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Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.

Background: Gastrectomy remains the curative option in gastric cancer. However, the growing concern that preoperative waiting jeopardizes survival has not been fully addressed. The present population-based cohort study aimed to clarify the impact of preoperative waiting time (PreWT)., Methods: We included patients with clinical Stage II-III gastric cancer who received curative surgery from 2008 to 2017 of Taiwan Cancer Registry. PreWT was defined as the time from endoscopic diagnosis to surgery. The prognostic impact on overall survival (OS) was evaluated with Cox and restricted cubic spline regressions., Results: A total of 3059 patients with a median age of 68 years were evaluated. The median PreWT was 16 days (interquartile range, 11-24 days), and patients with a shorter PreWT were younger, had a more advanced disease and received adjuvant therapies. Despite a shorter OS occurring with prolonged PreWT (median OS by PreWT [days]: 7-13, 2.7 years; 14-20, 3.1 years; 21-27, 3.0 years; 28-34, 4.7 years; 35-31, 3.7 years; 42-48, 3.4 years; 49-118, 2.8 years; p = 0.029), the differences were not significant after adjustment. The Cox and restricted cubic spline regressions showed that prolonged PreWT was not a significant prognostic factor for OS (p = 0.719)., Conclusions: The population-based study suggests that a PreWT of 49-118 days does not independently correlate with a poor prognosis in Stage II-III gastric cancer. The study provides rationale for a window period for preoperative therapies and patient optimization., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We prepared three-dimensional (3-D) organoids of human stomach cancers and examined the correlation between the tumorigenicity and cytotoxicity of Helicobacter pylori ( H. pylori ). In addition, the effects of hepatoma-derived growth factor (HDGF) and tumor necrosis factor (TNFα) on the growth and invasion activity of H. pylori -infected gastric cancer organoids were examined. Cytotoxin-associated gene A (CagA)-green fluorescence protein (GFP)-labeled H. pylori was used to trace the infection in gastric organoids. The cytotoxicity of Cag encoded toxins from different species of H. pylori did not affect the proliferation of each H. pylori -infected cancer organoid. To clarify the role of HDGF and TNFα secreted from H. pylori -infected cancer organoids, we prepared recombinant HDGF and TNFα and measured the cytotoxicity and invasion of gastric cancer organoids. HDGF controlled the growth of each organoid in a species-specific manner of H. pylori , but TNFα decreased the cell viability in H. pylori -infected cancer organoids. Furthermore, HDGF controlled the invasion activity of H. pylori -infected cancer organoid in a species-dependent manner. However, TNFα decreased the invasion activities of most organoids. We found different signaling of cytotoxicity and invasion of human gastric organoids in response to HDGF and TNFα during infection by H. pylori . Recombinant HDGF and TNFα inhibited the development and invasion of H. pylori -infected gastric cancer differently. Thus, we propose that HDGF and TNFα are independent signals for development of H. pylori -infected gastric cancer. The signaling of growth factors in 3-D organoid culture systems is different from those in two-dimensional cancer cells.

Chemotherapy is generally considered as the main treatment for metastatic gastric adenocarcinoma. The role of gastrectomy for metastatic gastric cancer without obvious symptoms is controversial. The objective of this study is to investigate survival outcomes of treatment modalities using a real-world data setting. A retrospective cohort study was designed using the Taiwan Cancer Registry database. We identified the treatment modalities and used Kaplan-Meier estimates and Cox regressions to compare patient survival outcomes. From 2008 to 2015, 5599 gastric adenocarcinoma patients were diagnosed with metastatic disease (M1). The median overall survival (OS) of patients with surgery plus chemotherapy had the longest survival of 14.2 months. The median OS of the patients who received chemotherapy alone or surgery alone was 7.0 and 3.9, respectively. Age at diagnosis, year of diagnosis, tumor grade, and treatment modalities are prognostic factors for survival. The hazard ratios for patients who received surgery plus chemotherapy, surgery alone, and supportive care were 0.47 (95% CI 0.44-0.51), 1.22 (95% CI 1.1-1.36), and 3.23 (95% CI 3.01-3.46), respectively, by multivariable Cox regression analysis when using chemotherapy alone as a referent. Chemotherapy plus surgery may have a survival benefit for some selected gastric adenocarcinoma patients with metastatic disease., (© 2021. The Author(s).)

The dismal outcome in patients with locally advanced or metastatic gastric cancer (GC) highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1) and the clinical outcome of patients with locally advanced or metastatic GC treated with mFOLFOX-4 neoadjuvant chemotherapy. Fifty-eight patients with histologically confirmed locally advanced or metastatic GC following neoadjuvant mFOLFOX-4 chemotherapy were enrolled between January 2009 and January 2018. We analyzed clinicopathological features and ERCC1, ERCC2, and XRCC1 expression to identify potential predictors of clinical response. Among the 58 patients, 16 (27.6%) were categorized into the response group (partial response) and 42 into the nonresponse group (stable disease in 24 patients and progressive disease in 18 patients). A multivariate analysis showed that ERCC1 overexpression (P = 0.003), ERCC2 overexpression (P = 0.049), and either ERCC1 or ERCC2 overexpression (P = 0.002) were independent predictors of response following mFOLFOX-4 neoadjuvant chemotherapy. Additionally, ERCC1 and ERCC2 overexpression did not only predict the response but also progression-free survival (both P < 0.05) and overall survival (both P < 0.05). ERCC1 and ERCC2 overexpression are promising predictive biomarkers for patients with locally advanced or metastatic GC receiving neoadjuvant mFOLFOX-4 chemotherapy and the potential clinical implication is mandatory for further investigation.

Epidemiological studies demonstrate that the incidence and mortality of gastric cancer in women are lower than in men worldwide. Many studies have reported the delayed menopause and hormone replacement therapy are associated with a reduced risk for gastric cancer. It has been reported that endogenous estrogen lowers gastric cancer incidence in women, and cancer patients treated with estrogens have a lower subsequent risk of gastric cancer. It has been reported that estrogen decreases the progression of gastric cancer by inhibiting erbB-2 oncogene expression. Overexpression of estrogen receptor might inhibit the proliferation and invasion of MKN28 gastric cancer cells. Accumulating evidence suggests that bone marrow mesenchymal stem cells contribute to the progression of gastric cancer. However, it is unknown if 17β-estradiol (E2) treatment is sufficient to inhibit human bone marrow mesenchymal stem cells (HBMMSCs)-mediated cell motility in human gastric cancer cells. The results from human cytokine arrays have shown that HBMMSCs notably secrete interleukin 6 (IL-6) protein. Administration of IL-6-specific neutralizing antibody significantly inhibits HBMMSCs-mediated motility activity in human gastric cancer cells. Treatment of recombinant IL-6 soluble protein confirmed the role of IL-6 in mediating HBMMSCs-upregulated cell motility. IL-6 mainly upregulates motility activity via activation of Src signaling pathway in human gastric cancer cells. We further observed that E2 treatment inhibits HBMMSCs-induced cellular motility via suppressing the activation of IL-6-Src/Cas/paxillin signaling pathway in human gastric cancer cells. Collectively, these results suggest that E2 treatment significantly inhibits HBMMSCs-induced cellular motility in human gastric cancer cells., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Gender differences in terms of mortality among many solid organ malignancies have been proved by epidemiological data. Estrogen has been suspected to cast a protective effect against cancer because of the lower mortality of gastric cancer in females and the benefits of hormone replacement therapy (HRT) in gastric cancer. Hence, it suggests that 17β-estradiol (E2) may affect the behavior of cancer cells. One of the key features of cancer-related mortality is metastasis. Accumulating evidences suggest that human bone marrow mesenchymal stem cells (HBMMSCs) and its secreted CCL-5 have a role in enhancing the metastatic potential of breast cancer cells. However, it is not clear whether E2 would affect HBMMSCs-induced mobility in gastric cancer cells. In this report, we show that CCL-5 secreted by HBMMSCs enhanced mobility in human AGS gastric cancer cells via activation of Src/Cas/Paxillin signaling pathway. Treatment with specific neutralizing antibody of CCL-5 significantly inhibited HBMMSCs-enhanced mobility in human AGS gastric cancer cells. We further observe that 17β-estradiol suppressed HBMMSCs-enhanced mobility by down-regulating CCL5-Src/Cas/paxillin signaling pathway in AGS cells. Collectively, these results suggest that 17β-estradiol treatment significantly inhibits HBMMSCS-induced mobility in human AGS gastric cancer cells.

Gastric cancer is the fourth most common cancer globally, and is the second most common cause of death from cancer worldwide. About three-quarters of newly diagnosed cases in 2008 were from Asian countries. With a high mortality-to-incidence ratio, management of gastric cancer is challenging. We discuss evidence for optimum management of gastric cancer in aspects of screening and early detection, diagnosis, and staging; endoscopic and surgical intervention; and the concepts of perioperative, postoperative, and palliative chemotherapy and use of molecularly targeted therapy. Recommendations are formulated on the basis of the framework provided by the Breast Health Global Initiative, using the categories of basic, limited, enhanced, and maximum level. We aim to provide a stepwise strategy for management of gastric cancer applicable to different levels of health-care resources in Asian countries., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the optimal intervention point of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, for inhibiting Helicobacter pylori (H. pylori)-associated gastric carcinogenesis in Mongolian gerbils (MGs)., Methods: One hundred and twelve MGs were divided into six groups (A-F). One hundred gerbils were inoculated with H. pylori (groups A-E). Twelve gerbils were inoculated with vehicle broth only (group F). After 4 wk, they were given N'-methyl-N'-nitro-N-nitroso-guanidine (MNNG) (50 microg/mL) in the drinking water for 20 wk. In groups B-E, the animals were given the stock celecoxib (10 mg/kg per day) diet from the 21st, 31st, 21st and 41st week respectively. The periods of administering celecoxib were 30, 20, 20, and 15 wk respectively. On the 51st week, the animals were sacrificed for histological examination. Local PCNA expression was examined by the immunohistochemistry method. The expression of COX-2 protein was assessed by western blot. Analysis used the chi(2) test. The difference was regarded as significant when P value was less than 0.05., Results: Seventeen percent (17/100) of H. pylori-infected MGs developed gastric cancer. All of these lesions were well-differentiated adenocarcinoma. The incidence rates of adenocarcinoma in groups A-F were 40%, 0%, 0%, 20%, 25%, and 0% respectively. The inflammatory scores were higher in group B than in other groups. There was no inflammatory response noted in group F. Celecoxib treatment resulted in a significant reduction in the proliferation of H. pylori-infected mucosal cells (groups B, C and D) (P < 0.01). The expression of COX-2 protein was significantly attenuated in the groups which were celecoxib-treated for more than 20 wk (groups B, C, D). The groups treated with celecoxib had a significantly lower rate of advanced gastric cancer (34% vs 75%, P < 0.001) There were no sudden deaths in any of the groups., Conclusion: Short-term treatment with celecoxib has an anti-carcinogenic effect, and resulted in less severe inflammation and inhibited the invasive degree of gastric cancer.