Death In Gastric Cancer Patients Research Articles

Cause of death among gastric cancer survivors in the United States from 2000 to 2020.

A number of studies have been conducted to explore the survival of gastric cancer (GC) patients, while studies about non-cancer causes of death in patients with GC are not well-conducted. The aim of this study was to deeply investigate the causes of death (COD) in GC patients, especially non-cancer ones. The Surveillance, Epidemiology and End Results (SEER) database was used to extract information including demographics, tumor characteristics and causes of death of GC patients meeting the inclusion criteria. The patients were stratified by demographic and clinical parameters. Standardized mortality ratios (SMRs) were calculated for all causes of death at different follow-up periods. A total of 116,437 patients with GC diagnosed between 2000 and 2020 were retrieved from the SEER database. Of these, 85,827 deaths occurred during the follow-up period, most of which occurred within 1 year after GC diagnosis. GC (n = 49,746; 58%) was the leading COD, followed by other cancer (n = 21,135; 25%) and non-cancer causes (n = 14,946; 17%). Diseases of heart were the most common non-cancer cause of death, accounting for 30%, followed by cerebrovascular diseases (n = 917; 6%) and chronic obstructive pulmonary disease (n = 900; 6%). Although gastric cancer remains the most common cause of death in gastric cancer patients, it should not be ignored that the risk of non-cancer causes tends to increase with the length of the latency period. These findings may provide important insights into the healthcare management of gastric cancer patients at various follow-up intervals.

Cancer-associated fibroblast expression of glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a prognostic marker in gastric cancer.

Glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a rate-limiting enzyme in hexosamine biosynthesis involved in the occurrence and progress of many cancers. What role it plays in gastric cancer (GC) is still unclear. In this study, transcriptome sequencing data from the Harbin Medical University (HMU)-GC cohort and The Cancer Genome Atlas (TCGA) dataset were combined with the HMU-TCGA training cohort to analyze the biological function and clinical significance of GFPT2. The correlation of GFPT2 with immune cells and stromal cells was analyzed in the GC immune microenvironment through transcriptome sequencing data and a public single-cell sequencing database. In cell lines, GC tissues, and the tissue microarray, GFPT2 protein expression was confirmed by western blotting and immunohistochemistry. The mRNA of GFPT2 was highly expressed in the tumor (p < 0.001), and GC cells and tumors expressed high levels of GFPT2 protein. Compared to low expression, high GFPT2 mRNA expression was associated with higher levels of tumor invasion, higher pathological stages, and poor prognosis (p = 0.02) in GC patients. In a drug susceptibility analysis, GFPT2 mRNA expression was associated with multiple chemotherapeutic drug sensitivity, including docetaxel, paclitaxel, and cisplatin. Gene enrichment analysis found that GFPT2 was mainly primarily involved in the extracellular matrix receptor interaction pathway. The ESTIMATE, CIBERSORT, and ssGSEA algorithms showed that GFPT2 was associated with immune cell infiltration. In addition, GFPT2 was more likely to be expressed within cancer-associated fibroblasts (CAFs), and high levels of GFPT2 expression were highly correlated with four CAFs scores (all p < 0.05). Finally, a prognostic model to assess the risk of death in GC patients was constructed based on GFPT2 protein expression and lymph node metastasis rate. In conclusion, GFPT2 plays an essential role in the function of CAFs in GC. It can be used as a biomarker to assess GC prognosis and immune infiltration.

Development of a Signature Based on Eight Metastatic-Related Genes for Prognosis of GC Patients.

Gastric cancer (GC) has been a common tumor type with high mortality. Distal metastasis is one of the main causes of death in GC patients, which is also related to poor prognosis. The mRNA profiles and clinical information of GC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Univariate Cox and LASSO Cox analyses were used to screen the optimal metastasis-related genes (MRGs) to establish a prognostic Risk Score model for GC patients. The nomogram was used to visualize the Risk Score and predict the 1-, 3-, 5-year survival rate. The immune cell infiltration was analyzed by CIBERSORT and the ratio of immune-stromal component was calculated by the ESTIMATE algorithm. A total of 142 differentially expressed genes were identified between metastatic and non-metastatic GC samples. The optimal 8 genes, comprising GAMT (guanidinoacetate N-methyltransferase), ABCB5 (ATP-binding cassette subfamily B member 5), ITIH3 (inter-alpha-trypsin inhibitor heavy chain 3), GDF3 (growth differentiation factor 3), VSTM2L (V-set and transmembrane domain-containing 2 like), CIDEA (cell death inducing DFFA like effector a), NPTX1 (neuronal pentraxin-1), and UMOD (uromodulin), were further screened to establish a prognostic Risk Score, which proved to be an independent prognostic factor. Patients in high-risk group had a poor prognosis. There were significant differences in the proportion of 11 tumor-infiltrating immune cells between high-risk and low-risk subgroups. In addition, the StromalScore, ImmuneScore, and ESTIMATEScore in high-risk group were higher than those in low-risk group, indicating that the tumor microenvironment of the high-risk group was more complex. A Risk Score model based on eight metastasis-related genes could clearly distinguish the prognosis of GC patients. The poor prognosis of patients with high-Risk Score might be associated with the complex tumor microenvironments.

MAPK4 silencing in gastric cancer drives liver metastasis by positive feedback between cancer cells and macrophages

Liver metastasis is a major cause of death in gastric cancer patients, but the underlying mechanisms are poorly understood. Through a combination of in vivo screening and transcriptome profiling followed by quantitative RT-PCR and tissue array analyses, we found that mitogen-activated protein kinase 4 (MAPK4) downregulation in gastric cancer tissues from patients is significantly associated with liver metastasis and poor prognosis. The knockdown of MAPK4 in gastric cancer cells promotes liver metastasis in orthotopic mouse models. MAPK4 depletion in gastric cancer cells induces the secretion of macrophage migration inhibitory factor (MIF) to polarize tumor-associated macrophages (TAMs) in orthotopic xenograft tumors. Moreover, TAMs activate epithelial–mesenchymal transition of gastric cancer cells to suppress MAPK4 expression, which further increases MIF secretion to polarize TAMs. Taken together, our results suggest a previously undescribed positive feedback loop between cancer cells and macrophages mediated by MAPK4 silencing that facilitates gastric cancer liver metastasis.

Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters.

Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.

The correlation of serum sirt6 with clinical outcome and prognosis in patients with gastric cancer

We aimed to evaluate the correlation between serum sirtuin 6 (sirt6) level and clinicopathological characteristics and prognosis of gastric cancer (GC) patients. The serum sirt6 levels of subjects (135 cases of GC, 68 cases of atrophic gastritis, 60 cases of healthy controls) were analyzed by enzyme-linked immunosorbent assay. The predictive and prognostic values of sirt6 serum level for GC were determined by performing receiver operating characteristic curve (ROC), Kaplan-Meier analysis, as well as univariate and multivariate Cox regression, respectively. GC patients showed lower sirt6 serum levels than that of atrophic gastritis patients and healthy control. Taking the healthy control as a reference, the area under the ROC curve (AUC) of sirt6 serum level for diagnosing GC was 0.955 with a sensitivity of 91.85% and a specificity of 90.0%. Based on ROC analysis using atrophic gastritis as the state variable, serum sirt6 had a high diagnostic efficiency for GC (AUC = 0.754). Serum sirt6 was related to the clinicopathological features (tumor size, Lauren's classification, tumor node metastasis staging, lymph node metastasis) and overall survival (log-rank χ2 = 12.22, P < .001). The AUC of serum sirt6 predicting death in GC patients was 0.731. At the optimal cutoff value (16.83 ng/mL), the sensitivity and specificity of sirt6 were 59.57% and 79.55%, respectively. Moreover, lower sirt6 level as independent risk factor was revealed to affect prognosis of GC patients (P = .018). Serum sirt6 level was positively associated with the tumor stage and metastasis conditions, which could be served as diagnostic and predictive biomarkers in GC.

Abnormal phenotype of Nrf2 is associated with poor prognosis through hypoxic/VEGF-A-Rap1b/VEGFR2 pathway in gastric cancer.

Metastasis is the major cause of death in gastric cancer patients and altered expression of Nrf2 is associated with cancer development. This study assessed Nrf2 and HO-1 expression and hypoxia-induced Nrf2 expression in the promotion of metastatic potential of gastric cancer cells, the relationship of Rap1b and Nrf2 was also discussed. Nrf2 and HO-1 expression were significantly associated with clinicopathological characteristic and were independent prognostic predictors in gastric cancer patients. Hypoxia up-regulated the expression of Nrf2, HO-1 and HIF-1α, whereas knockdown of Nrf2 inhibited cell invasion capacity and reduced the expression of Nrf2, HO-1 and HIF-1α. Patients in the Rap1b (+) Nrf2 (+) group had worst overall survival compared with those from other groups. Knockdown of Rap1b and Nrf2 significantly inhibited cell invasion capacity in the common group compared with the other groups. Hypoxia or VEGF-A facilitated the nuclear translocation of Nrf2 through Rap1b or VEGFR2. Hypoxia or VEGF-A did not induce the phosphorylation of P-Erk1/2 and P-Akt after knockdown of Rap1b or VEGFR2. Hypoxia promoted the gastric cancer malignant behavior through the upregulation of Rap1b and Nrf2. Hypoxia/VEGF-A-Rap1b/VEGFR2 facilitated the nuclear translocation of Nrf2. Targeting Rap1b and Nrf2 may be a novel therapeutic strategy for gastric cancer.

Application of Parametric Shared Frailty Models to Analyze Time-to-Death of Gastric Cancer Patients.

Despite its declining incidence, gastric cancer (GC) is one of the world's leading malignancies and a major global health concern due to its high prevalence and fatality rate. Furthermore, it is the world's fourth most common cancer and the second leading cause of cancer death. Studying the determinants of time to death of gastric cancer patients will give clinicians more information to develop specific treatment plans, forecast prognosis, and track the progress of death cases. The application of the frailty model can help account for random variation in survival that may exist due to unobserved factors, as well as show the impact of latent factors on death risk. As a result, the purpose of this study was to assess the determinants of time to death of GC patients' by applying the parametric shared frailty models. The data for this study were obtained from gastric cancer patients admitted to the Tikur Anbesa Specialized Hospital, Addis Ababa, from January 1, 2015, to February 29, 2020. With the aim of coming up with an appropriate survival model that determines factors that affect the time to death of gastric cancer patients, various parametric shared frailty models were compared. In all of the frailty models, patient regions were used as a clustering variable. The current study implemented exponential, Weibull, log-logistic, and lognormal distributions for baseline hazard functions with gamma and inverse Gaussian's frailty distributions. The performance of all models was compared using the AIC and BIC criteria. R statistical software was used to conduct the analysis. A retrospective study was undertaken on a total of 407 gastric cancer patients under follow-up at Tikur Anbesa Specialized Hospital. Of all 407 GC patients, 56.3% died while the remaining 43.7% were censored. The patients' median time to death was 21.9months, with a maximum survival time of 49.6months. In the current study, the clustering effect was significant in modeling the time to death from gastric cancer. The Weibull model with inverse Gaussian frailty has the minimum AIC and BIC value among the candidate models compared. The dependency within the clusters for the Weibull-inverse Gaussian frailty model was [Formula: see text] (13.4%). According to the results of our best model (Weibull-inverse Gaussian), the sex of the patient, the smoking status, the tumor size, the treatment taken, the vascular invasion, and the disease stage was found to be statistically significant at an alpha = 0.05 significance level. Time to death of GC patient's data set was well described by the Weibull-inverse Gaussian shared frailty. Furthermore, Weibull baseline distribution best fits the GC data set as it enables proportional hazard and accelerated failure time model, for time to failure data. There is unobserved heterogeneity between clusters (patient regions), indicating the need to account for this clustering effect. In this study, survival time to death among GC patients was discovered to be small. Covariates like older age, being male, having higher (advanced) stage of GC disease (stage three and stage four), advanced tumor size, being smoker, infected by Helicobacter pylori, and existence of vascular invasion significantly accelerate the time to death of GC patients. In contrast, talking combination of more treatments prolongs the time to death of patients. To improve the health of patients, interventions should be taken based on significant prognostic factors, with special attention dedicated to patients with such factors to prevent GC death.

MiR-216b inhibits gastric cancer proliferation and migration by targeting PARK7.

Postoperative recurrence and metastasis of gastric cancer is still a difficult problem in medical field. About 60% of patients with advanced gastric cancer die from peritoneal metastasis, which has become one of the main causes of death of gastric cancer patients. To elucidate the molecular mechanism of peritoneal metastasis of gastric cancer can help us better early diagnosis and improve treatment measures. This project intends to validate the above hypothesis from three different levels of tissue, cell, and animal models by means of fluorescence quantitative PCR, Western blot, double Luciferase Report Analysis and immunohistochemical detection, and to further explore the molecular mechanism of peritoneal metastasis of gastric cancer. Our previous studies have shown that PARK7 promotes peritoneal metastasis of gastric cancer through PI3K/Akt signaling pathway, but its specific regulatory mechanism remains unclear. Our preliminary study showed that the expression of microRNA-216b in gastric cancer tissues with peritoneal metastasis was significantly lower than that in patients without peritoneal metastasis, while the expression of PARK7 was the opposite.

Peritoneal metastatic gastric carcinoma cells exhibit more malignant behavior when co-cultured with HMrSV5 cells.

Metastasis and recurrence are major causes of death in gastric cancer patients. Because there are no obvious clinical symptoms during the early stages of metastasis, we sought to isolate highly invasive metastatic gastric cancer cells for future drug screening. We first established a mouse model to observe gastric cancer metastasis in vivo. The incidence of peritoneal metastasis of gastric cancer was much higher than liver or lymph metastasis. Peritoneal metastatic and non-metastatic NUGC-4 cells were isolated from the mouse model. Cell proliferation was measured using CCK-8 assays, while migration and invasion were investigated in Transwell assays. Proteins involved in epithelial-mesenchymal transition were detected by Western blotting. Metastatic gastric carcinoma cells were more proliferative and invasive than primary NUGC-4 cells. The supernatants of metastatic gastric carcinoma cells notably altered the morphology of HMrSV5 peritoneal mesothelial cells and promoted their epithelial-mesenchymal transition. Moreover, primary or metastatic gastric cancer cells co-cultured with HMrSV5 cells markedly increased cancer cell proliferation and invasiveness. Moreover, peritoneal metastatic gastric carcinoma cells in the presence of HMrSV5 cells exhibited most malignant behaviors. Thus, peritoneal metastatic gastric carcinoma cells exhibited high capacities for proliferation and invasion, and could be used as a new drug screening tool for the treatment of advanced gastric cancer and peritoneal metastatic gastric cancer.

Long-term survival after surgical resection of locoregional gastric adenocarcinoma recurrence — a case report

Introduction. Recurrence is the leading cause of death of gastric cancer patients after curative resection. This report describes a 44-year-old woman with gastric adenocarcinoma and surgically resected locoregional recurrence, who has survived for more than 13 years after diagnosis. Case report. A 33-year-old woman was admitted to the Gastroenterology Clinic with an episode of epigastric pain and minor weight loss. Two years earlier she had been diagnosed with gastric adenocarcinoma G2 of the antrum, pT2N1M0 (IIA) stage. She had undergone total gastrectomy with D2 lymphadenectomy and Roux-en-Y anastomosis followed by postoperative chemotherapy. Further diagnostic investigation after two years revealed the presence of metastatic cancer in the gastric bed. An explorative laparotomy was performed, and the surgeons successfully excised the enlarged lymph node. Post-operative pathologic examination proved gastric cancer metastasis. Since April 2007 the patient has stayed recurrence-free, and there have been no signs of recurrence on either US or CT scan, as of April 2018. This patient represents a rare case of long-term survival of recurrent gastric adenocarcinoma successfully treated with surgery despite particularly poor prognosis. Conclusions. Surgery for gastric cancer recurrence is a valuable treatment in chosen patients, provided it is performed by a team of specialised surgeons.

Influence of TS (rs34743033) and RUNX1 (rs2014300) gene polymorphisms on survival outcomes of fluorouracil-based chemotherapy in Chinese advanced gastric cancer patients

BackgroundThis study aimed to explore the clinical correlation of single-nucleotide polymorphisms of thymidylate synthase (TS) and runt-related transcription factor 1 (RUNX1) in patients with postoperative stage II and III gastric cancer (GC).Patients and methodsSamples were obtained from 661 patients with postoperative stage II and III GC. TS (rs34743033) and RUNX1 (rs2014300) were genotyped in 261 patients who received postoperative basic platinum and fluorouracil chemotherapy regimens and 400 patients who did not accept chemotherapy.ResultsTS (rs34743033) variant genotypes significantly prolonged the median overall survival (OS) time compared to the patients who only received adjuvant chemotherapy (HR 1.604, 95% CI 1.068–2.410, p=0.021). Moreover, 3R/3R variant genotypes were demonstrated to have a positive effect on the OS of patients who received chemotherapy based on cisplatin (HR 1.754, 95% CI 1.041–2.954, p=0.031) compared to oxaliplatin. A stratification analysis indicated that 2R/3R and 2R/2R variant genotypes were associated with inferior survival in GC patients with intestinal-type tumors, tumor less than 5 cm in size, and poorly differentiated tumors (p<0.05). However, RUNX1 (rs2014300) AA genotypes markedly increased the risk of death in GC patients compared with the GG/GA genotypes (p=0.007), but no significant difference was observed between chemotherapy based on platinum. The stratification analysis showed that the GA/AA genotype was significantly associated with inferior survival in well to moderately differentiated tumors (HR 2.001, 95% CI 1.082–3.703, p=0.023).ConclusionThese preliminary results indicated that the two polymorphisms had a significant effect on postoperative adjuvant chemotherapy. TS (rs34743033) and RUNX1 (rs2014300) may be used as biomarkers to predict prognosis and select chemotherapy regimens in GC patients.

Benefit of Adjuvant Traditional Herbal Medicine With Chemotherapy for Resectable Gastric Cancer.

Introduction: Stomach cancer, historically, has a low survival rate advances in curative resection procedures. Objectives: To assess the potential benefits of traditional herbal medicines in conjunction with chemotherapy in postoperative gastric cancer patients in terms of overall survival and disease-free survival. Data Sources: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, a Chinese database (CNKI), a Korean database, a Japanese database, AMED, and CINAHL up to September 2016. We summarized survival data from all RCTs. Study Selection: All RCTs of oral traditional medicines for resectable gastric cancer compared with chemotherapy alone were eligible. Data Extraction: Thirteen eligible trials with survival data (1075 patients) were deemed eligible for inclusion. Results: There were 217 documented deaths of the 574 patients assigned to adjuvant traditional medicines groups and 319 documented deaths of the 501 patients assigned to the chemotherapy-only groups. Adjuvant traditional medicines were associated with a statistically significant benefit in terms of overall survival rate (hazard ratio = 0.56; 95% confidence interval = 0.47-0.66; P < .00001) and disease-free survival (hazard ratio = 0.54; 95% confidence interval = 0.43-0.66; P < .00001). Conclusion: Among the RCTs included, the inclusion of postoperative adjuvant traditional medicines was associated with reduced risk of death in gastric cancer patients, when survival rates were compared with the group of patients who received chemotherapy alone. However, most of the included studies utilized are thought to be of low quality, so it would certainly appear that more trials are both advisable and necessary to arrive at correct and convincing conclusions.

Clinicopathological significance of the microRNA-146a/WASP-family verprolin-homologous protein-2 axis in gastric cancer.

Gastric cancer (GC) is one of the most common malignancies, and cancer invasion and metastasis are the leading causes of cancer‐induced death in GC patients. WASP‐family verprolin‐homologous protein‐2 (WASF2), with a role controlling actin polymerization which is critical in the formation of membrane protrusions involved in cell migration and invasion, has been reported to possess cancer‐promoting effects in several cancers. However, data of WASF2's role in GC are relatively few and even contradictory. In this study, we analyzed WASF2 expression in GC tissues and their corresponding adjacent normal tissues. We found that WASF2 was upregulated in GC tissues and high level of WASF2 was associated with lymph node metastasis of GC. Through gain‐ and loss‐of‐function studies, WASF2 was shown to significantly increase GC cells migration and invasion, but had no effect on proliferation in vitro. Importantly, WASF2 was also found to enhance GC metastasis in vivo. Our previous research suggested that WASF2 was a direct target of microRNA‐146a (miR‐146a). Furthermore, we analyzed miR‐146a's level in GC tissues and their corresponding adjacent normal tissues. We found that miR‐146a was downregulated in GC tissues and low miR‐146a level was associated with advanced TNM stage and lymph node metastasis. The level of WASF2 in GC tissues was negatively correlated with miR‐146a expression and had inverse clinicopathologic features. The newly identified miR‐146a/WASF2 axis may provide a novel therapeutic target for GC.

Strategies of diagnosis and treatment for peritoneal metastasis of gastric cancer

Peritoneal metastasis of gastric cancer is the main cause of death in gastric cancer patients. Peritoneal metastasis of gastric cancer is difficult to diagnose in its early stage due to lack of obvious clinical signs and symptoms, and poor treatment outcomes and prognosis are often associated with late stage peritoneal metastasis. Therefore, it is crucial to utilize effective early diagnostic tools and to improve the long-term outcomes and the prognosis of patients with advanced gastric cancer. Recently, systemic chemotherapy and intraperitoneal chemotherapy are the first line therapy, and cytoreductive operation plus abdominal cavity thermochemotherapy may be the best method in the treatment of peritoneal metastasis. However, conversion therapy has been gradually incorporated into the treatment of peritoneal metastasis of gastric cancer because of the better efficacy and the higher survival.

Overexpression of ANXA3 is an independent prognostic indicator in gastric cancer and its depletion suppresses cell proliferation and tumor growth.

BackgroundGastric cancer (GC) is one of the most common malignancies worldwide. Tumour metastasis is one of the leading causes of death in GC patients. This study aims to investigate the significance of ANXA3 expression and the mechanism by which ANXA3 is involved in the epithelial–mensenchymal transition (EMT) of gastric cancer cells.ResultsOur results confirmed that ANXA3 was high expression at the mRNA and protein level in GC cancer tissues and the majority of GC cell lines. In clinicopathological analysis, we found that increased expression of ANXA3 in tumors was closely associated with a poor prognosis. Xogenous ANXA3 transduction promoted proliferation, clone formation, migration, and invasion. Small interfering RNA silencing of ANXA3 inhibited these processes. Silence of ANXA3 inhibited tumorigenicity in vivo. Additionally, ANXA3 expression is associated with the epithelial–mesenchymal transition.MethodsFirstly, we investigated the ANXA3 expression on mRNA and protein level with RT-PCR and Western blot. Secondly, 183 GC patients tissues were used the to evaluate the clinicopathological characteristics and prognosis through immunohistochemistry. Furthermore, The functions of ANXA3 were analyzed in the cell proliferation, Colony Formation, migration, invasion and apoptosis of GC cell lines.ConclusionsOur research suggests that ANXA3 plays important roles in gastric cancer carcinogenesis and metastasis, and provides a valuable prognostic marker and potential target for treatment of gastric cancer patients.

Intraperitoneal free cancer cells in gastric cancer: pathology of peritoneal carcinomatosis and rationale for intraperitoneal chemotherapy/hyperthermic intraperitoneal chemotherapy in gastric cancer.

Peritoneal carcinomatosis (PC) is one of the most common causes of death in gastric cancer patients. Intraperitoneal free cancer cells (IFCCs) play a very important role in forming PC, but the administration of intraperitoneal chemotherapy (IPC) and/or hyperthermic intraperitoneal chemotherapy (HIPEC) could be an effective treatment for IFCCs. This review focuses on the origin of IFCCs, the mechanism of PC formatting, the rationale of IPC/HIPEC, and the current clinical trials on IPC/HIPEC to treat advanced gastric cancer patients.

Surgery combined with chemotherapy for recurrent gastric cancer achieves better long-term prognosis

Recurrence is the most important factor associated with death of gastric cancer patients after surgery. The aim of this study was to explore the prognosis factors and the effective therapy for recurrent gastric cancer (RGC) patients after radical resection. The clinical data of 144 RGC patients who underwent radical resection from January 1999 to March 2004 were reviewed. The 15 clinicopathological factors and treatment modalities on the survival were analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of these factors for RGC. The early recurrence (<2years) was found in 90 patients, while late recurrence (≥2years) occurred in 54 patients. The 2-year cumulative survival rates were 23.8% for recurrent patients receiving chemotherapy plus surgery vs. 1.2% in patients having chemotherapy only (p<0.001), while the median survival time was 11.0months vs. 6.0months (p<0.001). Multivariate analysis indicated TNM stage after the first operation (p=0.048), iASPP overexpression (p=0.013), time to recurrence (p<0.001) and treatment of recurrence (p<0.001) as independent prognostic factors. Surgery combined with chemotherapy for recurrent gastric cancer patients achieves ideal long-term prognosis, which should perform actively.

Peritoneal milky spots serve as a hypoxic niche and favor gastric cancer stem/progenitor cell peritoneal dissemination through hypoxia-inducible factor 1α.

Peritoneal dissemination is the most common cause of death in gastric cancer patients. The hypoxic microenvironment plays a major role in controlling the tumor stem cell phenotype and is associated with patients' prognosis through hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor that responds to hypoxic stimuli. During the peritoneal dissemination process, gastric cancer stem/progenitor cells (GCSPCs) are thought to enter into and maintained in peritoneal milky spots (PMSs), which have hypoxic microenvironments. However, the mechanism through which the hypoxic environment of PMSs regulated GCSPC maintenance is still poorly understood. Here, we investigated whether hypoxic PMSs were an ideal cancer stem cell niche suitable for GCSPC engraftment. We also evaluated the mechanisms through which the HIF-1α-mediated hypoxic microenvironment regulated GCSPC fate. We observed a positive correlation between HIF-1α expression and gastric cancer peritoneal dissemination (GCPD) in gastric cancer patients. Furthermore, the GCSPC population expanded in primary gastric cancer cells under hypoxic condition in vitro, and hypoxic GCSPCs showed enhanced self-renewal ability, but reduced differentiation capacity, mediated by HIF-1α. In an animal model, GCSPCs preferentially resided in the hypoxic zone of PMSs; moreover, when the hypoxic microenvironment in PMSs was destroyed, GCPD was significantly alleviated. In conclusion, our results demonstrated that PMSs served as a hypoxic niche and favored GCSPCs peritoneal dissemination through HIF-1α both in vitro and in vivo. These results provided new insights into the GCPD process and may lead to advancements in the clinical treatment of gastric cancer. Stem Cells 2014;32:3062–3074

Transforming growth factor-beta1 signaling blockade attenuates gastric cancer cell-induced peritoneal mesothelial cell fibrosis and alleviates peritoneal dissemination both in vitro and in vivo

Peritoneal dissemination is the most frequent metastatic pattern of advanced gastric cancer and the main cause of death in gastric cancer patients. Transforming growth factor-beta1 (TGF- ß1), one of the most potent fibrotic stimuli for human peritoneal mesothelial cells, has been shown to play an important role in this process. In this study, we investigated the effect of TGF- ß1 signaling blockade in gastric cancer cell (GCC)-induced human peritoneal mesothelial cell (HPMC) fibrosis. HPMCs were cocultured with the high TGF- ß1 expressing GCC line SGC-7901 and various TGF- ß1 signaling inhibitors or SGC-7901 transfected with TGF-ß1-specific siRNA. HPMC fibrosis was monitored on the basis of morphology. Expression of the epithelial cell marker, E-cadherin, and the mesenchymal marker, α-smooth muscle actin (α-SMA), was evaluated by Western blotting and immunofluorescence confocal imaging. GCC adhesion to HPMC was also assayed. In nude mouse tumor model, the peritoneal fibrotic status was monitored by immunofluorescent confocal imaging and Masson's trichrome staining; formation of metastatic nodular and ascites fluid was also evaluated. Our study demonstrated that GCC expressing high levels of TGF-ß1 induced HMPC fibrosis, which is characterized by both upregulation of E-cadherin and downregulation of α-SMA. Furthermore, HPMC monolayers fibrosis was reversed by TGF- ß1 signaling blockade. In vivo, the TGF- ß1 receptor inhibitor SB-431542 partially attenuated early-stage gastric cancer peritoneal dissemination (GCPD). In conclusion, our study confirms the significance of TGFß1 signaling blockade in attenuating GCPD and may provide a therapeutic target for clinical therapy.