Biomedical subjects

Yasuhiko Kitadai

Publications and source records attributed to Yasuhiko Kitadai.

At least 37 records · Page 2Linked to original sources

PubMed2004

Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma.

Suppressor of cytokine signaling (SOCS)-1 inhibits signaling of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway by several cytokines and has tumor suppressor activity. Methylation of the SOCS-1 CpG island has been shown to inactivate the SOCS-1 gene in certain human cancers. In our study, we investigated methylation status of the SOCS-1 gene by methylation-specific PCR in 75 gastric carcinoma (GC) tissues, 25 corresponding nonneoplastic mucosae and 10 normal gastric mucosae from healthy young individuals. We also performed bisulfite sequencing of DNAs from 2 GC tissues. In addition, SOCS-1 mRNA levels were examined in 50 GCs by quantitative RT-PCR. Hypermethylation of the SOCS-1 gene was detected in 33 (44%) of 75 GC tissues and in 3 (12%) of 25 corresponding nonneoplastic mucosae; the incidence was significantly different (p = 0.004). None of the 10 normal gastric tissues from healthy individuals showed hypermethylation. Methylation of the SOCS-1 gene was associated with lymph node metastasis, advanced tumor stage and reduced expression of SOCS-1 in GC tissues (p = 0.009, 0.034 and 0.002, respectively). Reduced expression of SOCS-1 in GC tissues was associated with lymph node metastasis and advanced tumor stage (p = 0.013 and 0.002, respectively). Our results suggest that transcriptional inactivation of the SOCS-1 gene by hypermethylation may be involved in development, progression and metastasis of GC.

Carcinoma↗

PubMed2004

A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer.

PURPOSE: Matrix metalloproteinase-9 (MMP-9, gelatinase B) plays a key role in cancer invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane barriers. A cytosine (C)-thymidine (T) single nucleotide polymorphism (SNP) at position -1562 in the MMP-9 promoter is reported to affect expression of this gene. The purpose of this study was to investigate the relation between the -1562 C/T polymorphism and the development and progression of gastric cancer. METHODS: The study population included 177 gastric cancer patients and 224 healthy control subjects. The SNP in the MMP-9 promoter was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological features was studied. RESULTS: Genotype frequencies in gastric cancer patients were similar to those in control subjects (P = 0.223). However, significant association was found between degree of tumor invasion, clinical stage, and lymphatic invasion and the MMP-9 polymorphism in gastric cancer patients (P<0.05, for each). CONCLUSIONS: Our results indicate that the T allele in the MMP-9 promoter is associated with the invasive phenotype of gastric cancer.

Aged↗

PubMed2004

Frequent epigenetic inactivation of RIZ1 by promoter hypermethylation in human gastric carcinoma.

The retinoblastoma protein-interacting zinc finger gene, RIZ1 (GenBank accession number U17838), is involved in chromatin-mediated gene expression and is also a target for frameshift mutation in microsatellite-unstable cancers. Methylation of the RIZ1 promoter CpG island has been shown to be a common mechanism in inactivating the RIZ1 gene in human liver and breast cancers. We investigated levels of RIZ1 mRNA in 45 gastric carcinoma tissues by quantitative RT-PCR and in gastric carcinoma cell lines by RT-PCR. In addition, we examined CpG island methylator phenotype (CIMP) status, p53 mutation status, and the correlation between promoter methylation status and RIZ1 mRNA expression. CIMP status was investigated by examining the methylation status of MINT1, MINT2, MINT12, MINT25 and MINT31. p53 mutation status was examined by PCR-single strand conformation polymorphism and promoter methylation status was examined by methylation-specific PCR. Promoter hypermethylation of the RIZ1 gene was found in 31 (69%) of 45 gastric carcinoma tissues and in 3 (21%) of 14 corresponding non-neoplastic mucosae, the incidence being significantly different (p = 0.002). None of the 12 normal gastric tissues from young non-cancer individuals showed hypermethylation. Promoter hypermethylation was associated with reduced RIZ1 expression in gastric carcinoma tissues (p = 0.029). Promoter hypermethylation of the RIZ1 gene was significantly associated with CIMP (p = 0.002). Mutation status of the p53 gene was not associated with methylation status or RIZ1 expression in gastric carcinoma. In gastric carcinoma cell lines MKN-28 and KATO-III, the RIZ1 promoter was hypermethylated and RIZ1 transcription was inactive. Treatment of these cells with demethylating agent 5-aza-2'-deoxycytidine restored RIZ1 transcription. Our results suggest that transcriptional inactivation of the RIZ1 gene by promoter hypermethylation may participate in stomach carcinogenesis.

Cell Line, Tumor↗

PubMed2004

A single nucleotide polymorphism in the MMP-1 promoter is correlated with histological differentiation of gastric cancer.

PURPOSE: Matrix metalloproteinase-1 (MMP-1) plays a key role in cancer invasion and metastasis by degradation of extracellular matrix (ECM) and basement membrane barriers. The 1G/2G single nucleotide polymorphism (SNP) in the MMP-1 promoter at position -1607 bp has been reported to affect the transcriptional activity. In the light of these findings, we investigated whether this SNP in the MMP-1 promoter is associated with the development, differentiation, and progression of gastric cancer. METHODS: The 215 gastric cancer patients and 166 controls were used in this study. The SNP of the MMP-1 promoter was analyzed by PCR-RFLP and sequencing. The genotype frequency was compared between cases and controls, and the association with clinicopathological parameters among cases was studied. RESULTS: The frequency of 1G/2G genotypes in gastric cancer patients was similar to those in controls (p=0.57). The degree of tumor invasion, the presence of lymph node metastasis, and clinical stage showed no significant association with the SNP. On the other hand, we found a significant association with histological differentiation and gender among gastric cancer patients (p<0.05, respectively). CONCLUSIONS: The presence of 2G allele in the MMP-1 promoter did not enhance the risk of gastric cancer; however, it may be involved in differentiation of gastric cancer.

Aged↗

PubMed2004

Regulation of vascular endothelial growth factor (VEGF)-C and VEGF-D expression by the organ microenvironment in human colon carcinoma.

Vascular endothelial growth factor (VEGF)-C and VEGF-D are potent lymphangiogenic factors produced by tumour and stromal cells. The purpose of this study was to investigate the expression of VEGF-C and VEGF-D in the organ microenvironment. We implanted human KM12 colon carcinoma cell lines into the subcutis and caecal wall of nude mice. The expression of VEGF-C and VEGF-D mRNAs and proteins were examined by reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Under culture conditions, VEGF-C mRNA was not detected in KM12 cells; however, VEGF-C expression was detected after implantation of KM12 cells into nude mice. VEGF-C and VEGF-D protein contents were higher in orthotopic (caecal wall) tumours than in ectopic (subcutis) tumours. Small vessels expressing VEGF receptor-3 were observed in the peripheral portions of caecal tumours. In metastatic liver tumours, VEGF-C and VEGF-D proteins were produced in lower amounts than those in caecal tumours. These data suggest that the expression of lymphangiogenic factors is influenced by the organ microenvironment. Therefore, experimental studies of colon cancer lymphangiogenesis should be performed with orthotopic implantation models.

Animals↗

PubMed2004

Expression of hypoxia-inducible factor (HIF)-1alpha is associated with vascular endothelial growth factor expression and tumour angiogenesis in human oesophageal squamous cell carcinoma.

The purpose of this study was to examine the relationship between hypoxia inducible factor (HIF)-1alpha expression, vascular endothelial growth factor (VEGF) expression, and tumour vascularity in squamous cell carcinoma of the oesophagus. Expression of HIF-1alpha and VEGF was examined in two oesophageal squamous cell carcinoma cell lines (TE2, TE3) and 82 archival surgical specimens of human oesophageal squamous cell carcinoma tissue. In both cell lines, the levels of HIF-1alpha protein and VEGF mRNA were increased under hypoxic conditions. Thirty-two of the 82 (39%) tumour specimens showed high levels of HIF-1alpha immunoreactivity in the nuclei and/or cytoplasm of cancer cells. HIF-1alpha expression correlated significantly with venous invasion, VEGF expression, and microvessel density. Among the 47 patients who did not receive pre-operative chemotherapy, the outcome of those with high HIF-1alpha-expressing tumours was significantly poorer than that of those with low HIF-1alpha-expressing tumours. These results suggest that HIF-1alpha and VEGF expression are important determinants of survival in squamous cell carcinoma of the oesophagus.

Blotting, Western↗

PubMed2004

Clinicopathologic and endoscopic features of colorectal serrated adenoma: differences between polypoid and superficial types.

BACKGROUND: Serrated adenoma is a distinct histologic colorectal lesion. There are two macroscopic types: polypoid and superficial. The aim of this study was to clarify clinicopathologic and endoscopic differences between polypoid and superficial serrated adenomas. METHODS: An analysis was conducted of the clinicopathologic and endoscopic features for 240 polypoid and 127 superficial serrated adenomas examined by colonoscopy, and the surface pit patterns of 114 polypoid and 64 superficial serrated adenomas examined by magnifying videoendoscopy. RESULTS: The male:female gender ratio for the polypoid serrated adenomas (3.5:1) was significantly higher than that for the superficial serrated adenomas (1.7:1). Superficial serrated adenomas were significantly larger than polypoid serrated adenomas (mean [standard deviation], respectively, 10.1 [7.9] mm vs. 6.3 [4.6] mm). In the distal segments of the colorectum, polypoid serrated adenomas were more common than superficial serrated adenomas. Granulonodular and lobular appearances at endoscopy were significantly more common for polypoid (23.3%) than for superficial serrated adenomas (7.1%). Pit patterns differed between the lesion types: polypoid serrated adenomas had type III(L) or IV pit patterns; all superficial serrated adenomas had the type II pit pattern. The relative frequency of occurrence of high-grade dysplasia and carcinoma in situ among superficial serrated adenomas (25.2%) was significantly greater than that among polypoid serrated adenomas (9.2%). The tubulovillous growth pattern was significantly more common in polypoid tumors (31.5%) than in superficial tumors (0%). CONCLUSIONS: Polypoid and superficial serrated adenomas have different clinicopathologic characteristics and growth patterns.

Adenoma↗

PubMed2004

Initial experience with catheter probe US when using a multibending endoscope.

BACKGROUND: High-frequency catheter probe US provides detailed images when the scanning plane is perpendicular to the area of interest and the latter is within the focal zone. A multibending endoscope has been developed that has two bending sections that can be deflected independently. The aim of this study was to determine whether this new endoscope enhances high-frequency catheter probe US. METHODS: High-frequency catheter probe US was performed with the multibending endoscope in 33 patients with upper-GI lesions. The endoscope was carefully maneuvered until the scanning plane was perpendicular to the area of interest and the target area was within the focal zone of the probe. The effects of deflecting the second bending section on the image and on the rotating elements in the probe were evaluated. RESULTS: For 28 lesions, no improvement was observed with use of both bending sections. However, for 5 lesions, the US image was improved by use of the second bending section. These lesions were located in the stomach on the lesser or greater curve. In no instance did deflection of both bending sections result in uneven rotation of the mechanical elements in the probe. CONCLUSIONS: For certain lesions, US images obtained with a catheter probe can be improved by using an endoscope with a second bending section.

Catheterization↗

PubMed2004

Magnifying colonoscopic features of ulcerative colitis reflect histologic inflammation.

BACKGROUND: Colonoscopy plays an important role in the diagnosis of ulcerative colitis and the determination of disease activity. Standard colonoscopic findings, however, do not often agree with histologic findings. The aim of this study was to clarify the relation between magnifying colonoscopic features and histologic inflammation in the course of ulcerative colitis. METHODS: We performed magnifying colonoscopy examinations in 60 patients with ulcerative colitis. We classified the features into six types and analyzed the relations among these features, standard colonoscopic features (Matts grades), and pathohistological findings. RESULTS: It was difficult to distinguish the remission stage from the active stage by standard colonoscopy in cases of Matts grade 2 disease. There was a relation, however, between the magnifying colonoscopic types and the degrees of histologic inflammation. The magnifying colonoscopic types reflected histologic inflammation status more accurately than did standard colonoscopic findings. CONCLUSION: Magnifying colonoscopy is useful for determining the degree of histologic change without biopsy in patients with ulcerative colitis.

Adult↗

PubMed2004

Expression of VEGF-C and VEGF-D at the invasive edge correlates with lymph node metastasis and prognosis of patients with colorectal carcinoma.

Vascular endothelial growth factor (VEGF)-C and VEGF-D are potent lymphangiogenic factors produced by tumor and stromal cells. The purpose of this study was to determine whether expression of VEGF-C and/or VEGF-D correlates with clinicopathological features of human colorectal carcinoma. Expression of mRNAs for VEGF-C, VEGF-D, and their receptor VEGFR-3 was examined by reverse transcription-polymerase chain reaction (RT-PCR) in six colon carcinoma cell lines and in fresh endoscopic biopsy specimens from 20 patients with colorectal carcinoma. Expression of VEGF-C and VEGF-D protein was also examined immunohistochemically in 139 archival surgical specimens of human colorectal carcinoma. Of the six cell lines, one (Colo320D) constitutively expressed VEGF-C and four (Colo320D, DLD-1, km12sm, km12c) constitutively expressed VEGF-D mRNA. Expression of VEGF-D mRNA was increased under low oxygen conditions, and all six cell lines constitutively expressed VEGF-D mRNA under hypoxic conditions. Of the 139 specimens of human colorectal carcinoma, 65 (46.8%) showed intense VEGF-C immunoreactivity and 41 (29.5%) showed intense VEGF-D immunoreactivity. In 49 (75.3%) of the 65 and 20 (48.8%) of the 41 cases, heterogeneous intratumoral staining was observed for VEGF-C and VEGF-D, respectively, with the highest levels of expression at the invasive edges. VEGF-C expression correlated with the depth of tumor invasion, lymphatic involvement, venous involvement, lymph node metastasis, and liver metastasis, and VEGF-D expression correlated with the depth of tumor invasion, lymph node metastasis, and liver metastasis. No correlation was observed between VEGF-C and VEGF-D expression in tumors. The survival time of patients with VEGF-C-positive tumors was significantly shorter than that of patients with VEGF-C-negative tumors, and the survival time of patients with VEGF-D-positive tumors was significantly shorter than that of patients with VEGF-D-negative tumors. The survival time of patients with both VEGF-C- and VEGF-D-positive tumors was significantly shorter than that of patients with both VEGF-C- and VEGF-D-negative tumors. These results suggest that VEGF-C and VEGF-D may be independent and important prognostic factors in patients with human colorectal carcinoma.

Adenocarcinoma↗

PubMed2004

Mutation of the von Hippel-Lindau (VHL) gene in human colorectal carcinoma: association with cytoplasmic accumulation of hypoxia-inducible factor (HIF)-1alpha.

We screened for mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and examined the relationship of these mutations with expression of hypoxia-inducible factor (HIF)-1alpha protein in human colorectal carcinomas. DNAs were extracted from 130 paraffin-embedded tumor specimens and subjected to polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis followed by direct sequencing. We identified 13 mutations in the coding sequence of VHL, 12 of which were unique events. Three mutations were located in exon 2 and the others in exon 3. These mutations were detected in 10 of 88 (11.4%) tumors tested. Furthermore, seven of the 13 (53.8%) VHL mutants immunohistochemically showed high HIF-1alpha expression. The mean percentage of cells with strong cytoplasmic HIF-1alpha expression was 67.5% in tumors with VHL mutations, and this level was significantly higher than that in tumors without mutations (50.8%, P < 0.05). These findings suggest that mutations in VHL may play a role in colorectal carcinoma via activation of the HIF-related transcriptional cascade.

Aged↗

PubMed2004

Chromosomal and microsatellite instability in sporadic gastric cancer.

BACKGROUND: Gastric cancer can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). It is hypothesized that these two pathways are not always independent and that some tumors show overlap between these two mechanisms. METHODS: A total of 98 sporadic gastric cancers were classified based on their MSI status, using microsatellite assay with BAT26. Evidence for CIN was investigated by identifying loss of heterozygosity (LOH) events on chromosome arms, 5q, 10p, 17p, 17q, and 18q, which are regions harboring tumor suppressor genes that are significant in gastric cancer development. RESULTS: Twelve tumors (12%) showed high-frequency MSI (MSI-H). Overall, 43 of the tumors (44%) had at least one LOH event, with most frequent chromosomal losses observed on 10p and 18q (30%, respectively), followed by 5q (21%), 17p (14%), and 17q (12%). Interestingly, overlap was observed between CIN and MSI pathways. Of 43 cancers with LOH events, four (9%) were also MSI-H. It was also found that 48% of cancers without MSI-H had no LOH events identified, comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. CONCLUSION: These results suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways in sporadic gastric cancers.

Adult↗

PubMed2004

Frequent loss of RUNX3 expression by promoter hypermethylation in gastric carcinoma.

The RUNX3 gene is a member of the Runt domain family of transcription factors that are master regulators of gene expression in major developmental pathways. Recently, lack of RUNX3 function was found to be associated with genesis and progression of gastric carcinoma. We studied methylation of CpG islands in the RUNX3 gene by methylation-specific PCR in 80 gastric carcinoma specimens, 45 corresponding non-neoplastic mucosae, and 7 gastric carcinoma cell lines. We also measured levels of RUNX3 mRNA in 50 of the gastric carcinoma cases by quantitative RT-PCR and in the gastric carcinoma cell lines by RT-PCR. Hypermethylation of the RUNX3 promoter was found in 57 (71%) of 80 gastric carcinomas, and promoter hypermethylation of RUNX3 occurred more frequently in intestinal and diffuse-adherent type tumors than in diffuse-scattered type tumors (p = 0.046). Reduced RUNX3 expression was associated with promoter hypermethylation (p = 0. 036), however, there was no correlation between RUNX3 mRNA expression levels and T grade, N grade, tumor stage, or histological type. In corresponding non-neoplastic mucosae, hypermethylation of the RUNX3 promoter was found in 38 (84%) of 45 specimens. Among seven gastric carcinoma cell lines, three cell lines (MKN-28, MKN-74, TMK-1) with diminished expression of RUNX3 had promoter methylation and three cell lines (MKN-1, MKN-7, MKN-45) with RUNX3 expression showed no promoter methylation. Our results overall suggest that transcriptional inactivation of RUNX3 by promoter hypermethylation may participate in the stomach carcinogenesis.

Adenocarcinoma↗

PubMed2004

Mucin phenotype and background mucosa of intramucosal differentiated-type adenocarcinoma of the stomach.

OBJECTIVES: Gastric carcinomas have been divided into differentiated (intestinal) and undifferentiated (diffuse) types. Recently, classification studies based on mucin expression have revealed that some differentiated-type carcinomas are of a gastric phenotype. In this study, we investigated the clinicopathological features of differentiated-type adenocarcinomas and evaluated the background mucosa of the stomach based on mucin expression by the tumors. METHODS: Seventy-six intramucosal differentiated-type adenocarcinomas of the stomach were evaluated macroscopically and histologically. The mucin expression of tumor cells was examined by immunohistochemical staining with monoclonal antibodies against human gastric mucin (45M1), class III mucin (HIK1083), small intestinal mucinous antigen (SIMA-4D3), and MUC2 (Ccp58). Tumors were classified by phenotype as gastric (G-type), intestinal (I-type), mixed (M-type), or null (N-type). Not only the clinicopathological features but also the background mucosa of the stomach of G-type and I-type carcinomas were compared histologically and serologically. RESULTS: Seventeen tumors (22.4%) were classified as G-type, 31 (40.8%) as I-type, 22 (28.9%) as M-type, and 6 (7.9%) as N-type. The frequencies of elevated type tumors and papillary adenocarcinomas and the ratio of moderately/well-differentiated adenocarcinomas were higher in G-type than in I-type carcinomas. The scores for glandular atrophy and intestinal metaplasia were higher and the scores for chronic inflammation, polymorphonuclear neutrophil activity, and the density of Helicobacter pylori were lower in G-type than in I-type tumors. The serum level of pepsinogen I and the pepsinogen I/II ratio were significantly lower in G-type than in I-type tumors. CONCLUSIONS: G-type carcinoma is the predominant phenotype of papillary adenocarcinoma. The background mucosa of G-type carcinoma is associated with glandular atrophy and intestinal metaplasia, whereas that of I-type carcinoma is associated with active and chronic inflammation induced by H. pylori infection.

Adenocarcinoma↗

PubMed2004

Expression of human telomerase reverse transcriptase mRNA in esophageal cancers and precancerous lesions.

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.

Carcinoma, Squamous Cell↗

PubMed2004

Angiogenic switch occurs during the precancerous stage of human esophageal squamous cell carcinoma.

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.

Base Sequence↗

PubMed2004

Clinical significance of angiopoietin-2 expression at the deepest invasive tumor site of advanced colorectal carcinoma.

Angiopoietin (Ang)-2 and vascular endothelial growth factor (VEGF) are thought to be critical regulators in tumor angiogenesis. We investigated the clinical significance of Ang-2 expression at the deepest invasive tumor site under the influence of VEGF expression in relation to angiogenesis, invasive/metastatic potential, and prognosis of advanced colorectal carcinoma (CRC). One hundred and fifty-two patients who underwent surgical resection for advanced CRC were enrolled in this study. Ang-2 and VEGF expression were examined immunohistochemically. Tumor microvessel density (MVD) was examined by immunohistochemical staining against CD34. Ang-2 and VEGF were expressed at the deepest invasive tumor site in 90 (59.2%) and 64 (42.1%) of 152 lesions, respectively. Patients with Ang-2 expression at the deepest invasive tumor site showed significantly (p<0.01) more frequent poorly histologic grade (71.9%), lymphatic involvement (65.9%), venous involvement (69.1%), lymph node metastasis (75.0%), liver metastasis (80.0%) and advanced disease (Dukes' stage C, 70.2%; stage D, 80.0%) than patients without Ang-2 expression. MVD was not significantly up-regulated by Ang-2 expression alone at the deepest invasive tumor site but was significantly up-regulated by VEGF expression at the deepest invasive tumor site under the positive-Ang-2 condition. In patients treated by curative surgery, patients with tumors showing both positive-Ang-2 and positive-VEGF condition at the deepest invasive tumor site had significantly poorer prognoses than patients with tumors under other conditions. Multivariate analysis with logistic regression for 5-year survival in cases of curative surgery showed that lymph node metastasis, VEGF expression and Ang-2 expression were significant factors to predict poor prognosis. Our results suggest that Ang-2 expression in collaboration with VEGF expression at the deepest invasive tumor site may result in tumor angiogenesis and that these angiogenic factors at the deepest invasive tumor site may be correlated with invasive/malignant potential and prognosis of advanced CRC.

Adenocarcinoma↗

PubMed2004

Frequent loss of heterozygosity on chromosome 10p14-p15 in esophageal dysplasia and squamous cell 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.

Adult↗