Hepatic Metastasis Of Gastric Cancer Research Articles

Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53\u2013Bcl-2 intrinsic apoptosis pathway

BackgroundGastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies.MethodsWe performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients.ResultsEthanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis.ConclusionsUpregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53–Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.

Ginkgo Biloba Extract Inhibits Metastasis and ERK/Nuclear Factor kappa B (NF-κB) Signaling Pathway in Gastric Cancer.

BackgroundGinkgo biloba extract (EGb761), a standard extract of the Chinese traditional medicine Ginkgo biloba, plays an anti-tumor role in various cancers. However, whether EGb761 is involved in the invasion and metastasis of gastric cancer remains unclear.Material/MethodsIn the current study, cell viability assay, Western blotting, wound-healing assay, Transwell invasion assay, and orthotopic transplantation model were performed to explore the effects of EGb761 on gastric cancer.ResultsIn vitro, the results showed that EGb761 suppressed the proliferation of gastric cancer cells in a dose-dependent manner. Furthermore, the migration and invasiveness were weakened and the protein levels of p-ERK1/2, NF-κB P65, NF-κB p-P65, and MMP2 were decreased by EGb761 or U0126 (an inhibitor of ERK signaling pathway) exposure in gastric cancer cells. Moreover, the combined treatment with EGb761 and U0126 significantly inhibited ERK, NF-κB signaling pathway, and the expression of MMP2 than those of single drug. In vivo, EGb761 inhibited the tumor growth and hepatic metastasis of gastric cancer in the mouse model. Results of immunohistochemistry indicated that the expression of ERK1/2, NF-κB P65 and MMP2 were decreased by EGb761 in the tumor tissues.ConclusionsEGb761 plays a vital role in the suppression of metastasis and ERK/NF-κB signaling pathway in gastric cancer.

Gastric cancer with synchronous and metachronous hepatic metastasis predicted by enhancement pattern on multiphasic contrast-enhanced CT

ObjectiveThe purpose of this study was to examine the relationship between the CT features of the primary-site gastric cancer and the concurrent existence or postoperative recurrence of hepatic metastasis. Materials and methodsFrom January 2013 to July 2016, 125 patients with advanced gastric cancer who were evaluated by gastroscopy and contrast-enhanced CT at our institution were included. Eleven patients had hepatic metastasis at the time of diagnosis (synchronous hepatic metastasis). Five patients had hepatic recurrence after surgery (metachronous hepatic metastasis, median follow-up period of 313 days), and another 56 patients had no hepatic recurrence during follow-up period (negative hepatic metastasis, median follow-up period of 1102 days). Two radiologists independently reviewed the CT images and they determined the peak enhancement phase, and then measured the CT attenuation value of the gastric lesion for each phase. We compared the parameters of synchronous, metachronous and negative hepatic-metastasis. We calculated diagnostic performance of CT for diagnosing synchronous and metachronous hepatic metastasis. ResultsThe peak enhancement was significantly diff ;erent between the three groups for both readers (reader 1, p = 0.0001; reader 2, p = 0.0002). Most of the synchronous and metachronous hepatic metastasis had peak enhancement in the arterial or portal phase. The CT attenuation values of synchronous and metachronous hepatic metastasis were significantly higher than those of negative hepatic metastasis in the delayed phase according to both readers (reader 1, p = 0.0003; reader 2, p = 0.0002). In predicting synchronous hepatic metastasis using peak enhancement, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 72.7%, 89.3%, 57.1%, 94.3%, and 86.6% for reader 1, and 54.5%, 94.6%, 66.7%, 91.4%, and 88.1% for reader 2. In predicting metachronous hepatic metastasis, the sensitivity, specificity, PPV, NPV, and accuracy were 60.0%, 89.3%, 33.0%, 94.3%, and 86.9% for reader 1, and 40.0%, 94.6%, 40.0%, 94.6%, and 90.2% for reader 2. ConclusionOur study showed that gastric cancer with synchronous and metachronous hepatic metastasis tends to show early enhancement with a washout pattern on contrast-enhanced CT. This feature would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of gastric cancer.

SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells.

Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.

Identification of a novel molecule target for the diagnosis, prediction, and treatment of hepatic metastasis of gastric cancer.

53 Background: Hepatic metastasis of gastric cancer has become a growing issue, because effective treatment and specific biomarkers are not available. The aim of this study was to identify a molecule mediating hepatic metastasis, which serves as a diagnostic marker, and to determine its potential as a therapeutic target. Methods: Stable knockdown gastric cancer cells were established using genome editing technique and cell activities were compared to control cells in vitro and in vivo. Tissue expression levels of the candidate molecule were evaluated in 300 patients with gastric cancer and correlated to clinicopathological parameters including patterns of metastasis and recurrences. Results: Global expression analysis revealed that synaptotagmin VII (SYT7) was overexpressed in gastric cancer tissues with hepatic metastasis. Gastric cancer cell lines differentially expressed high levels of SYT7 that positively correlated with those of SNAI1 and TGFB3, and inversely with RGS2. Stable knockout of SYT7 inhibited the proliferation of gastric cancer cells, indicated by increased apoptosis, and decreased cell migration, invasion, and adhesion abilities. The tumorigenicity of SYT7 knockout cells was moderately reduced in a mouse subcutaneous model and more strikingly decreased in a hepatic metastasis model. The protein expression levels of BCL2 and HIF1A were decreased in tumors formed by SYT7 knockout cells, and SYT7 levels in primary gastric cancer tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. Conclusions: SYT7 serves as a target for treating hepatic metastasis of gastric cancer as well as a diagnostic tool.

Abstract 3112: Roles of asialoglycoprotein receptor 2 in gastric cancer progression

Abstract Background Hepatic metastasis and relapse contribute to the high incidence of gastric cancer (GC)-related fatalities, and represent a frequent and crucial problem for oncologists. Knowledge of the unique molecular attributes to hepatic metastasis will improve our understanding of the biology of metastatic GC and facilitate development of specific biomarkers and appropriate targeted therapies, leading to efficacious personalized treatment. Methods Transcriptome and bioinformatics analyses were conduct to identify a candidate molecule that specifically mediate hepatic recurrences of GC. Small interfering RNA (siRNA) experiments to determine the effect of knockdown on phenotype. Expression levels of the candidate molecule was determined in the gastric tissues of 200 patients with GC. Results Asialoglycoprotein receptor 2 (ASGR2), a membrane trafficking protein, was identified as a candidate biomarker specific to hepatic metastasis. Transcription levels of ASGR2 were differential among GC cell lines and increased compared to a control nontumorigenic epithelial cell line. Inhibiting ASGR2 expression decreased the invasion and migration abilities of GC cells. Increased expression of ASGR2 mRNA in GC tissues was significantly associated with lymphatic involvement, vessel invasion, advanced stage and hepatic metastasis. In patient subgroup of stage II GC, those with increased ASGR2 expression had significantly shorter overall and disease-free survival than those without. Conclusions ASGR2 may represent a biomarker for hepatic metastasis of GC and as a target for therapy. Citation Format: Haruyoshi Tanaka. Roles of asialoglycoprotein receptor 2 in gastric cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3112. doi:10.1158/1538-7445.AM2017-3112

Metastatic pathway-specific transcriptome analysis identifies MFSD4 as a putative tumor suppressor and biomarker for hepatic metastasis in patients with gastric cancer.

Gastric cancer (GC) with hepatic metastasis remains a fatal disease. Global expression profiling was conducted using tissues from patients who had GC with synchronous hepatic metastasis, and major facilitator superfamily domain containing 4 (MFSD4) was identified as a candidate biomarker for hepatic metastasis in GC. Functional and expression analyses of this molecule in GC cell lines and clinical samples were conducted. We analyzed MFSD4 expression, DNA methylation, and copy number. RNA interference experiments evaluated the effects of MFSD4 expression on cell phenotype and apoptosis. We analyzed tissues of 200 patients with GC to assess the diagnostic performance of MFSD4 levels for predicting hepatic recurrence, metastasis, or both. Differential expression of MFSD4 mRNA by GC cell lines correlated positively with the levels of NUDT13 and OCLN mRNAs and inversely with those of BMP2. Hypermethylation of the MFSD4 promoter was detected in cells with lower levels of MFSD4 mRNA. Inhibition of MFSD4 expression significantly increased the invasiveness and motility of GC cells but did not influence cell proliferation or apoptosis. MFSD4 mRNA levels in primary GC tissues were reduced in patients with concomitant hepatic metastasis or recurrence compared with those without. Low levels of MFSD4 mRNA in primary GC tissues were an independent risk factor of hepatic recurrence and metastasis. MFSD4 expression in gastric tissues may represent a useful biomarker for identification of patients at high risk for hepatic recurrence, metastasis, or both.

Hepatic Solitary Metastasis of Gastric Cancer: Radiofrequency

The prognosis of gastric cancer with hepatic metastasis is very poor, even though several treatment modalities exist, such as surgical resection. Indeed, a standard therapy has not been established in such patients. Recently, attempts were made to treat hepatic metastasis of gastric cancer with radiofrequency (RF), which was originally used in primary or metastatic liver cancer. RF has been reported to show similar survival compared to surgical resection and is emerging as a new treatment modality even though it is still not conclusive with respect to efficacy and safety due to the paucity of reports. A prospective study is warranted to evaluate the efficacy of RF in the treatment of gastric cancer with hepatic metastasis compared with conventional modalities.

Cellular adjustment of gastric cancer for hepatic metastasis in successive orthotopic implantation model

In order to examine the mechanisms of hepatic metastasis in gastric cancer, a repeated orthotopic implantation method was used in nude mice with YCC-16, which was isolated from the blood of a gastric cancer patient. This study compared the biological and cytogenetic phenotypes of the five cell lines, the parental YCC-16, the orthotopic primary S1L0 and the 3 subsequent liver metastatic clones of S1L1, S2L2 and S3L3. E-cadherin and DAG1 gene expression levels were measured using real-time PCR. The parental YCC-16 showed multiple metastases, whereas the liver metastatic clones metastasized to the liver only. The liver metastatic rate showed increased trend with subsequent passages (passage?: 2/5, 40%; passage?: 3/5, 60%; passage?: 4/5, 80%). Otherwise, the liver metastatic clones had phenotype with a higher motility than that of the cell line from the orthotopic primary tumor (S1L0), and clonogenecity increased with subsequent passages in liver metastatic cell lines. The five cell lines had similar and additional chromosomal abnormalities were found in the selected clones. The E-cadherin expression level was decreased in all of the five cell lines, which was comparable to the common chromosomal changes. YCC-16 presented the lowest DAG1 expression level while S1L0 presented the highest. In the liver metastatic clones, the DAG1 expression level increased gradually with passages. Both the genetic alteration and cellular adjustment to the microenvironment are required for hepatic metastasis in gastric cancer. This model offers an opportunity to study the mechanisms of a hepatic metastasis of gastric cancer at the genetic and cellular level.

Related factors and prognosis of hepatic metastasis and peritoneal dissemination in gastric cancer

To investigate the related factors and prognosis of peritoneal dissemination and hepatic metastasis in gastric cancer, and the impact of palliative surgery on the prognosis. The clinicopathologic and follow-up data of the patients with gastric carcinoma treated in our hospital from Aug. 1994 to Jul. 2005 were analyzed retrospectively. The clinicopathologic factors correlated with peritoneal dissemination included serosal penetration, whole stomach cancer, undifferentiated type, female and hepatic metastasis, while those correlated with hepatic metastasis included Borrmann IV, lymph node metastasis and peritoneal dissemination (P< 0.05). The postoperative one-year survival rate of the patients with hepatic metastasis (H group) were lower than that of the patients with peritoneal dissemination (P group)(P< 0.05). The one- year survival rate of the patients with peritoneal dissemination undergoing palliative resection was significantly higher than that of the patients undergoing by-pass operation or feeding neostomy, and exploratory laparotomy (P< 0.05), while there was no significant difference among the three groups of the patients with hepatic metastasis. The short-term prognosis of the patients with hepatic metastasis is poorer than that of the patients with peritoneal dissemination. Palliative resection could improve the short-term survival rate of the patients with peritoneal dissemination, while it had no significant impact on the survival rate of the patients with hepatic metastasis.

An optimal therapeutic expression level is crucial for suicide gene therapy for hepatic metastatic cancer in mice

The most serious problem in current gene therapy is discrepancies between experimental data and actual clinical outcomes, which may be due to insufficient analyses and/or inappropriate animal models. We have explored suicide gene therapy by using various clinically relevant animal models and doubt the clinical use of maximal suicide gene expression, which has been generally recommended. To explore this subject further, we studied what expression level of suicide gene and what promoter led to the maximal clinical benefit in the case of hepatic metastatic cancer in mice. Therapeutic and adverse side effects of 4 adenoviral vectors that express herpes simplex virus thymidine kinase (HSV-tk) under different promoters were scrupulously investigated in 2 mouse models of hepatic metastasis of gastric cancer that possess clinical characteristics. Surprisingly, increases in HSV-tk expression beyond a certain point, achieved by the Rous sarcoma virus long terminal repeat promoter, not only enhanced the adverse side effects of lethal hepatotoxicity and ganciclovir-independent cytotoxicity but also failed to further increase therapeutic potential. Moreover, the carcinoembryonic antigen (CEA) tumor-specific promoter, the therapeutic potential of which had been underestimated, was much more useful—even in the case of low CEA-producing cancer—than had been previously reported. In conclusion, the optimal therapeutic expression level of a suicide gene is a novel concept and a crucial factor for successful cancer gene therapy. The present results, which contradict those of previous studies, alert researchers about possible problems with ongoing and future clinical trials that lack this concept. (H EPATOLOGY 2003;37:155-163.)

Serum alpha-fetoprotein subfractions in hepatic malignancies identified by different reactivities with concanvalin A, lentil lectin or phytohemagglutinin-E

Using a modified method of concanavalin A (Con A), lentil lectin (LCH) or phytohemagglutinin-E (PHA-E) affinity crossed-line immunoelectrophoresis (ACIE), we studied alpha-fetoprotein (AFP) subfractions in 69 sera, including 58 from patients with primary liver cancer and 11 from patients with hepatic metastasis of gastric cancer. We found that Con A non-reactive subfraction (type b) or LCH weakly-reactive subfraction (type B) was more frequently detected in metastatic liver cancer, as compared with liver cancer hepatoma. The amount of Con A non-reactive subfraction (type b) or of PHA-E reactive subfraction (type X) was significantly higher in case of metastatic liver cancer than in primary liver cancer. Since different affinities between AFP and lectins are due to the microheterogeneity in AFP sugar chain, our findings suggest that AFP in primary liver cancer and metastatic liver cancer is glycosylated in a different manner. It is also indicated that different patterns of AFP subfractions identified by the combination of Con A, LCH or PHA-E ACIE facilitate a differential diagnosis of these hepatic malignancies.

Serum alpha-fetoprotein subfractions in patients with primary hepatoma or hepatic metastasis of gastric cancer.

Alpha-fetoprotein (AFP) subfractions were studied in 38 sera including 34 patients with primary hepatoma and 4 from patients with hepatic metastasis of gastric cancer. Fractionation of AFP was carried out by concanavalin A (Con A) or lentil lectin (LCH) crossed-line affinity immunoelectrophoresis. With use of Con A, fetal-liver-originated subfraction (peak a) was commonly found in both primary hepatoma and metastatic liver cancer, while yolk-sac-originated subfraction (peak b) was detected in 7 of 34 (20.6%) primary hepatomas and 4 of 4 (100%) metastatic liver cancers. With use of LCH, fetal-liver-originated subfractions (peaks A and/or C) were commonly found in both primary hepatoma and hepatic metastasis of gastric cancer, while yolk-sac-originated subfraction (peak B) was found only in metastatic liver cancer. These findings suggest that glycosylation of AFP in primary hepatoma differs from that in hepatic metastasis of gastric cancer. It is also suggested that AFP synthesized in hepatic cancers and fetal liver are differently glycosylated and AFP synthesis of hepatic malignancies are not always retrogenetically expressed, as in case of the fetal liver. Clinically, different patterns of AFP subfraction identified by Con A or LCH crossed-line affinity immunoelectrophoresis facilitate a differential diagnosis of primary hepatoma and hepatic metastasis of gastric cancer, in cases of elevated serum AFP levels. In the current study, attention was also given to the retrogenetic expression of AFP synthesis in hepatic metastasis of gastric cancer.