[Show abstract][Hide abstract] ABSTRACT: Systemic chemotherapy is the key treatment for advanced gastric cancer. The benefit of adjuvant surgery following preoperative chemotherapy in gastric cancer with liver metastasis has not been well established.
Forty-nine gastric cancer patients diagnosed with synchronous liver metastasis initially treated with chemotherapy were categorized into the following two groups: surgery group: 25 patients who underwent gastrectomy and subsequently received postoperative chemotherapy and control group: 24 patients who received chemotherapy alone.
The median overall survival of patients in the surgery group and control group was 20.5 and 9.1 months, respectively, (P = 0.006). The median progression-free survival in the surgery group was 10.9 months, with statistical significance when compared with 5.0 months in the control group (P = 0.001). Multivariate analysis demonstrated that response to chemotherapy was the only independent factor in predicting prognosis. The survival of patients who achieved partial response (PR) was prolonged if they received adjuvant surgery (P = 0.024). No significant difference in the survival of patients underwent combined hepatic resection when compared with patients performed gastrectomy only.
For gastric cancer with synchronous liver metastasis, adjuvant gastrectomy followed by chemotherapy might be beneficial for survival comparing with chemotherapy alone, especially in patients response to initial preoperative chemotherapy.
World Journal of Surgical Oncology 07/2015; 13(1):212. DOI:10.1186/s12957-015-0627-1 · 1.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood.
We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants.
We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab.
Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options.
Journal of Translational Medicine 04/2015; 13(1). DOI:10.1186/s12967-015-0476-2 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Xenotransplantation of human cancers into immunodeficient mice is a very useful approach for studying human tumor biology. However, the occasional occurrence of lymphomagenesis in some mice can spoil the model and must be investigated in detail. We found that a high percentage (32.5%, 26/80) of cancer patient-derived xenografts (PDXs) resembled lymphoma in NOD/SCID mice. Of the 26 xenografts, 23 were human-derived expressing human CD45 (hCD45+) and proved to be of the B-cell subtype (CD3-/CD20+), and they were all positive for Epstein - Barr virus (EBV). The remaining 3 xenografts proved to be mouse-derived for both hCD45- and negative amplification of a human gene. The most interesting finding is that gastric cancer had much higher rates (24/126, 19.0%) of lymphoma formation in the PDX model than did colorectal cancer (1/43, 2.3%). Statistical analysis revealed that cancer type and inflammation in the parent tumor are significantly associated with lymphomagenesis. Further validation discovered lymphomagenesis by inoculating only gastritis mucosa. Therefore, our findings suggest that it is necessary to take precautions when directly xenografting cancer tissues with remarkable baseline inflammation, such as gastric cancer into immunodeficient NOD/SCID strains. Further, the established xenograft models should be validated by both leukocyte markers and human gene signatures.
[Show abstract][Hide abstract] ABSTRACT: There is a growing interest in integrating biomaterial repositories into larger infrastructures in order to meet research demands. However, even for a single hospital or institute, where both population-based and multiple disease-based biobanks have existed for a long time, the integration of existing separate biobanks into a virtual cancer biobank is still challenging. The guidelines and procedures for biobanking are varied and not universally enforced or followed in separate biobanks. Within the last 2 years, we initiated a project to establish a centralized biobank facility in a common storage environment. Analyzing the challenges and interests of stakeholders for the biobanks, a working group comprised of representatives from the central and separate banks, ethic committees, and research administration offices reached an agreement to implement a central facility by following the ISBER best practices for biobanking, and including regular project reviews by the ethical and scientific boards. Furthermore, by implementing a modified minimum information system with biobank data sharing, a network based intra-hospital virtual cancer bank was established to facilitate sharing information of samples held by separate banks. Meanwhile, this virtual biobank network, which has integrated patient information from hospital health care systems, will gradually integrate follow-up information from the cancer registry office and data from epidemiology studies, providing controlled access for sample providers and resource users. In the future, this infrastructure designed for a single hospital may be helpful for building a broader virtual network for data and specimen exchanges.
Biopreservation and Biobanking 02/2015; 13(1):43-48. DOI:10.1089/bio.2014.0086 · 1.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In big data era, researchers pay more attention to the correlation between biological information of patient samples and related clinical information of diseases. The large volume correlation analysis will help predict the initiation, development and outcome for specific diseases. Disease-related biobank is the core facility bridging the gap between the clinical information and biological information of the disease. The volume, diversity, and especially the quality, and standardization of sample and sample-related information will influence the outcome of big data prediction. Therefore, the establishment of quality management system, and implement of standard inspection and test method are very urgent for continuous improvement of biobanks.
[Show abstract][Hide abstract] ABSTRACT: Cytokines are soluble proteins that exert their functions by binding specific receptors. Many cytokines play essential roles in carcinogenesis and have been developed for the treatment of cancer. In this study, we identified a novel potential cytokine using immunogenomics designated colon-derived SUSD2 binding factor (CSBF), also known as chromosome 10 open reading frame 99 (C10orf99). CSBF/C10orf99 is a classical secreted protein with predicted molecular mass of 6.5 kDa, and a functional ligand of Sushi Domain Containing 2 (SUSD2). CSBF/C10orf99 has the highest expression level in colon tissue. Both CSBF/C10orf99 and SUSD2 are down-regulated in colon cancer tissues and cell lines with different regulation mechanisms. CSBF/C10orf99 interacts with SUSD2 to inhibit colon cancer cell growth and induce G1 cell cycle arrest by down-regulating cyclin D and cyclin-dependent kinase 6 (CDK6). CSBF/C10orf99 displays a bell-shaped activity curve with the optimal effect at ~10 ng/ml. Its growth inhibitory effects can be blocked by sSUSD2-Fc soluble protein. Our results suggest that CSBF/C10orf99 is a novel potential cytokine with tumor suppressor functions.
[Show abstract][Hide abstract] ABSTRACT: Although preclinical work with rapalogs suggests potential in the treatment of gastric cancer, they have been less successful clinically. In this study, we report the impact of the investigational drug PP242, a potent and selective small-molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis. The antiproliferative effect of PP242 was assessed using the Cell Counting Kit-8 assay. The migration and invasion potential were analyzed using wound-healing and transwell assays, respectively. The Matrigel capillary tube formation assay was performed to mimic in-vivo angiogenesis. Immunoblotting and immunofluorescence were used to observe protein levels and distribution of actin fibers. Finally, p-mammalian target of rapamycin (mTOR) expression was detected on gastric cancer tissues using immunohistochemistry. First, PP242 potently inhibited cell proliferation in gastric cancer cell lines and in human endothelial cells in vitro at the IC50 ranged from 50 to 500 nmol/l. Then, an inhibitory effect of PP242 on metastasis was observed in gastric cancer cell AGS, along with the cytoskeletal rearrangements and suppression of the phosphorylation of PI3K downstream factors including AKT, mTOR, and P70S6K. Furthermore, PP242 was found to decrease the tube formation and migration of human umbilical vein endothelial cells. Using immunohistochemistry, we found that p-mTOR staining was observed in 41.8% (82/196) of gastric cancer tissues and correlated with depth of mural invasion, lymph node metastasis, tumor node metastasis stage, and vascular invasion. These results show that PP242 suppresses cell proliferation and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway, which might be an effective novel therapeutic candidate against gastric cancer in the future.
[Show abstract][Hide abstract] ABSTRACT: To clarify the relationship between clinicopathological features and lymph node metastasis and to propose the potential indications of lymph node metastasis for prognosis in early gastric cancer (EGC) patients.
We retrospectively observed 226 EGC patients with lymph node resection, and analyzed the associations between lymph node metastasis and clinicopathological parameters using the chi-square test in univariate analysis and logistic regression analysis in multivariate analysis. Overall survival analysis was determined using the Kaplan-Meier and log-rank test. We conducted multivariate prognosis analysis using the Cox proportional hazards model.
Of all the EGC patients, 7.5% (17/226) were histologically shown to have lymph node metastasis. The differentiation, lymphovascular invasion and depth of invasion were independent risk factors for lymph node metastasis in EGC. The 5- and 10-year survival rates were significantly lower in patients with lymph node metastasis than in those without and the patients also had shorter progress-free survival time. Lymph node metastasis and tumor size were independent prognostic factors for EGC. The status of the lymph nodes was a significant factor in predicting recurrence or metastasis after surgery.
The undifferentiated carcinoma and lymphovascular and/or submucosal invasion were associated with a higher incidence of lymph node metastasis in EGC patients, whom need to perform subsequent D2 lymphadenectomy or laparoscopic lymph node dissection and more rigorous follow-up or additional chemotherapy/radiation after D2 gastrectomy for poor prognosis and high recurrence/metastasis rate.
Chinese Journal of Cancer Research 04/2014; 26(2):192-9. DOI:10.3978/j.issn.1000-9604.2014.04.06 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The programmed cell death-1 receptor/programmed cell death-1 ligand (PD-1/PD-L1) pathway plays a crucial role in tumor evasion from host immunity. This study was designed to evaluate the association between circulating PD-L1 expression and prognosis in patients with advanced gastric cancer.
Totally 80 advanced gastric cancer patients and 40 health controls from Beijing Cancer Hospital were enrolled in the present study. Circulating PD-L1 expression was tested by enzyme-linked immunosorbent assay (ELISA). The associations between the expression level of PD-L1 and clinicopathological features and prognosis were analyzed statistically.
Expression of PD-L1 in advanced gastric cancer patients was significantly up-regulated compared with health people (P=0.006). The expression of PD-L1 was significantly correlated with differentiation and lymph node metastasis (P=0.026 and P=0.041, respectively). Although we didn't find significant difference in all advanced gastric cancer patients with different PD-L1 expression, the adenocarcinoma patients with higher up-regulated PD-L1 expression had much better prognosis than low expression patients (65.6% vs. 44.7%, P=0.028).
PD-L1 was elevated in advance gastric cancer patients and may play an important role in tumor immune evasion and patients prognosis.
Chinese Journal of Cancer Research 02/2014; 26(1):104-11. DOI:10.3978/j.issn.1000-9604.2014.02.08 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Considerable concentrations of circulating nucleic acids have been reported in peripheral blood from cancer patients. These circulating nucleic acids bear a variety of tumor-specific information and potentially represent a stable source of non-invasive tumor biomarkers. The assessable genetic and epigenetic changes of circulating nucleic acids include DNA mutations, copy number alterations, abnormal methylation and disruption of microRNA. Such alterations reflecting molecular characteristics of tumor tissues, provide a new clue for noninvasive, real-time and monitoring test. In the present article, the main findings of research status related to the utility of circulating nucleic acids for early diagnosis, prognosis and monitoring of gastric cancer are reviewed. In addition, the advantage, the examination technique and the application prospection of circulating nucleic acids as tumor markers are also reviewed.
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 01/2014; 17(1):21-5.
[Show abstract][Hide abstract] ABSTRACT: To investigate the expression of serum endothelial cell specific molecule 1(ESM-1) in gastric cancer and to evaluate the effect of serum ESM-1 as a potential serum biomarker.
Serum ESM-1 was detected by enzyme-linked immunosorbent assay(ELISA) and CEA, CA19.9, CA72.4 were detected by electrochemiluminescence immunoassay(ECLIA) in 102 patients with gastric cancer preoperatively. At the same time, serum ESM-1, CEA, CA19-9, CA72-4 in 41 healthy adults volunteers were detected with the same method. In addition, the follow-up data of all the patients were collected.
Compared to healthy volunteers, the serum ESM-1 level in gastric cancer patients increased(P<0.01). The sensitivity and specificity of serum ESM-1 were 73.9% and 51.2% respectively. In contrast, the sensitivities of CEA, CA19-9 and CA72-4 were only 16.1%, 18.3% and 23.2% respectively. High level of serum ESM-1 indicated poor outcomes(P<0.05).
Serum ESM-1 increases in the peripheral blood of the gastric cancer patients. It may be a potential serum marker to help diagnosis and prediction of prognosis of gastric cancer patients.
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 01/2014; 17(1):51-5.
[Show abstract][Hide abstract] ABSTRACT: PRL-3 is a member of phosphatases of regenerating liver family, characterized by phosphatase active domain and C-terminal prenylation motif. Overexpression of PRL-3 has been implicated in multiple cancers. Here we examined the clinical significance of PRL-3 in gastric cancer together with its metastatic biological functions utilizing different structural mutants.
PRL-3 expression was analyzed immunohistochemically in 196 gastric cancer patients and 21 cases of liver metastasis. A series of wild type PRL-3 or its mutant plasmids were expressed in BGC823 cells to investigate the relationship between its catalytic activity, cellular localization and metastatic potential in vitro.
Positive staining of PRL-3 was observed in 19.4% (38/196) gastric cancer tissues compared with 76.2% (16/21) in liver metastasis. Statistical analysis revealed that PRL-3 expression correlated with lymph node metastasis and vascular invasion (P < 0.05). Patients with high PRL-3 expression showed poorer 5-year overall survival (P = 0.011). Wild type PRL-3 expressing cells resulted in enhanced migration and invasion ability, which were greatly crippled in form of PRL-3(C104S) or PRL-3(DeltaCAAX) mutants accompanied with its alteration in subcellular localization.
Metastasis associated protein PRL-3 may serve as a potential prognostic biomarker in human gastric cancer. Both the phosphatase catalytic activity and cellular localization are critical for its function.
Journal of Translational Medicine 12/2013; 11(1):309. DOI:10.1186/1479-5876-11-309 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A preclinical trial identified 4 of 20 (20%) gastric cancer (GC) patient-derived xenografts responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 2/4 (50%) responders with average copy number 5.8 and >15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.
[Show abstract][Hide abstract] ABSTRACT: CMTM3 (CKLF-like MARVEL transmembrane domain containing 3) is a novel tumor suppressor gene with frequent epigenetic inactivation. In this study, we demonstrated the role played by CMTM3 in gastric cancer cells as a TSG, and examined the correlation between CMTM3 expression and clinicopathological parameters by immunohistochemistry in gastric cancer patients with different pathological stages (n = 350). We found that CMTM3 expression was reduced or silenced by epigenetic regulation in gastric cell lines, and dramatically downregulated in primary gastric cancer tissues. Restoration of CMTM3 significantly affected migration and invasion of AGS and SGC-7901 cells (P < 0.001). In vivo experiments showed that peritoneal disseminated metastases were significantly suppressed by CMTM3 (P < 0.001). We further showed that the expression of MMP2 and the phosphorylation of Erk1/2 were decreased when CMTM3 was restored. In addition, by immuohistychemisty staining, we found that the expression of CMTM3 was remarkably weaker in gastric cancer tissues than that in normal mucosae (P = 0.008), and was significantly correlated with Gender (P = 0.033), Tumor Depth (P = 0.049), Stage (P = 0.021), Histologic Grade (P = 0.022). More importantly, CMTM3 expression was associated with prognosis in gastric cancer patients (P = 0.041), and was a significant independent prognostic indicator (HR = 0.704, 95%CI, 0.498 to 0.994; P = 0.046). Our findings indicate that CMTM3 regulates migration and invasion of gastric cancer cells. Moreover, CMTM3 is a candidate marker for prognosis of gastric cancer in clinic. This article is protected by copyright. All rights reserved.
Cancer Science 10/2013; 105(1). DOI:10.1111/cas.12304 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study aims to investigate the roles of ghrelin signaling in human gastric carcinoma cell lines AGS and SGC7901. Effects of ghrelin signaling on CDK6, P53, NF-κB/P65 and MMP2 mRNA and/or protein expression were determined by real-time PCR and western blot. MTT method and flow cytometry were performed to assess the gastric cancer cell proliferation. The SGC7901 cells overexpressing ghrelin were inoculated into nude mice to produce tumors which were measured later. The wound-healing assay and cell invasion assay were used to test the cell migration and invasive ability of gastric cancer. Ghrelin signaling promotes the oncogene CDK6 gene expression and represses the tumor suppressor gene P53 gene expression in gastric cancer. Ghrelin activates NF-κB/P65 signaling pathway through GHS-R in gastric cancer. Ghrelin upregulates the metastasis factor MMP2 expression via GHS-R/NF-κB signaling pathway in gastric cancer cells and promotes tumor cells migration and invasion, suggesting that ghrelin signaling is a critical pathway in cancer metastasis. Ghrelin induces cell proliferation, migration and invasion via GHS-R/NF-κB signaling pathway in gastric cancer cells. Ghrelin treatment must be avoided for gastric cancer patients.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To investigate Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) expressions in gastric cancer and to evaluate its clinical significance. METHODS: LGR5 expression was assessed by immunohistochemistry in 257 gastric cancer patients after surgery. The relationships between LGR5 expression and clinicopathological features and patients prognosis were statistically analyzed. RESULTS: The expression of LGR5 was significantly higher in gastric cancers as a cancer stem cell marker than in adjacent normal tissues (P<0.001), and more frequently in patients with intestinal type, well-moderate differentiation and stage I and II (P<0.05). Although we found gastric cancer patients with LGR5 positive expression had a poorer prognosis, it didn't meet statistical signiﬁcance (P>0.05). LGR5 negative expression was significantly related to the favorable overall survival in stage I and II gastric cancer patients (P<0.05). Furthermore, patients with high LGR5 expression tended to be more likely to get progression and have poorer progress-free survival (P<0.05). Multivariate Cox regression analysis revealed that LGR5 expression was an independent factor of overall survival for the patients with stage I and II gastric cancer (P<0.05). CONCLUSIONS: Our results show that LGR5 may play an important role in tumorigenesis and progression and would be a powerful marker to predict the prognosis of patients with stage I and II gastric cancer.
Chinese Journal of Cancer Research 02/2013; 25(1):79-89. DOI:10.3978/j.issn.1000-9604.2013.01.07 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To analyze the differences in clinicopathologic characteristics and prognosis between mucinous gastric carcinoma (MGC) and signet-ring cell carcinoma (SRCC). METHODS: Clinicopathologic and prognostic data of 1,637 patients with histologically confirmed MGC or SRCC who received surgical operations in the Department of Gastroenterological Surgery, Beijing Cancer Hospital between December 2004 and December 2009 were retrospectively collected and analyzed. The clinicopathological features were analyzed statistically using χ(2) test. Survival was analyzed using the Kaplan-Meier method and multivariate analysis of Cox proportional hazards regression model (backward, stepwise). RESULTS: A total of 181 patients with gastric cancer (74 MGC, 107 SRCC) were included. MGC, when compared with SRCC, was featured by senile patients, stage III and IV, upper third stomach, large tumor size, positive lymph node metastasis, and positive lymphatic vascular invasion (P<0.05). The overall 5-year survival rate showed no difference between the two groups (48.8% vs. 44.8%, P>0.05). However, the survival rate for MGC patients was significant lower than that for SRCC patients when compared among the age <60 years, negative distant metastasis, and tumor localized at upper third stomach (P<0.05). Multivariate Cox proportional hazards models revealed that distant metastasis was a significant independent prognostic indicator in MGC group, and lymph node metastasis and distant metastasis was significant independent prognostic indicators in SRCC group. CONCLUSIONS: While compared with SRCC, MGC is associated with a more aggressive tumor biologic behavior. There is no statistically significant difference in distant metastasis, an independent prognostic indicator for both MGC and SRCC, which might be the reason for no significant difference of the overall survival rate between the patients with MGC and SRCC.
Chinese Journal of Cancer Research 02/2013; 25(1):32-38. DOI:10.3978/j.issn.1000-9604.2013.01.05 · 2.16 Impact Factor