Peritoneal metastasis of gastric cancer serving as the most frequent form of metastasis, is one of the leading causes of death. A portion of surgically treated patients often suffer from small peritoneal residual metastasis, which will lead to recurrence and metastasis of gastric cancer patients after surgery. Given these, the prevention and treatment of peritoneal metastasis of gastric cancer deserves more attention. Molecular residual disease (MRD) refers to the molecular abnormalities of tumor origin that cannot be found by traditional imaging or other laboratory methods after treatment, but can be found by liquid biopsy, representing the possibility of tumor persistence or clinical progress. In recent years, the detection of MRD based on ctDNA has gradually become a research hotspot in the prevention and treatment of peritoneal metastasis. Our team established a new method for MRD molecular diagnosis of gastric cancer, and reviewed the research achievements in this field.
Humans ; Stomach Neoplasms/pathology* ; Peritoneal Neoplasms/secondary* ; Liquid Biopsy ; Neoplasm, Residual/genetics*

INTRODUCTIONSporadic colorectal cancers with BRAF mutations constitute two distinct subgroups of colorectal cancers. Recent studies have linked the presence of the BRAF mutation to a familial inheritance pattern. This was a proof-of-concept study that aimed to examine: (a) the extent of field change in sporadic colorectal cancers with BRAF mutation; and (b) the extent of resection margins required and the pattern of DNA mismatch repair protein loss in these tumours.

METHODSEight microsatellite instability-high tumours with positive BRAF mutation from an existing histopathological database were selected for BRAF mutation and mismatch repair protein analysis.

RESULTSAll the resection margins were negative for BRAF mutation. Three tumours had loss of MLH1 and PMS2 expressions, and five tumours had no protein loss. Six peritumoral tissues were negative and one was positive for BRAF mutation.

CONCLUSIONThe results suggest that any early field change effect is restricted to the immediate vicinity of the tumour and is not a pan-colonic phenomenon. Current guidelines on resection margins are adequate for BRAF mutation-positive colorectal cancers. Any suggestion of a hereditary link to these tumours is likely not related to germline BRAF gene mutations. The pattern of protein loss reinforces previous findings for the two subgroups of BRAF mutation-positive colorectal cancers.

Colorectal Neoplasms ; genetics ; pathology ; Female ; Humans ; Male ; Microsatellite Instability ; Mutation ; Neoplasm Metastasis ; Peritoneal Neoplasms ; pathology ; secondary ; Proto-Oncogene Proteins B-raf ; genetics ; Stomach Neoplasms ; pathology ; secondary

BACKGROUND AND OBJECTIVEThere is a mounting evidence of the role of HER2 overexpression inpatients with gastric cancer, and it has been solidly correlated with poor outcomes and more aggressive diseases. This study was to investigate the relationship between the expression of HER2/neu and the clinical characteristics of advanced gastric carcinomas, including survival.

METHODSThe clinical data of 83 patients admitted in Cancer Hospital, Chinese Academy of Science, from 2006 to 2008 were reviewed. The HER2/neu status in 83 advanced gastric carcinomas was evaluated using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The survival rate was calculated by Kaplan-Meier method and the log-rank test using SPSS13.0 software.

RESULTSThe median age of the patients was 60 years and the male-to-female ratio was 2.95:1. HER2/neu overexpression (2+ and 3+) and amplification were found in 25 (30.1%) and 29 (34.9%) advanced gastric carcinomas, respectively. HER2/neu amplification/overexpression was associated with worse survival in patients with advanced gastric carcinoma. The median survival of the patients without HER2/neu amplification was 12.6 months and that of those with HER2 amplification was 5.5 months.

CONCLUSIONSHER2/neu status may be a clinical predictor of prognosis in advanced gastric cancer patients.

Adenocarcinoma ; drug therapy ; genetics ; metabolism ; pathology ; secondary ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma, Signet Ring Cell ; drug therapy ; genetics ; metabolism ; pathology ; secondary ; Female ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Genes, erbB-2 ; Humans ; Liver Neoplasms ; secondary ; Lung Neoplasms ; secondary ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Staging ; Receptor, ErbB-2 ; metabolism ; Stomach Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; Survival Rate

OBJECTIVETo study the correlation between expression of urokinase-type plasminogen activator (uPA) and capability of tumor cell seeding to the peritoneal membrane by different gastric cancer lines.

METHODSExpression of uPA in 4 human gastric cancer cell lines was examined by semi-quantitative RT-PCR, ELISA and Western blot. uPA activity was determined by an assay kit. After ip inoculation of cancer cells to nude mice, tumors on peritoneal membrane was grossly examined for tumor cell seedings.

RESULTSSGC7901 was the highest in uPA expression among human gastric cancer cell lines AGS, SGC7901, MKN45, and MKN28. MKN45 had the strongest uPA activity, while AGS was lowest in both uPA expression and activity. Peritoneal seeding tumors of various sizes were observed in mice inoculated with SGC7901 and MKN45 cells. In addition to peritoneal seedings, bloody ascites was present in mice inoculated with MKN28. The MKN45-inoculated mice took the least time to develop tumors and had the shortest surviving period. No peritoneal seeding was seen in mice inoculated with AGS cells.

CONCLUSIONThree of 4 human gastric cancer cell lines studied express uPA mRNA and activity, which correlate with their peritoneal seeding potentials.

Adenocarcinoma ; enzymology ; secondary ; Animals ; Cell Line, Tumor ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Seeding ; Peritoneal Neoplasms ; secondary ; RNA, Messenger ; biosynthesis ; genetics ; Stomach Neoplasms ; enzymology ; pathology ; Urokinase-Type Plasminogen Activator ; biosynthesis ; genetics

OBJECTIVETo investigate the effects of silencing heparanase (HPA) on growth, angiogenesis and metastasis of human gastric carcinoma transplanted in nude mice.

METHODSHuman gastric carcinoma SGC-7901 cells and those cells with silenced HPA (gastric carcinoma SGC-7901-HPA(-)) were separately transplanted subcutaneously in 6 nude mice. The time, size and speed of tumor growth were recorded. RT-PCR and Western-blot were used to detect the expression of HPA mRNA and protein in the subcutaneous tumors of the two groups. Immunohistochemical staining was used to detect microvessel density (MVD) in the subcutaneous tumors of the two groups. Cells of the subcutaneous transplanted tumors of the two groups were separately injected into the peritoneal cavity of nude mice, 6 mice each. The growth of metastatic tumors in nude mice was observed.

RESULTSHuman gastric carcinoma SGC-7901 cells and SGC-7901-HPA(-) cells were subcutaneously inoculated in nude mice, and tumors appeared at 4 days and 7 days after inoculation, respectively. The MVD was (20.69 ± 1.20)/HP and (11.35 ± 1.94)/HP, respectively (P < 0.05). The expressions of HPA mRNA and protein of the subcutaneously transplanted SGC-7901-HPA(-) tumor were decreased. Four voluminous metastatic tumors caused by SGC-7901 cells occurred in 3 mice in the liver, right kidney, omentum and intestine. Two smaller abdominal metastatic tumors of SGC-7901-HPA(-) cells were found in the liver and right kidney.

CONCLUSIONSilencing HPA can inhibit the tumor growth, angiogenesis and metastasis of human gastric cancer in nude mice. It suggests that HPA might become a new target for prevention and treatment of gastric cancer.

Adenocarcinoma ; blood supply ; enzymology ; genetics ; pathology ; secondary ; Animals ; Cell Line, Tumor ; Gene Silencing ; Glucuronidase ; biosynthesis ; genetics ; physiology ; Humans ; Kidney Neoplasms ; secondary ; Liver Neoplasms ; secondary ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microvessels ; pathology ; Neoplasm Transplantation ; Neovascularization, Pathologic ; RNA, Messenger ; metabolism ; Stomach Neoplasms ; blood supply ; enzymology ; genetics ; pathology

OBJECTIVETo explore the relationship between heparanase mRNA expression and clinicopathological parameters in human gastric cancer.

METHODSRT-PCR was used to detect the expression of heparanase mRNA in 43 human gastric carcinomas and 10 adjacent normal gastric tissues.

RESULTSHeparanase mRNA was expressed in 29 of the 43 cases of gastric cancer with a positive rate of 67.4%, which was significantly higher than that in adjacent normal gastric tissues (P = 0.013). The expression level was higher in late-stage tumors (stage III and IV) than in early-stage tumors (stage I and II) (P = 0.001), in tumors with invasion to serosa than those without serosal invasion (P = 0.009), in tumors with lymph node metastasis than those without lymph node metastasis (P = 0.018), and in large-sized tumors than in small-sized ones (P = 0.009). The expression was not correlated with patients' age, sex, tumor location, histologic types, differentiation, peritoneal dissemination and liver metastasis (P > 0.05).

CONCLUSIONHeparanase might play an important role in the development of invasion and metastasis of gastric cancer.

Adenocarcinoma ; enzymology ; pathology ; Adult ; Aged ; Aged, 80 and over ; Female ; Glucuronidase ; biosynthesis ; genetics ; Humans ; Liver Neoplasms ; metabolism ; secondary ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Staging ; RNA, Messenger ; biosynthesis ; genetics ; Stomach Neoplasms ; enzymology ; pathology

BACKGROUND/AIMS: DNA double strand break (DSB) is one of the critical types of DNA damage. When unrepaired DSB is accumulated in the nucleus of the cells having mutations in such genes as p53, it will lead to chromosomal instability and further more to mutation of tumor-activating genes resulting in tumorogenesis. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. The aim of this study was to define the differences in expression of 53BP1 and gamma-H2AX, the markers of DSB, among normal, gastric adenoma, and gastric adenocarcinoma tissues. METHODS: Tissue microarray was made with the tissues taken from 121 patients who underwent gastrectomy for gastric adenocarcinoma, and 51 patients who underwent endoscopic mucosal resection for gastric adenoma. Immunochemical stain was performed for the marker of DSB, 53BP1 and gamma-H2AX in the tissue microarray. The normal tissues were collected from histologically confirmed tissues with no cellular atypia obtained from the patients with gastric adenocarcinoma. RESULTS: In gastric carcinoma cells, 53BP1 and gamma-H2AX were highly expressed as compared to normal epithelial cells and gastric adenoma (p<0.01). There were no differences in the expression of 53BP1 and gamma-H2AX between normal epithelium and gastric adenoma. The expression of 53BP1 in the adenoma with grade II and III atypism was more elevated than in those with grade I atypism. The expression of 53BP1 and gamma-H2AX were not significantly different according to the clinicopathologic parameters in the patients with gastric adenocarcinoma. CONCLUSIONS: The DSB in DNA seems to be associated with the development of gastric adenocarcinoma, but does not affect the premalignant adenoma cells.
Adenocarcinoma/genetics/*metabolism/secondary ; Adenoma/genetics/*metabolism/pathology ; Adult ; Aged ; Aged, 80 and over ; Chromosomal Instability ; *DNA Breaks, Double-Stranded ; Female ; Histones/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Middle Aged ; Neoplasm Staging ; Stomach Neoplasms/genetics/*metabolism/pathology

BACKGROUND AND OBJECTIVEIn recent years, incidence and mortality of lymphoma are markedly increasing worldwide. However, the pathogenesis and mechanism of invasion and metastasis for lymphoma are not yet fully clarified. It is mainly due to the lack of ideal animal models, which can precisely simulate the invasion and metastasis of lymphoma in the human body. So, it is very necessary to establish a highly metastatic nude mouse model of human lymphoma. This study developed a liver-metastatic model of primary gastric lymphoma in nude mice by using orthotopic surgical implantation of histologically intact patient specimens into the corresponding organs of the recipient small animals.

METHODSA histologically intact fragment of liver metastasis derived from a surgical specimen of a patient with primary gastric lymphoma was implanted into the submucosa of the stomach in nude mice. Tumorigenicity, invasion, metastasis, morphologic characteristics (via light microscopy, electron microscopy, and immunohistochemistry), karyotype analysis, and DNA content of the orthotopically transplanted tumors were studied.

RESULTSAn orthotopic liver metastatic model of human primary gastric lymphoma in nude mice (termed HGBL-0304) was successfully established. The histopathology of the transplanted tumors showed primary gastric diffuse large B-cell lymphoma. CD19, CD20, CD22, and CD79alpha were positive, but CD3 and CD7 were negative. The serum level of lactate dehydrogenase (LDH) was elevated [(1010.56+/-200.85) U/L]. The number of chromosomes ranged from 75 to 89. The DNA index (DI) was 1.45+/-0.25 (that is, heteroploid). So far, the HGBL-0304 model has been passed on for 45 generations of nude mice. A total of 263 nude mice were used for the transplantation. Both the growth and resuscitation rates of liquid nitrogen cryopreservation of the transplanted tumors were 100%. The transplanted tumors autonomically invasively grew and damaged a whole layer in the stomach of nude mice. The metastasis rates of liver, spleen, lymph node, and peritoneal seeding were 100%, 94.3%, 62.6%, and 43.5%, respectively.

CONCLUSIONSThe study successfully establishes an orthotopic liver metastatic model of human primary gastric lymphoma in nude mice. The HGBL-0304 model can completely simulate the natural clinical process of primary gastric lymphoma and provides an ideal animal model for the research on the biology of metastasis and antimetastatic experimental therapies of primary gastric lymphoma.

Aged ; Aneuploidy ; Animals ; Antigens, CD ; metabolism ; CD79 Antigens ; metabolism ; Disease Models, Animal ; Humans ; L-Lactate Dehydrogenase ; blood ; Liver ; pathology ; Liver Neoplasms ; genetics ; metabolism ; secondary ; ultrastructure ; Lymphatic Metastasis ; Lymphoma, Large B-Cell, Diffuse ; genetics ; metabolism ; pathology ; ultrastructure ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Invasiveness ; Neoplasm Transplantation ; Splenic Neoplasms ; secondary ; Stomach Neoplasms ; genetics ; metabolism ; pathology

OBJECTIVETo investigate whether correlation exists between mRNA expression of IGF-II and hepatocyte growth factor (HGF) and tumor progression and prognosis in gastric cancer.

METHODSIn situ hybridization technique was used to examine mRNA expression of IGF-II and HGF, and immunohistochemical technique was used to examine protein expression of CD34 in 105 specimens of gastric carcinoma.

RESULTSIn situ hybridization revealed that the positive rates of IGF-II mRNA and HGFmRNA were 49.5% and 57.1%, respectively. In stage T3-T4 cases, positive mRNA expression rates of IGF-II and HGF, the frequencies of vessel invasion, lymph node metastasis and distant metastasis were significantly higher than those in stage T1-T2 cases. The mean microvascular density (MVD) in stage T3-T4 tumors, vessel invasion, lymph node metastasis and distant metastasis were significantly more frequent than those in stage T1-T2 tumors. The mean MVD in tumors with positive IGF-II and HGF expressions was significantly higher than that in tumors without IGF-II and HGF expression. There were positive correlations between MVD and expression of IGF-II and HGF. The mean survival time and 5-year survival rate in cases with positive IGF-II and HGF expression and MVD value > or = 39.5 were significantly shorter those that in cases with negative IGF-II and HGF expression and MVD value < 39.5.

CONCLUSIONIGF-II and HGF promote angiogenesis in gastric cancer, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

Adenocarcinoma, Papillary ; blood supply ; metabolism ; secondary ; Adult ; Aged ; Carcinoma, Ductal ; blood supply ; metabolism ; secondary ; Carcinoma, Signet Ring Cell ; blood supply ; metabolism ; secondary ; Disease Progression ; Female ; Hepatocyte Growth Factor ; biosynthesis ; genetics ; Humans ; Insulin-Like Growth Factor II ; biosynthesis ; genetics ; Liver Neoplasms ; blood supply ; metabolism ; secondary ; Lymphatic Metastasis ; Male ; Microcirculation ; Middle Aged ; Neoplasm Invasiveness ; Neovascularization, Pathologic ; Peritoneal Neoplasms ; blood supply ; metabolism ; secondary ; Prognosis ; RNA, Messenger ; biosynthesis ; genetics ; Stomach Neoplasms ; blood supply ; metabolism ; pathology ; Survival Rate

Our previous study revealed that mutations of the p53 gene were detected by cDNA sequencing in one of four (25%) primary gastric tumors and in five of six (83%) gastric cancer cell lines. It was of interest that all five cell lines established from metastatic lesions had p53 gene mutations, while the single cell line established from a primary tumor lacked an abnormality. Thus, the current study was initiated to determine the frequency of p53 mutations in 10 pairs of samples from primary gastric carcinomas and their lymph node metastases, in addition to morphologically normal gastric mucosa. In addition, we correlated the findings with other relevant molecular markers including the metastasis associated nm23-H1 gene and loss of heterozygosity (LOH) using multiple polymorphic markers for chromosome 17p and sequencing the entire open reading frame (ORF) of the p53 gene. Five of ten (50%) patients were constitutionally heterozygous for one or more 17p and/or p53 probes (pYNZ 22, BamHI RFLP; pMct35.1, Mspl RFLP; php53cl, Bg/II RFLP), while none had LOH at the 17p and/or p53. A Bg/II RFLP for analysis of possible nm23-H1 somatic allelic deletion revealed no LOH out of four informative cases. One paired sample demonstrated the substitution of valine for isoleucine at codon 41 (GTT to ATT) in both primary gastric tumor and metastasis. Another metastatic sample demonstrated the substitution of proline for threonine at codon 278 (CCT to C/ACT) in addition to a non-mutated codon, while only the wild-type p53 sequence was present in the paired primary gastric tumor tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence ; Chromosome Deletion ; DNA, Complementary/chemistry ; *Genes, p53 ; Humans ; Molecular Sequence Data ; Mutation ; Neoplasm Metastasis/*genetics ; Polymorphism, Restriction Fragment Length ; RNA, Messenger/analysis ; Stomach Neoplasms/*genetics/pathology/secondary