Human Gastric Adenoma Research Articles

The effects of recombinant human GH on promoting tumor growth depend on the expression of GH receptor in vivo

Cancer-related malnutrition is a mortal threat to gastric carcinoma patients. However, conventional nutrition treatment is not effective for recovery. Recombinant human GH (rhGH) is widely accepted clinically to treat severe malnutrition caused by non-malignant diseases, but not approved to treat malignant diseases due to the safety concern. To explore the safety of rhGH on gastric cancer, we assessed the effect of rhGH on two tumor-bearing mice models in vivo established by human gastric adenoma cell lines of SGC-7901 and MKN-45. VEGF expression in tumor tissues was detected using immunohistochemistry. The expression of GH receptor (Ghr), Jak-2, Stat3, Vegf, Hif-1α, Fgf, and Mmp-2 was measured by RT-PCR and protein expression of STAT3, phosphorylated STAT3, VEGF, HIF-1α, and MMP-2 was measured by western blotting. The immunocytochemistry results showed that the GHR expression of SGC-7901 was strongly positive (GHR(+++)), while GHR expression of MKN-45 was regarded as negative (GHR(-)). After 14 days of rhGH treatment in SGC-7901 (GHR(+++)) tumor-bearing mice, we found that the tumor growth was significantly increased, and the expressions of downstream factors and VEGF were increased. However, in MKN-45 (GHR(-)) tumor-bearing mice, tumor growth was not significantly increased by rhGH, but tumor-free body weight was increased especially in high-dose rhGH-treated group (P<0.05). These findings suggest that the level of GHR expression is a key target that influences the effectiveness of rhGH on promoting the growth of gastric cancer and angiogenesis. rhGH may promote the activation of tumor angiogenesis factors through the Jak-2-STAT3 pathway.

Detection of cancer clones in human gastric adenoma by increased DNA-instability and other biomarkers.

An immunohistochemical differential staining of cancerous cells with anti-cytidine antibody after denaturation of nuclear DNA by acid hydrolysis with 2N HCl at 30 degree C for 20 min (DNA-instability test) has been used as a marker of malignancy. The test was applied to bioptic tissues of human gastric polyp assessed histopathologically as foveolar hyperplastic polyp (13 cases), mild (58 cases), moderate (86 cases), and severe (20 cases) dysplasia, and adenocarcinomas (14 cases). The serial sections of the same tissues were also subjected to immunohistochemical staining for Ki67, p53, DNA-fragmentation factor (DFF45), and basic fibroblast growth factor (bFGF). The DNA-instability test was positive in 14 (100%) adenocarcinoma cases, 20 (100%) severe dysplasia cases, 52 (60.5%) moderate dysplasia cases, and 12 (20.7%) mild dysplasia cases, indicating malignancy. All foveolar hyperplastic polyps were negative to the DNA-instability testing. Furthermore, the percentage of glands positive in the DNA-instability test steadily increased in going from mild (10%), to moderate (40%), to severe (100%) dysplasia, and adenocarcinoma (100%). All other biological markers tested in the present study showed significantly higher values in the adenoma glands, being positive to DNA-instability testing, irrespective of the dysplasia grade, as compared to those in the adenoma glands that were negative to DNA-instability testing. Furthermore, the former values were comparable to those in adenocarcinoma. These results indicate that cancer cell clones are already present at the adenoma stages showing a positive DNA-instability test, enhanced proliferative activity, p53 mutation, induction of DFF45 and bFGF. These factors allow cancer cell proliferation, producing heterogeneous subclones due to DNA-instability, enhancing their survival by escaping apoptosis, and providing abundant nutrients during the early-stage progression of gastric cancer. Based on these findings, we herein propose the concept of "procancer" (as opposed to "pre-cancer") as being a unique stage during the course of carcinogenesis and cancer progression. We designate the term to cancer clones at the very early stages of malignant progression that do not show distinguishable morphological atypia but do show positive DNA-instability testing and positive staining for various biomarkers such as Ki67, p53, DFF45, and bFGF. We also define the abnormal positive staining of these biomarkers, including the DNA-instability test as "functional atypia", compared to the ordinary morphological atypia.

Expression of Cyclooxygenase-2 and Bcl-2 in Human Gastric Adenomas

BackgroundCyclooxygenase (COX)-2 is the rate-limiting enzyme in prostaglandin synthesis. An increased expression has been implicated in the development and progression of human gastric cancers and colorectal adenomas and cancers. This study aimed to determine the involvement and association of COX-2 and Bcl-2 in precancerous gastric adenomas.MethodsSeventy-nine gastric polyps were obtained by endoscopic mucosal resection or polypectomy from January, 2000 to July, 2003. Immunohistochemical expression of COX-2 and Bcl-2 was observed, and their relationships with various clinicopathological factors were analyzed.ResultsHistologically, 13 hyperplastic polyps and 66 tubular adenomas, of which 17 showed high-grade dysplasia, were observed. Increased COX-2 expression was observed in low-grade and high-grade tubular adenomas compared to hyperplastic polyps (p=0.004 and p=0.001, respectively). COX-2 expression was significantly higher in larger (>1 cm) compared with smaller (≤1 cm) tubular adenomas (p=0.034), but no relation was observed in hyperplastic polyps. While Bcl-2 expression differed significantly according to histology, increased Bcl-2 expression was observed especially in COX-2 positive low-grade tubular adenomas.ConclusionsCOX-2 expression increased in a size-dependent manner in tubular adenomas, suggesting a role in polyp growth. The increased expression of Bcl-2 in tubular adenomas, especially in COX-2 positive tubular adenomas, suggests that COX-2 action may be related to Bcl-2 expression.

Fhit expression in human gastric adenomas and intramucosal carcinomas: correlation with Mlh1 expression and gastric phenotype.

The fragile histidine triad (FHIT) gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumour suppressor gene involved in a variety of tumours, including gastric carcinomas. Recently, it has been reported that the FHIT gene may be a target of damage in some of mismatch-deficient tumours. To clarify further the role of the Fhit protein in gastric carcinogenesis, we investigated whether Fhit expression in early gastric neoplasia is associated with mismatch repair protein expression and cellular phenotype. Fhit, Mlh1 and phenotypic expression were evaluated immunohistochemically in 87 early gastric neoplasias, comprising 32 adenomas and 55 intramucosal carcinomas, resected by endoscopic mucosal resection therapy. Significant loss or reduction of Fhit expression was noted in four (12.5%) of the 32 adenomas and 21 (38.2%) of the 55 intramucosal carcinomas. The rate of abnormal Fhit expression was significantly higher in intramucosal carcinomas than in adenomas (P=0.021). Moreover, reduced Fhit expression was found to be significantly associated with loss of Mlh1 expression in early gastric neoplasia (P=0.0011). Furthermore, we also detected a significant association between reduced Fhit expression and gastric phenotype (P=0.0018). These results suggested that reduced Fhit expression occurs in the early stage of gastric carcinogenesis and could be correlated with a lack of Mlh1 expression and gastric phenotype.

Promotion of angiogenesis may play a role in the pro-tumorigenic activity of COX-2 during growth of human hyperplastic gastric polyps, but not human gastric adenomas

Promotion of angiogenesis may play a role in the pro-tumorigenic activity of COX-2 during growth of human hyperplastic gastric polyps, but not human gastric adenomas

Expression of Fas and Fas ligand in human gastric adenomas and intestinal-type carcinomas: correlation with proliferation and apoptosis.

Fas (APO-1/CD95), a member of the tumor necrosis factor/nerve growth factor receptor superfamily, mediates apoptosis in response to agonistic antibodies or Fas ligand (FasL) binding. Previous reports indicated an up-regulation of FasL in gastric carcinomas to evade host immune attack. Fas/FasL expression, however, has not been analyzed in terms of apoptosis and proliferation in gastric adenoma and carcinoma. This study was conducted on seven human gastric carcinoma cell lines, 47 gastric adenomas, and 75 intestinal-type adenocarcinomas (48 early and 27 advanced carcinomas). Fas/FasL expression was examined by immunohistochemistry, apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method, and Fas gene mutation by a reverse transcriptase (RT) polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing method. Fas and FasL expressions were noted in 18 (38.3%) and 17 (36.2%) adenomas, in 21 (43.8%) and 33 (68.8%) early carcinomas, and in 10 (37.0%) and 19 (70.4%) advanced carcinomas, respectively. The frequency of FasL expression was significantly higher in advanced carcinomas than in the early carcinomas and adenomas; in contrast, there was no significant difference in Fas expression among the three groups. The mean apoptotic index (AI) was 4.96+/-0.51 in the adenomas, 2.96+/-0.23 in the early carcinomas, and 1.67+/-0.17 in the advanced carcinomas. A significantly higher Al was noted in the lesions with Fas expression than in those without Fas expression in all three groups. No missense mutations of the Fas gene were detected in any of the gastric carcinoma cell lines, or in the gastric adenomas or carcinomas. Upregulation of FasL may correlate with the progression of gastric carcinoma. Apoptosis in gastric adenoma and carcinoma cells may occur via Fas-dependent and -independent pathways, but further clarification is needed.

Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas.

The increased expression of cyclooxygenase (COX)-2 has been implicated in the development and progression of colorectal cancer. We sought to determine the involvement of COX-2 in human gastric cancer. COX-2 mRNA was assayed in both gastric cancer cell lines and biopsy specimens from 37 gastric adenocarcinomas, five gastric adenomas, and five hyperplastic polyps by reverse transcription-polymerase chain reaction. COX-2 mRNA was found in four of five gastric cancer cell lines, two from intestinal type and two from diffuse type. COX-2 mRNA was expressed in 19 of 37 (51%) human gastric cancer specimens. The tumor diameter was greater in patients with COX-2 expression than in those without (6.5 +/- 4.6 vs. 3.8 +/- 2.7 cm, P < 0.05). The incidence of COX-2 mRNA expression was significantly higher in patients with pT2-pT4 tumors than in those with pT1 tumors (71 vs. 35%, P < 0.05). Significantly higher expression of COX-2 mRNA was also observed in patients with lymph node involvement than in those without (75 vs. 40%, P < 0.05). COX-2 mRNA was found in one of five adenomas, while it was absent in five hyperplastic polyps. The paired normal gastric musosa did not express COX-2 mRNA in any of the 47 patients. These results provide clinical evidence that COX-2 may contribute to tumor progression in human gastric adenocarcinoma.

Immunohistochemical analysis of intercellular adhesion molecule-1 expression in human gastric adenoma and adenocarcinoma

In this study, we examined the distribution of intercellular adhesion molecule-1 (ICAM-1) in gastric adenomas and carcinomas immunohistochemically at the light and electron microscopic levels. ICAM-1 was expressed on tumour cells in 12 of 28 gastric carcinomas and in 3 of 11 adenomas but not on most normal gastric epithelial cells. ICAM-1 was localized on luminal sites of neoplastic glands in adenomas and in intestinal-type carcinomas, and rarely on the surface of tumour cells of diffuse carcinomas. Expression of ICAM-1 on the tumour cells was more frequent in intestinal-type than diffuse carcinomas (P < 0.005). At the ultrastructural level, ICAM-1 was present prominently on the apical membrane and weakly on the lateral surface of the tumour cells of the intestinal-type carcinoma and also localized on the perinuclear membrane and the membrane of the endoplasmic reticulum of cancer cells. There was no significant association between ICAM-1 expression and HLA antigen expression or the number of infiltrating lymphocyte subsets. These results may implicate the synthesis of ICAM-1 by gastric cancer cells, but the expression is infrequent and may not be sufficient for host immune surveillance of the tumour cell.