinoma
• aspirin
• helicobacter pylori
• chemoprevention
• cox-2
• prospective study

• Adenocarcinoma/drug therapy
• Adenocarcinoma/epidemiology
• Adenocarcinoma/prevention & control
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Aspirin/therapeutic use
• Female
• Follow-Up Studies
• Humans
• Male
• Proportional Hazards Models
• Prospective Studies
• Risk Factors
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/prevention & control

• P01 CA087969 NCI NIH HHS
• U01 CA167552 NCI NIH HHS
• UM1 CA186107 NCI NIH HHS
• K07 CA218377 NCI NIH HHS
• UM1 CA167552 NCI NIH HHS
• R35 CA253185 NCI NIH HHS

Chronic atrophic gastritis (AG) with intestinal metaplasia (IM) significantly increases the risk of gastric cancer. Some medicines have showed definite therapeutic effects in AG and IM regression.

To validate the efficacy of Lamb’s tripe extract and vitamin B₁₂ capsule (LTEVB₁₂) initial therapy and celecoxib rescue therapy for IM and AG.

A total of 255 patients were included to receive LTEVB₁₂ initial therapy (2 capsules each time, three times daily for 6 mo) in hospital in this study. The patients with failure of IM regression continued to receive celecoxib rescue therapy (200 mg, once daily for 6 mo). After each therapy finished, the patients underwent endoscopy and biopsy examination. The regression efficiency was assessed by the operative link on gastritis assessment (OLGA) and the operative link on the gastric intestinal metaplasia assessment (OLGIM) staging system. Logistic regression analysis was applied to identify factors associated with the curative effect.

For LTEVB₁₂ initial therapy, the reversal rates of IM and AG were 52.95% and 48.24%, respectively. Analogously, for celecoxib rescue therapy, the effective rates for IM and AG were 56.25% and 51.56%, respectively. The IM regression rate of complete therapy was up to 85.03%. In different OLGA and OLGIM stages of IM patients, therapeutic efficiency showed a significant difference in each group (P < 0.05). For both therapies, patients with high stages (III or IV) of both the OLGA and OLGIM evaluation systems showed a higher IM or AG regression rate than those with low stages (I or II). Among patients with high stages (OLGIM III and IV), the IM regression rate was above 70% for each therapy. Eating habits, fresh vegetable intake, and high-salt diet were identified as independent factors for the IM reversal effect of LTEVB₁₂ therapy, especially high-salt diet (odds ratio = 1.852, P < 0.05).

Monotherapy could reverse IM and AG. LTEVB₁₂ initial therapy and celecoxib rescue therapy significantly increase the regression effect. IM may not be the point of no return among gastric precancerous lesions.

• Atrophy gastritis
• Intestinal metaplasia
• Celecoxib
• Stomach neoplasms
• Operative link on the gastric intestinal metaplasia assessment
• Operative link on the gastritis assessment

Patients with precancerous gastric conditions are at a high risk for gastric carcinoma. The Chinese medicine Weifuchun (WFC) is used in treating chronic superficial gastritis and in postoperative adjuvant treatment of gastric cancer. Both monotherapy and combination therapy of WFC with other drugs can result in a favorable therapeutic outcome. WFC can dramatically improve clinical outcomes in patients with gastric precancerous lesions by targeting multiple pathways including pathways involved in the pharmacological action of Radix Ginseng Rubra (red ginseng), Rabdosia amethystoides, and fried Fructus Aurantii, including regulation of NF-κB, RUNX3/TGF-beta/Smad, Hedgehog (Hh) and Wnt signaling pathways, modulation of the expression of oncogenes and tumor suppressor genes, and indirect inhibition of Helicobacter pylori (Hp) by maintaining gastric microbial ecosystem. In this review, we will discuss the clinical efficacy and therapeutic regimen of WFC for gastric precancerous lesions and the molecular mechanisms involved. This review will highlight WFC-based therapeutic strategies in disrupting progress to gastric cancer and provide more information on the pharmacological mechanisms of WFC and its clinical application for the treatment of precancerous gastric lesions.

• Weifuchun
• efficacy
• gastric microbial ecosystem
• gastric precancerous lesions
• molecular mechanism

To research the molecular mechanism of ghrelin in apoptosis, migratory, and invasion of gastric cancer (GC) cells.

After GC AGS cells were handled with ghrelin (10^–8 M), cyclooxygenase-2 inhibitor NS398 (100 μM), and Akt inhibitor perifosine (10uM), the rates of apoptosis were detected by TUNEL assay and flow cytometry assay. We assessed the expressions of PI3K, p-Akt, and COX-2 proteins by making use of Western blot analysis. The cell migratory and invasion were detected by using wound-healing and transwell analysis.

The migratory and invasion were increased in ghrelin-treated cells, while the rates of apoptosis were decreased. GC AGS cells treated with ghrelin showed an increase in protein expression of p-Akt, PI3K, and COX-2. After cells were treated with Akt inhibitor perifosine, the protein expression of p-Akt, PI3K, and COX-2 and the cell migratory, invasion, and apoptosis were partly recovered. After cells were treated with cyclooxygenase-2 inhibitor NS398, the protein expression of COX-2 and the cell migratory and invasion were decreased, while the rates of apoptosis were increased.

Ghrelin regulates cell migration, invasion, and apoptosis in GC cells through targeting PI3K/Akt/COX-2. Ghrelin increases the expression of COX-2 in GC cells by targeting PI3K/Akt. Ghrelin is suggested to be one of the molecular targets in GC.

• Atrophic gastritis
• Gastric cancer
• Intestinal metaplasia
• Prevention
• Surveillance

• endoscopy
• gastric adenocarcinoma
• gastric pre-cancer
• gastritis
• helicobacter pylori-gastritis

• Adenocarcinoma/diagnosis
• Adenocarcinoma/microbiology
• Adenocarcinoma/surgery
• Biomarkers, Tumor/blood
• Disease Management
• Disease Progression
• Early Detection of Cancer/methods
• Evidence-Based Medicine/methods
• Gastritis, Atrophic/diagnosis
• Gastritis, Atrophic/microbiology
• Gastritis, Atrophic/surgery
• Gastroscopy/methods
• Helicobacter Infections/complications
• Helicobacter Infections/drug therapy
• Helicobacter pylori
• Humans
• Precancerous Conditions/diagnosis
• Precancerous Conditions/microbiology
• Precancerous Conditions/surgery
• Risk Assessment/methods
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/surgery

• DNA repair
• Genomic instability
• Helicobacter pylori
• Oxidative stress
• Stem cells

• Gastric intestinal metaplasia
• Helicobacter pylori
• gastric cancer surveillance
• intestinal-type gastric cancer
• serologic biopsy
• spasmolytic polypeptide-expressing metaplasia

• Angiogenesis
• Cancer
• Gastritis
• IBD
• Microbiota
• Ulcer

To investigate the role of miR-21 in cyclooxygenase-2 inhibitor NS398-induced apoptosis and invasion in gastric cancer (GC) cells.

AGS cells were treated with NS398 and transfected with miR-21. Quantitative real-time polymerase chain reaction was used to measure miR-21 mRNA expression. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and flow cytometric analysis. The protein expression of cleaved caspase-3, Bcl-2, Bax, Bak, and PTEN was detected by Western blot. The capacities for invasion and migration were measured by transwell and wound-healing assays, respectively.

Treatment of AGS cells with NS398 induced apoptosis in a dose-dependent manner accompanied by significant downregulation of miR-21 mRNA expression. Upregulation of miR-21 expression by transfection of miR-21 mimics into AGS cells blocked NS398-induced apoptosis. Treatment of AGS cells with NS398 induced changes in Bcl-2 protein family members, showing an increase in the protein expression of Bax, Bak, and PTEN, with a concomitant decrease in the protein expression of Bcl-2. In cells transfected with miR-21 mimics, these changes were reversed. The decrease in cellular invasiveness and migration induced by NS398 was blocked by upregulation of miR-21.

miR-21 mediates anticancer effects of NS398 in GC cells by regulating apoptosis-related proteins. miR-21 is one of the molecular targets of this specific cyclooxygenase-2 inhibitor in the prevention and treatment of GC.

• apoptosis
• cyclooxygenase 2 inhibitors
• gastric cancer cells
• stomach neoplasms

Helicobacter pylori colonizes not only on the surface of mucous membrane, but also beneath the surface mucous gel layer (SMGL). As diclofenac Na decreases the secretion of SMGL, in this study we examined this drug as an adjuvant therapy to a quadruple therapy for H. Pylori eradication.

One hundred and seventy-two patients were randomly assigned to three groups. Fifty four patients received quadruple therapy, that is, azithromycine 250 mg, amoxicillin 500 mg, bismuth subcitrate 240 mg, and omeprazole 20 mg bid for 1 week (group A) and 65 patients received the same dosage of those agents plus diclofenac Na tab, 100 mg daily for 1 week (group B). Sixty two patients received the quadruple therapy for 2 weeks (group C). Eradication of the infection was assessed 4-6 weeks after completion of treatment by stool antigen assay for H. pylori.

While the rate of H. pylori eradication in the groups A and B was 66.7% and 82.1%, respectively (P = 0.062), the rate of H. pylori eradication in groups B and C were 82.1% and 82.3% respectively (P = 0.987).

It seems that diclofenac Na can shorten anti-H. pylori regimens for 1 week. More investigations are needed for more clarification of the efficacy of NSAIDs for successful eradication of H. pylori. (IRCT code: IRCT201204059256N2)

• Diclofenac Na
• Helicobacter pylori
• eradication

• Adult
• Aged
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Celecoxib
• Cyclooxygenase 2/metabolism
• Down-Regulation/drug effects
• Drug Synergism
• Helicobacter Infections/metabolism
• Helicobacter Infections/pathology
• Helicobacter pylori
• Humans
• Lewis Blood Group Antigens/immunology
• MAP Kinase Signaling System/drug effects
• Middle Aged
• Pyrazoles/therapeutic use
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Ulcer/metabolism
• Stomach Ulcer/microbiology
• Stomach Ulcer/pathology
• Sulfonamides/therapeutic use
• Treatment Outcome
• Tumor Cells, Cultured

Although the incidence of gastric cancer has been declining in recent decades, it remains a major public health issue as the second leading cause of cancer death worldwide. In China, gastric cancer is still the main cause of death in patients with malignant tumors. Most patients are diagnosed at an advanced stage and mortality is high. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer. The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated. Helicobacter pylori infection, tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer. The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells, while inhibiting apoptosis, assisting angiogenesis and lymphatic metastasis, and participating in cancer invasion and immunosuppression. This review is intended to discuss, comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression, and elucidate the molecular mechanisms which might be involved in the carcinogenesis.

• Cyclooxygenase-2
• Gastric cancer
• Prostagladin
• Carcinogenesis
• Molecular mechanism

• Animals
• Biomarkers, Tumor/metabolism
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Cyclooxygenase 2/metabolism
• Disease Progression
• Humans
• Incidence
• Prognosis
• Risk Factors
• Signal Transduction
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/epidemiology
• Stomach Neoplasms/immunology
• Stomach Neoplasms/pathology

• Base Sequence
• Blotting, Western
• Celecoxib
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Cyclooxygenase 2 Inhibitors/pharmacology
• DNA Primers
• Disease Progression
• Down-Regulation
• Humans
• Immunohistochemistry
• In Situ Hybridization
• MicroRNAs/drug effects
• MicroRNAs/metabolism
• Oligonucleotide Array Sequence Analysis
• Pyrazoles/pharmacology
• Real-Time Polymerase Chain Reaction
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Sulfonamides/pharmacology

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Line, Tumor
• Cyclooxygenase 2/genetics
• Cyclooxygenase 2/metabolism
• Cyclooxygenase 2 Inhibitors/pharmacology
• Cyclooxygenase 2 Inhibitors/therapeutic use
• Disease Models, Animal
• Gene Expression
• Humans
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/pathology

Gastric cancer remains the second most frequent cause of cancer-related mortality in the world. Screening programs in some Asian countries are impractical in the majority of other countries worldwide. Therefore, follow-up of precancerous lesions is advisable for secondary gastric cancer prevention. Intestinal metaplasia (IM) is recognized as a precancerous lesion for gastric cancer, increasing the risk by 6-fold. IM is highly prevalent in the general population, being detected in nearly 1 of every 4 patients undergoing upper endoscopy. The IM prevalence rate is significantly higher in patients with Helicobacter pylori (H. pylori) infection, in first-degree relatives of gastric cancer patients, in smokers and it increases with patient age. IM is the “breaking point” in the gastric carcinogenesis cascade and does not appear to regress following H. pylori eradication, although the cure of infection may slow its progression. Gastric cancer risk is higher in patients with incomplete-type IM, in those with both antral and gastric body involvement, and the risk significantly increases with IM extension over 20% of the gastric mucosa. Scheduled endoscopic control could be cost-effective in IM patients, depending on the yearly incidence of gastric cancer in IM patients, the stage of gastric cancer at diagnosis discovered at surveillance, and the cost of endoscopy. As a pragmatic behavior, yearly endoscopic control would appear justified in all IM patients with at least one of these conditions: (1) IM extension > 20%; (2) the presence of incomplete type IM; (3) first-degree relative of gastric cancer patients; and (4) smokers. In the remaining IM patients, a less intensive (2-3 years) could be proposed.

• Intestinal metaplasia
• Gastric cancer
• Follow-up
• Prevention
• Risk factors

AIM: To perform a proteomic investigation of the effect of celecoxib on Helicobacter pylori (H. pylori).

METHODS: Total proteins of untreated and celecoxib-treated H. pylori 26695 were extracted and separated by 2-dimensionals polyacrylamide gel electrophoresis (2-DE). Differential protein expression was detected using computer-assisted image analysis. Differential proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and matrix-assisted laser desorption/ionization time-of-flight-tandem mass spectrometry (MALDI-TOF-MS/MS). The levels of mRNA expression were measured by real-time polymerase chain reaction.

RESULTS: Seventeen differentially expressed spots were detected between untreated and celecoxib-treated H. pylori 26695. Seven spots were positively identified as three proteins: heat shock protein 60 (HSP60), elongation factor TU (EF-TU) and gamma-glutamyltranspeptidase (GGT). The protein expression of HSP60, GGT, and EF-TU, and mRNA expression of GGT and EF-TU were down-regulated (0.07 ± 0.06 vs 1.01 ± 0.16; 0.31 ± 0.13 vs 0.98 ± 0.01, both P < 0.05), while the mRNA expression of HSP60 was up-regulated in the presence of celecoxib (1.85 ± 0.26 vs 1.07 ± 0.27, P < 0.05).

CONCLUSION: Celecoxib could down-regulate the protein expression of HSP60, GGT and EF-TU and mRNA expression of GGT and EF-TU in H. pylori; however, the mRNA expression of HSP60 was up-regulated. These results suggest that celecoxib might interfere with the pathogenicity of H. pylori.

• Helicobacter pylori
• Celecoxib
• Proteomics

• Animals
• Humans
• Infections/complications
• Neoplasms/etiology
• Neoplasms/prevention & control

• cyclooxygenase-2
• chemoprevention
• helicobacter pylori
• mongolian gerbil

• Adenocarcinoma/chemically induced
• Adenocarcinoma/enzymology
• Adenocarcinoma/microbiology
• Adenocarcinoma/pathology
• Adenocarcinoma/prevention & control
• Animals
• Anticarcinogenic Agents/administration & dosage
• Celecoxib
• Cell Proliferation/drug effects
• Cyclooxygenase 2/metabolism
• Cyclooxygenase 2 Inhibitors/administration & dosage
• Disease Models, Animal
• Drug Administration Schedule
• Gastric Mucosa/drug effects
• Gastric Mucosa/enzymology
• Gastric Mucosa/microbiology
• Gastric Mucosa/pathology
• Gerbillinae
• Helicobacter pylori/pathogenicity
• Methylnitronitrosoguanidine
• Neoplasm Invasiveness
• Proliferating Cell Nuclear Antigen/metabolism
• Pyrazoles/administration & dosage
• Stomach Neoplasms/chemically induced
• Stomach Neoplasms/enzymology
• Stomach Neoplasms/microbiology
• Stomach Neoplasms/pathology
• Stomach Neoplasms/prevention & control
• Sulfonamides/administration & dosage
• Time Factors