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Colorectal carcinoma is one of the most common malignancies in the world, and its incidence has increased in recent years. We have reported that expression of hypoxia-inducible factor (HIF)-1alpha correlates with expression of vascular endothelial growth factor (VEGF), tumor stage, lymphatic invasion, venous invasion, and liver metastasis. It has also been reported that a single nucleotide polymorphism (SNP) in exon 12 of HIF-1alpha gene is present in renal cell carcinoma and head and neck squamous cell carcinoma patients. We investigated the C1772T polymorphism in colorectal cancer patients and healthy control subjects to clarify the mechanism of HIF-1alpha activation in colorectal carcinoma. The exon 12 genotype was not associated with sex or age. The distribution of HIF-1alpha genotypes in controls was 89 C/C (89%), 11 C/T (11%), and 0 T/T (0%). The distribution of HIF-1alpha genotypes in colorectal cancer patients was 100 C/C (100%), 0 C/T (0%), and 0 T/T (0%). The difference in genotype distribution between patients and control subjects was significant (p

Colorectal carcinoma is one of the most common malignancies in the world, and its incidence has increased in recent years. We have reported that expression of hypoxia-inducible factor (HIF)-1alpha correlates with expression of vascular endothelial growth factor (VEGF), tumor stage, lymphatic invasion, venous invasion, and liver metastasis. It has also been reported that a single nucleotide polymorphism (SNP) in exon 12 of HIF-1alpha gene is present in renal cell carcinoma and head and neck squamous cell carcinoma patients. We investigated the C1772T polymorphism in colorectal cancer patients and healthy control subjects to clarify the mechanism of HIF-1alpha activation in colorectal carcinoma. The exon 12 genotype was not associated with sex or age. The distribution of HIF-1alpha genotypes in controls was 89 C/C (89%), 11 C/T (11%), and 0 T/T (0%). The distribution of HIF-1alpha genotypes in colorectal cancer patients was 100 C/C (100%), 0 C/T (0%), and 0 T/T (0%). The difference in genotype distribution between patients and control subjects was significant (p0.0005). These results suggest that the C1772T polymorphism in HIF-1alpha is not involved in progression or metastasis of colorectal carcinoma.

High frequencies of loss of heterozygosity (LOH) on chromosome 10p14-p15 have been reported in various tumors, including glioma, pulmonary carcinoid and cervical, hepatic and prostatic carcinomas. These findings suggest the presence of a tumor suppressor gene at the loci. However, analysis of LOH on chromosome 10p14-p15 in esophageal tumors has not been reported. Therefore, we examined LOH on chromosome 10p14-p15 in 88 esophageal squamous cell carcinomas (SCC) (35 superficial- and 53 advanced-types) and 44 dysplasias by microsatellite assay. Five oligonucleotide primer sets for microsatellite loci D10S191, D10S501, D10S559, D10S558 and D10S249 were used. In dysplasias, frequent LOH was detected with markers D10S191 (26%) and D10S249 (33%). In superficial esophageal SCCs, frequent LOH was detected with markers D10S191 (26%), D10S559 (50%), D10S558 (29%) and D10S249 (33%). In advanced esophageal SCCs, we found frequent LOH was detected with markers D10S191 (38%), D10S501 (25%) and D10S559 (30%). There were no significant correlations between LOH on chromosome 10p14-p15 and clinicopathologic features, including patient age, sex, tumor location, depth of invasion and lymph node metastasis. These data suggest that a putative tumor suppressor gene for esophageal carcinogenesis may be located on chromosome 10p14-p15 and that malfunction of this gene may be involved in the development but not progression of esophageal tumors.

We previously reported that vascular endothelial growth factor (VEGF) expression correlates with vessel density in human esophageal squamous cell carcinomas. However, tumor angiogenesis is not controlled simply by the presence of VEGF, and is likely regulated by several angiogenic factors produced by tumor and host cells. The goal of the present study was to determine the angiogenic profile of precancerous and cancerous lesions of the esophagus. Expression of mRNAs for VEGF, platelet derived endothelial cell growth factor (PD-ECGF), basic fibroblast growth factor (bFGF), and interleukin (IL)-8 was examined in six esophageal carcinoma cell lines and fresh biopsy specimens from 16 patients with invasive esophageal carcinoma by RT-PCR. Immunohistochemical analyses with antibodies against VEGF, PD-ECGF, bFGF, and IL-8 were performed on archival specimens of 60 normal esophageal mucosa, 11 dysplasias and 49 carcinomas of the esophagus. Microvessels were stained with anti-CD34 antibody and quantified by counting the number of vessels in a x200 field in the most vascularized areas of the tumor. Esophageal carcinoma cell lines and tumor tissues expressed mRNAs for one or more these angiogenic factors at various levels. An initial increase in vessel density and enhanced expression of PD-ECGF and VEGF were observed in dysplastic epithelium. Vessel density was significantly higher in more advanced lesions. bFGF and IL-8 were not expressed in dysplasias and mucosal carcinomas, but expression was increased in late stage squamous cell carcinoma. These findings suggest that the angiogenic switch is a very early event in the development of invasive carcinoma. Several different angiogenic factors produced by tumor cells and host cells may regulate angiogenesis during different steps of esophageal carcinogenesis.

Telomerase activity confers immortality to cells through stabilization of chromosomes and contributes to the development of most human cancers. Human telomerase reverse transcriptase (hTERT) is a catalytic subunit of telomerase. Expression of hTERT mRNA has been reported to be correlated with telomerase activity. The purpose of this study was to investigate localization of hTERT mRNA in human esophageal precancerous and cancerous lesions by in situ mRNA hybridization with avidin-biotin staining. Ki-67 immunoreactivity was also examined. We analyzed 51 squamous cell carcinomas, 9 dysplasias and 60 normal mucosae. The integrity of mRNA in each sample was verified with a poly-d(T)20 probe. Seventy-eight samples (65%), including 35 carcinomas, 4 dysplasias and 39 normal mucosae, contained intact mRNA. At the single-cell level, hTERT was expressed at high levels in both the cytoplasm and nucleus. In all cases, the majority of cancer and dysplastic cells showed high levels of hTERT expression. In all 39 normal mucosae, basal cells expressed hTERT mRNA, and this was also observed in infiltrating lymphocytes. The distribution of cells expressing hTERT was similar to that of Ki-67-positive cells. These results suggest that overexpression of hTERT mRNA may be correlated with proliferative activity reflected by Ki-67 immunoreactivity and is an early event in carcinogenesis of the esophagus.

It was reported that somatic mutations in the mitochondrial DNA (mtDNA) are associated with high-frequency microsatellite instability (MSI-H) of the nuclear in gastric cancers. However, no correlation between mtDNA mutations and nuclear MSI-H was found in colorectal, breast, and renal cancers. Therefore, the association between mtDNA mutations and nuclear MSI-H in gastric cancers is controversial. We examined mtDNA mutations and nuclear MSI in a large panel of gastric cancers. One-hundred and five gastric cancers were selected. Mutations in the mononucleotide repeat (D310) of mtDNA and nuclear MSI at 5 microsatellite loci were examined by microsatellite assay. Somatic mutations in the mtDNA and nuclear MSI-H were detected in 16 (15%) and 14 (13%) of the gastric cancers, respectively. mtDNA mutations were detected in 2 of the 14 (14%) and 14 of the 91 (15%) tumors with and without nuclear MSI-H, respectively. There was no significant difference between them. These results suggest that somatic mutations in the mtDNA and nuclear MSI-H play important roles in gastric carcinogenesis, and that mtDNA mutations may not be associated with nuclear MSI-H in gastric cancers.

Previous studies suggest that a telomerase repressor/senescence gene, which acts as a tumor suppressor gene, may be located on chromosome 10p15. However, there are no studies on alterations on chromosome 10p15 in gastric cancers. We, therefore, examined loss of heterozygosity (LOH) on the 10p15 in gastric cancers by microsatellite assay. Two microsatellite loci, D10S501 and D10S602, were used. Fifty-seven gastric cancers, including 36 intestinal type and 21 diffuse type, were selected. LOH at D10S602 and D10S501 was detected in 6 of 18 (33%) and 5 of 27 (19%) gastric cancers, respectively. There was no significant correlation between LOH at these loci and clinicopathologic features, including patient age, sex, tumor location, histologic subtype, depth of invasion, and lymph node metastasis. These data suggest that a putative telomerase repressor/senescence gene may be located on chromosome 10p15, especially at the D10S602, in gastric carcinogenesis, and that the putative gene malfunction may be involved in the early stages of gastric carcinogenesis.

Hypoxia inducible factor (HIF)-1 is reported to transactivate expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. The aim of this study was to elucidate the clinical significance of HIF-1alpha expression in gastrointestinal stromal tumors (GIST). Specimens obtained from 53 patients who underwent surgical resection for GIST of the stomach were used in this study. Specimens were examined immunohistochemically for HIF-1alpha, VEGF, and Ki-67 expression. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD31 antibody and was estimated by averaging the counts from three high-power fields in the area showing the greatest neovascularization. HIF-1alpha expression was detected in 17 (32.1%) of 53 lesions and was correlated significantly with tumor size, liver metastasis, VEGF expression, and MVD. Prognosis was significantly poorer in patients with tumors expressing HIF-1alpha than in patients with tumors lacking HIF-1alpha expression. HIF-1alpha may play a role in angiogenesis and tumor progression of GIST through regulation of VEGF.

Hypoxia inducible factor (HIF)-1 is reported to transactivate expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. The aim of this study was to elucidate the clinical significance of HIF-1alpha expression in gastrointestinal stromal tumors (GIST). Specimens obtained from 53 patients who underwent surgical resection for GIST of the stomach were used in this study. Specimens were examined immunohistochemically for HIF-1alpha, VEGF, and Ki-67 expression. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD31 antibody and was estimated by averaging the counts from three high-power fields in the area showing the greatest neovascularization. HIF-1alpha expression was detected in 17 (32.1%) of 53 lesions and was correlated significantly with tumor size, liver metastasis, VEGF expression, and MVD. Prognosis was significantly poorer in patients with tumors expressing HIF-1alpha than in patients with tumors lacking HIF-1alpha expression. HIF-1alpha may play a role in angiogenesis and tumor progression of GIST through regulation of VEGF.

The aim of this study was to clarify whether the pit pattern on the surface of submucosal colorectal carcinoma is associated with level of invasion. We examined the VN pit-pattern (loss or decrease of pits with an amorphous structure) area of the tumor surface in 18 submucosal carcinomas that were classified based on gross appearance as either superficial or broad based sessile polypoid tumors. Pit pattern determination was made according to a previously reported system. We then evaluated the relation between the VN pit-pattern area, the maximum diameter of the VN pit-pattern area obtained stereoscopically after resection, and the depth of submucosal invasion. There was a significant correlation between the area and maximum diameter of the VN pit-pattern segment. There was also significant correlation between the maximum diameter of the VN pit-pattern area and the depth of submucosal invasion. Lesions with a maximum VN pit-pattern area diameter

This study was designed to examine angiogenesis in rectal carcinoid tumors in relation to the clinicopathologic features. Seventy-seven rectal carcinoid tumors were studied clinicopathologically and experimentally. Cellular proliferation and microvessel density (MVD) were examined immunohistochemically. We used the antibodies MIB-1 for Ki-67, DO7 for p53, and NU-4A1 for CD34 expression in this study. Ki-67 labeling index (LI) of all lesions was below 3%, and the median Ki-67 LI of all lesions was 0.68+/-0.70% (mean +/- SD). A correlation was recognized between tumor size, metastasis and Ki-67 LI (p

Helicobacter pylori (Hp) is a major risk factor for gastric carcinogenesis. In Japan, the incidence of Hp infection in young adults has declined markedly. The purpose of this study was to clarify this trend in the incidence of Hp-associated gastric carcinoma (GCa) in young (under 30 years of age) Japanese patients. We enrolled 53 such patients who underwent surgical resection of GCa in one of 18 hospitals in the Hiroshima prefecture between 1976 and 1999. The patients were classified into groups based on three 8-year periods (1976-83, 1984-91, and 1992-1999) in which their cases occurred. We compared the numbers of patients and estimated the histology of carcinomas, grades of gastritis and Hp infection histologically. Of the 53 patients, 49 (92%) showed Hp infection. The frequency of GCa in young adults has decreased gradually (21, 18, and 14 patients in 1976-83, 1984-91 and 1992-99, respectively). The numbers of Hp-positive carcinomas decreased radically (21, 17 and 11 patients, respectively). This trend was associated with improvement in the degree of gastritis in non-neoplastic mucosa. Of the four Hp-negative patients, three had signet ring cell carcinoma. Moreover, the numbers of patients with non-signet ring cell carcinoma also decreased (18, 12 and 7 patients in each period, respectively). These results suggest that Hp-associated carcinoma has declined gradually in young Japanese.

Recent studies have shown 70-80% of gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regressing in response to eradication of Helicobacter pylori (H. pylori). Genetic mechanism of regression of gastric MALT lymphoma after H. pylori eradication remains unclear. To clarify the issue, we evaluated microsatellite instability (MSI) at 12 microsatellite loci in 15 patients with gastric low-grade MALT lymphoma, who received eradication therapy of H. pylori. H. pylori infection was observed in all the patients. After eradication therapy of H. pylori, patients were observed for a median of 21 months (range, 6-49 months). Eradication was acheived in all the patients. Nine of the 15 (60%) patients showed complete regression (CR), 3 (20%) partial regression (PR), and 3 (20%) no change (NC). MSI was detected in 3 of the 15 (20%) patients with low-grade MALT lymphoma. Compared with response to eradication therapy of H. pylori, MSI was detected in 1 of the 12 (8%) CR and PR patients, and in 2 of the 3 (67%) NC patients. Especially, MSI at D18S61 was detected in 2 of the 3 (67%) NC patients but in none of the 12 CR and PR patients. There was a significant difference between frequency of MSI at D18S61 in NC patients and that in CR and PR patients (p

The c-myc gene is involved in important cellular processes, including cell proliferation, differentiation, and apoptosis. We analyzed mutation of the c-myc gene in 51 patients with gastric lymphoma [27 patients with low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, 11 with high-grade MALT lymphoma, and 13 with diffuse large B-cell lymphoma (DLL)], by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. We also evaluated the relationship between mutation of the c-myc gene and regression of low-grade MALT lymphoma after Helicobacter pylori (H. pylori) eradication. Mutation in exon 2 of the c-myc gene was present in 2 of 20 (10%) patients with low-grade MALT lymphoma, in 1 of 7 (14%) patients with high-grade MALT lymphoma, and none of 10 patients with DLL. The 3 patients who had mutations of the gene, showed different patterns of mobility shift, suggesting different mutations. In addition, 15 patients with low-grade MALT lymphoma received anti-H. pylori therapy. All the patients achieved eradication. Nine of the 15 (60%) patients with low-grade MALT lymphoma showed complete regression (CR), 3 (20%) showed partial regression (PR), and 3 (20%) showed no change (NC). One of the 9 (11%) CR patients had a mutation of the c-myc gene. None of the 3 PR and 3 NC patients had mutation of the gene. There was no significant difference between the frequencies among the c-myc gene mutation in CR, in PR and in NC patients. These data suggest that mutation of the c-myc gene may not be commonly associated with development of gastric MALT lymphoma and DLL, and may not be associated with regression of low-grade MALT lymphoma after H. pylori eradication.

The deepest invasive portion of colorectal carcinoma (CRC) is considered to be the part, which ultimately will invade, spread locally and give metastasis. We have previously reported that histologic differentiation at the deepest invasive portion of CRC closely correlate with metastatic potential and is useful in understanding the curability of endoscopic mucosal resection (EMR). The aim of this study is to clarify the conditions of curative EMR for CRC with submucosally (sm) massive invasion. A total of 521 cases with sm invasive CRC (Group A, 470 surgically resected cases; Group B, 51 followed-up cases after EMR) were studied. The depth of sm invasion was defined as the practically measured distance from muscularis mucosae. Histologic subclassification was performed at the deepest invasive tumor margin as: well-differentiated (W), moderately differentiated (M) and poorly differentiated (Por). By assessing glandular configuration and cellular arrangement, M type was further subdivided into two different groups; moderately-well differentiated (Mw) and moderately-poorly differentiated (Mp). In group A, lymph node (LN) metastasis was detected in 45 (9.6%) of 470 cases. W or Mw lesions showed LN metastasis in 4.9% (19/388). Mp or Por lesions showed LN metastasis in 37.3% (25/67) (W/Mw vs Mp/Por; p