Searching for a marker of malignant conversion in gastrointestinal tumors.
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Adenomatous Polyposis Coli↗
Biomedical subjects
F Itoh
Publications and source records attributed to F Itoh.
DNA methylation and gastrointestinal malignancies: functional consequences and clinical implications.
Evidence now suggests that the transcriptional silencing of selected genes by DNA methylation plays a crucial role in the development and progression of human gastrointestinal malignancies. To date, genes involved in the regulation of the cell cycle, DNA repair, angiogenesis, and apoptosis have all been shown to be inactivated by the hypermethylation of their respective 5' CpG islands. The specific causes and effects of the changes in DNA methylation that occur in cancer remain unknown, however. Nevertheless, recently developed techniques for detecting changes in DNA methylation have dramatically increased the amount of information available on the patterns of methylation that occur as cancers progress. One key process involved in aberrant methylation is related to aging, and because it affects a large number of CpG islands, age-related methylation may be a primary cause of the increased incidence of cancer seen among older individuals. Other patterns of methylation are cancer-specific and are detected only in a subset of tumors exhibiting the CpG island methylator phenotype (CIMP). In this regard, the majority of sporadic colorectal cancers, exhibiting microsatellite instability (MSI) appear to be associated with CIMP, which leads to aberrant methylation of human MutL homologue (hMLH1) and the loss of its expression. We anticipate that as the various components of the molecular machinery involved in aberrant DNA methylation become better understood, they will prove to be useful targets, serving as the basis for the development of new methods for the diagnosis and treatment of gastrointestinal malignancies.
DNA↗
Prevalence of Barrett's esophagus and expression of mucin antigens detected by a panel of monoclonal antibodies in Barrett's esophagus and esophageal adenocarcinoma in Japan.
Barrett's esophagus (BE) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Moreover, it has been reported that short-segment BE may be associated with adenocarcinoma of the esophagogastric junction. The objective of this study was to define the prevalence of BE and the mucin profile in BE, including the short-segment type, and to compare the mucin profile in BE with the profiles of Barrett's adenocarcinoma and distal esophageal adenocarcinoma among Japanese. In total, 650 adult subjects underwent endoscopic examination for evaluation of BE. Although the prevalence of traditional (long segment) BE was 0.62%, the overall prevalence of BE including short-segment type was 15.7%. In Barrett's epithelium, the short-segment type predominantly had gastric type mucin, while the middle- and long-segment types possessed intestinal mucin, especially colonic type mucin (sulfo-Lewis(a)), with high frequency. In Barrett's epithelium with adenocarcinoma, all Barrett's epithelium adjacent to carcinomas showed a predominance of immunoreactivity to sulfo-Lewis(a). In Barrett's adenocarcinomas, colonic type mucin was detected in 100% by monoclonal antibody (MoAb) 91.9H. Small-intestinal mucin and gastric mucin were stained in 50% and 12.5% of the subjects, respectively. Colonic type mucin was also detected with high frequency (80%) in distal esophageal adenocarcinomas without Barrett's epithelium. These data suggest that the epitope, not of small-intestinal type or gastric type mucin, but of colonic type mucin (sulfo-Lewis(a)), may be associated with, at least in part, the malignant phenotype of BE.
Adenocarcinoma↗
Signaling of transforming growth factor-beta family members through Smad proteins.
Smads are pivotal intracellular nuclear effectors of transforming growth factor-beta (TGF-beta) family members. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity trigger phosphorylation of receptor-regulated Smads (R-Smads), whereas Smad2 and Smad3 are phosphorylated by TGF-beta, and activin type I receptors, Smad1, Smad5 and Smad8, act downstream of BMP type I receptors. Activated R-Smads form heteromeric complexes with common-partner Smads (Co-Smads), e.g. Smad4, which translocate efficiently to the nucleus, where they regulate, in co-operation with other transcription factors, coactivators and corepressors, the transcription of target genes. Inhibitory Smads act in most cases in an opposite manner from R- and Co-Smads. Like other components in the TGF-beta family signaling cascade, Smad activity is intricately regulated. The multifunctional and context dependency of TGF-beta family responses are reflected in the function of Smads as signal integrators. Certain Smads are somatically mutated at high frequency in particular types of human cancers. Gene ablation of Smads in the mouse has revealed their critical roles during embryonic development. Here we review the latest advances in our understanding of the Smad mechanism of action and their in vivo functions.
DNA-Binding Proteins↗
Association between complement regulatory protein factor H and AM34 antigen, detected in senile plaques.
BACKGROUND: We have previously shown that monoclonal antibody AM34, which is reactive with senile plaques, may recognize the C terminus of complement factor H. In this study, we investigated the expression of factor H in tissue from a human brain and the relation between AM34 antigen and factor H. METHOD: Total ribonucleic acid (RNA) was extracted from a normal human brain. A reverse transcriptase-polymerase chain reaction method was employed for detecting messenger RNAs coding for factor H and related proteins. Protein extracts from a normal human brain were also analyzed to detect factor H and related proteins by means of Western blotting. The cerebrospinal fluid from an Alzheimer's disease patient was immunoprecipitated with AM34 and anti-factor-H antibodies, and then it was subjected to gel electrophoresis followed by immunoblotting with AM34 and anti-factor-H antibodies. RESULTS: 26 clones of complementary DNA fragment were obtained by reverse transcriptase-polymerase chain reaction. Among them, seven clones were identical to factor H, and the others were related proteins and unreported sequences. A Western blot analysis of protein extracts from the normal brain tissue exhibited a 150-kd band, indicating the presence of factor H. AM34 was immunoreactive with the 150-kd molecule contained in the immunoprecipitates with anti-factor H antibodies, and vice versa. These results suggest that AM34 antigen could be identical to complement factor H. CONCLUSIONS: The results of our experiments indicate that factor H is possibly detected in the human brain, and that the AM34 antibody could recognize factor H. Because AM34 is capable of staining senile plaques positively, factor H is suggested to be associated with senile plaques in the human brain.
Aged↗
Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract.
BACKGROUND: Little is known about the genetic alterations in multiple primary cancers of the gastrointestinal tract. Microsatellite instability (MSI) is frequently observed in hereditary non-polyposis colorectal cancer (HNPCC), and multiple primary cancers is a feature of this syndrome. AIMS: To identify MSI incidence, target gene mutation, and mismatch repair (MMR) protein status in patients with multiple primary cancers of the gastrointestinal tract. SUBJECTS: Fifty seven cancers from 22 Japanese patients with multiple primary cancers of the stomach, duodenum, colon, and rectum. METHODS: MSI was examined at 5-7 microsatellite loci. Mutation analysis for TGFbetaRII, IGFIIR, and BAX was performed in cancers with MSI. MMR protein status was examined by immunohistochemical analysis using a monoclonal antibody against hMSH2 and hMLH1. RESULTS: MSI was observed in 16 of 22 patients (73%) and in 29 of 57 lesions (51%). High frequency MSI (MSI-H) was found often in patients with multiple cancers in the same organ (p = 0.042), especially in multiple gastric cancer patients (p = 0.038). In contrast, patients with multiple cancers in different organs had a tendency to show low frequency MSI (MSI-L) or microsatellite stable (MSS) phenotype. Both target gene mutation and decreased expression of MMR protein were found only in seven lesions of three patients with MSI at more than four microsatellite loci. CONCLUSIONS: These results suggest that genetic instability may play an important role in the development of multiple gastrointestinal cancers but there may be different genetic alterations between multiple gastrointestinal cancers of the same and different organs.
Aged↗
Neutropenia accompanying parvovirus B19 infection after gynecologic surgery.
The hematologic data and symptoms of 7 patients seropositive for parvovirus B19 IgM antibody after gynecologic surgery were analysed. Parvovirus may have been transmitted by fibrin glue prepared from heat-treated human plasma and used for hemostasis during surgery. The peripheral blood neutrophil count decreased to below 1 x 10(9)/l between postoperative day (POD) 10 and 18, but recovered spontaneously to within the normal range. G-CSF injection was effective in preventing neutropenia or obtaining a prompt recovery. The reticulocyte count fell below 10 x 10(9)/l between POD 13 and 19, and also recovered spontaneously. A slapped-cheek rash was not observed in any of the 7 patients.
Adolescent↗
Non-glutamate type pyrrolo[2,3-d]pyrimidine antifolates. III. Synthesis and biological properties of N(omega)-masked ornithine analogs.
The glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-g lutamic acid (1b, TNP-351) and the related compound (1a), was replaced with various N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-2,omega-diaminoalkanoic acids, and the inhibitory effects of the resulting products (9, 11, 14, 18, 21, 23, 25, 30, 36) on dihydrofolate reductase (DHFR), the growth of murine fibrosarcoma Meth A cells, and methotrexate-resistant human CCRF-CEM cells, were examined. Compounds (9a-f) acylated with a hemiphthaloyl group were efficiently synthesized by coupling pyrrolo[2,3-d]pyrimidine carboxylic acids (7a,b) and N(omega)-phthaloyl 2,omega-diaminoalkanoic acid methyl esters (6a-c) and subsequent hydrolysis. The other N(omega)-acyl- and sulfonyl-ornithine analogs (21, 23, 25) were synthesized by acylation of free amino intermediates (19a,b) derived from tert-butoxycarbonyl-ornithine analogs (17a,b). A free ornithine analog (18) did not strongly inhibit Meth A cell growth, whereas all N(omega)-acyl-, sulfonyl-, carbamoyl- and aryl-ornithine analogs (9, 11, 21, 23, 25, 30, 36) exhibited much more potent inhibitory activities against both DHFR and Meth A cell growth. In particular, compounds 9c, 21k and 36a also showed remarkable growth-inhibitory activities against methotrexate-resistant CCRF-CEM cells. These results demonstrate that the potent inhibitory activities of N(omega)-masked ornithine analogs against the growth of Meth A cells and methotrexate-resistant CCRF-CEM cells, results from effective uptake via reduced folate carrier and their potent DHFR inhibition.
Cell Division↗
Infrequent widespread microsatellite instability in hepatocellular carcinomas.
Widespread or high-frequency microsatellite instability (MSI) due to the defective DNA mismatch repair (MMR) occurs in the majority of hereditary non-polyposis colorectal cancer and a subset of sporadic malignant tumors. The incidence of MSI and underlying DNA MMR defects have been well characterized in gastrointestinal carcinogenesis, but not in hepatocarcinogenesis. To address the issue, we analyzed 55 Japanese hepatocellular carcinomas using several indicators of DNA MMR defects, such as microsatellite analysis, loss of heterozygosity (LOH) and mutation analysis of MMR genes, methylation of hMLH1 promoter, and frameshift mutations of mononucleotide repeat sequences within possible target genes. Mutation of beta2-microglobulin gene, which is presumably involved in MSI-positive tumor cell escape from immune surveillance was also examined. Some of these analyses were also carried out in 9 human liver cancer cell lines. None of the 3 quasi-monomorphic mononucleotide markers sensitive for MSI, BAT26, BAT25, and BAT34C4 presented shortened unstable alleles in any of the carcinoma, cirrhosis, chronic hepatitis tissues, or cell lines. LOH at MMR genes was infrequent (4.4 approximately 7.1%), and no mutations were detected. Neither hMLH1 hypermethylation nor frameshift mutation in the target genes was detected. No mutations were found in beta2-microglobulin. Widespread MSI due to the defective DNA MMR appears to play little if any part in Japanese hepatocarcinogenesis.
Adult↗
Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype.
Aberrant methylation of 5' CpG islands is thought to play an important role in the inactivation of tumor suppressor genes in cancer. In colorectal cancer, a group of tumors is characterized by a hypermethylator phenotype termed CpG island methylator phenotype (CIMP), which includes methylation of such genes as p16 and hMLH1. To study whether CIMP is present in gastric cancer, the methylation status of five newly cloned CpG islands was examined in 56 gastric cancers using bisulfite-PCR. Simultaneous methylation of three loci or more was observed in 23 (41%) of 56 cancers, which suggests that these tumors have the hypermethylator phenotype CIMP. There was a significant concordance between CIMP and the methylation of known genes including p16, and hMLH1; methylation of p16 was detected in 16 (70%) of 23 CIMP+ tumors, 1 (8%) of 12 CIMP intermediate tumors, and 1 (5%) of 21 CIMP- tumors (P<0.0001). Methylation of the hMLH1 gene was detected in three of five tumors that showed microsatellite instability, and all three of the cases were CIMP+. The CIMP phenotype is an early event in gastric cancer, being present in the normal tissue adjacent to cancer in 5 of 56 cases. These results suggest that CIMP may be one of the major pathways that contribute to tumorigenesis in gastric cancers.
Adaptor Proteins, Signal Transducing↗
Distinct methylation pattern and microsatellite instability in sporadic gastric cancer.
Aberrant 5' CpG island methylation is an alternative mechanism of gene inactivation during the development of cancer as demonstrated for several tumor-suppressor genes. Also, marked relationship of microsatellite instability (MSI) and DNA methylation has been reported in sporadic colorectal cancer, which is a result of epigenetic inactivation of hMLH1 in association of promoter hypermethylation. In the present study, we investigated the 5' CpG island hypermethylation of hMLH1, E-cadherin and p16 in 61 primary gastric cancers (GCs) by using combined bisulfite restriction analysis (COBRA) and methylation-specific PCR (MSP), and their MSI status. Of 61 GCs investigated, 5 (8.1%) tumors presented hMLH1 methylation, 16 (26.2%) and 25 (40.9%) showed E-cadherin and p16 methylation respectively, and 8 (13.1%) presented high-frequency MSI (MSI-H). Of the 8 MSI-H patients, 5 presented hMLH1 methylation, whereas no low-frequency MSI (MSI-L) and microsatellite stable (MSS) cases exhibited hMLH1 methylation (5/8 vs. 0/43, p < 0.00001). Furthermore, these patients also presented E-cadherin and p16 hypermethylation. Our data showed a significant correlation between hMLH1 methylation and MSI in GC, and suggested that a common mechanism of aberrant de novo methylation can be postulated in these cancers.
Adaptor Proteins, Signal Transducing↗
Xenopus Smad4beta is the co-Smad component of developmentally regulated transcription factor complexes responsible for induction of early mesodermal genes.
Smad4 is defined as the common-mediator Smad (co-Smad) required for transducing signals for all TGF-beta superfamily members. This paper describes two Smad4s in Xenopus: XSmad4alpha, which is probably the Xenopus orthologue of human Smad4, and a distinct family member, XSmad4beta, which differs primarily at the extreme N-terminus and in the linker region. Both XSmad4s act as co-Smads, forming ligand-dependent complexes with receptor-regulated Smads 1 and 2 and synergizing with them to activate transcription of mesodermal genes in Xenopus embryos. The two XSmad4 genes have reciprocal temporal expression patterns in Xenopus embryos and are expressed in varying ratios in adult tissues, suggesting distinct functional roles in vivo. XSmad4beta is the predominant maternal co-Smad and we go on to demonstrate its role in the transcriptional regulation of early mesodermal genes. We have identified two distinct nuclear complexes that bind the activin-responsive element of the Xenopus Mix.2 promoter: one formed in response to high levels of activin signaling and the other activated by endogenous signaling pathways. Using specific antisera we demonstrate the presence of endogenous XSmad4beta and also XSmad2 in both of these complexes, and our data indicate that the DNA-binding components of the complexes are different. Furthermore, we show that the presence of these complexes in the nucleus perfectly correlates with the transcriptional activity of the target gene, Mix.2, and we show that one of the XSmad4beta-containing transcription factor complexes undergoes a developmentally regulated nuclear translocation.
Activins↗
Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellite instability.
Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers. However, the relationship between expression of COX-2 and clinico-pathological or genotypic features has not been elucidated. To address the issue, expression of COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected in some gastric cancer cell lines without MSI at various levels, but not in those with MSI. Our results suggest that overexpression of COX-2 may play an important role in tumor progression of gastric cancer and also support the notion that gastric cancers with and without MSI represent distinctive pathways of carcinogenesis. We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999.
Adaptor Proteins, Signal Transducing↗
Association of matrilysin expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma.
Matrix metalloproteinase-7 (matrilysin) has been implicated in tumor invasion and metastasis as well as tumor initiation and growth. In this study, we analyzed an association between immunohistochemically detected matrilysin expression at the invasive front in esophageal squamous cell carcinomas and clinicopathological characteristics and determined whether matrilysin predicts recurrence and/or survival Matrilysin expression at the invasive front was detected in 49% of 100 carcinoma tissues and was associated with the depth of invasion (P < 0.0001), advanced tumor stage (P = 0.0159), recurrences (P = 0.0002), and recurrences within the first postoperative year (P = 0.002). Patients with matrilysin-positive carcinoma had a significantly shorter disease-free and overall survival time than did those with a matrilysin-negative one (P < 0.0001). Matrilysin remained a significant predictive value for disease-free and overall survival in multivariate analysis, including conventional clinicopathological factors (P = 0.0007 and 0.0004, respectively). Our results suggest that matrilysin may play a key role in the progression of esophageal carcinoma and that its detection may be useful for the prediction of recurrence and poor prognosis and, possibly, for selecting patients for anti-matrix metalloproteinase therapy.
Carcinoma, Squamous Cell↗
Expression of MUC2 gene in gastric regenerative, metaplastic, and neoplastic epithelia.
It has been reported that MUC2 mucin is expressed in goblet cells of gastric intestinal metaplasia, but not in its normal epithelium. To confirm this finding, we have examined the expression of the MUC2 gene by reverse transcriptase-polymerase chain reaction and immunohistochemical methods in gastric tissues obtained by routine upper gastrointestinal tract endoscopy and compared the results with pathological findings based on hematoxylin and eosin (H&E) staining. In 16.7% of the tissue specimens tested, MUC2 mRNA was detected in spite of the absence of intestinal metaplasia in HE specimens. A possible explanation for this was the identification by immunohistochemistry of MUC2 protein in regenerative gastric mucosal cells in biopsies that did not contain intestinal metaplasia. Sialyl-Le(x) epitope, which is suggested to be located on MUC2 mucin core protein (MUC2 protein), was also immunohistochemically detected in both goblet cells of intestinal metaplasia and regenerative epithelium. With regard to carcinoma, MUC2 protein was predominantly expressed in intestinal-type adenocarcinoma. These data indicate that MUC2 mucin is expressed in gastric regenerative epithelium in addition to intestinal metaplasia and intestinal type adenocarcinoma.
Adult↗
Gene or genome? The meaning of gains/losses of chromosome.
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Chromosome Aberrations↗
Association of cyclin D1 expression with factors correlated with tumor progression in human hepatocellular carcinoma.
The amplification and/or rearrangement of the cyclin D1 gene, a positive regulatory element of the G1 to S phase of the cell cycle, has been reported in various human tumors, suggesting an oncogenic role of this gene. In this study, we investigated the expression of cyclin D1 in the formalin-fixed and paraffin-embedded human hepatocellular carcinoma (HCC) tissues of 25 patients, using monoclonal antibody 5D4 raised against cyclin D1. Two distinct patterns of staining were observed in HCC cells, nuclear and cytoplasmic. The nuclear staining pattern of cyclin D1 was detected in the tissues of only 2 of the 25 HCC patients (8%) examined and no particular clinicopathological characteristics were found in these patients. In contrast, the cytoplasmic staining pattern, without nuclear staining, was detected in 8 of the 25 patients with HCC (32%). A significant correlation was found between the expression of cytoplasmic cyclin D1 and patients with tumor thrombus in the portal vein (Vp), as well as those with intrahepatic metastasis (IM). These results indicate that the cytoplasmic cyclin D1 expression appears to be related to the prognosis of HCC. The Ag nucleolar organizer regions (NORs) counts in cyclin D1-positive and -negative patients were not significantly different, suggesting that immunostaining for cyclin D1 has the potential to be a unique prognostic marker in human HCC. Simultaneous immunohistochemical study with p53 antibody in the same series of HCC revealed that 88% of the patients positive for cyclin D1 also expressed p53 and that in 91% of the patients negative for p53, cyclin D1 was not expressed. These results suggest that cyclin D1 is expressed later than the alteration of p53 in the progression of human HCC.
Adult↗
Treatment effects of bisphosphonates on ovariectomy-induced osteopenia in rats: comparison between clodronate and etidronate.
We studied the effects of clodronate and etidronate on bone loss induced by ovariectomy (OVX) in rats. Drug administration was initiated 8 weeks after the surgery and continued for 12 weeks (twice per week, s.c.). Lumbar (L4-L5) bone mineral density (BMD) and femoral BMD in the sham-operated group were increased to 113% and 114%, respectively, whereas those in OVX group were suppressed to 98.8% and 105%. Clodronate significantly restored the suppressed BMD over the entire dose range used (4-25 mg/kg). Etidronate restored BMD only at 4 mg/kg. In a histomorphometric analysis of lumbar vertebrae, both bisphosphonates depressed the amount of labeled surface, which was increased by OVX, to 11.9%-20.1% of the OVX group value for clodronate and to 0.23%-9.7% of the OVX group value for etidronate. The osteoid area was significantly increased by etidronate treatment over the entire dose range (OS/BS, 175%-295%). On the other hand, the osteoid area in the clodronate group did not increase at any dose tested (OS/BS, 38.1%-49.9%). Urinary excretion of deoxypyridinoline and plasma level of osteocalcin were elevated in the OVX group (162%-182% and 123%, respectively), suggesting that OVX enhanced bone turnover. Both bisphosphonates suppressed the bone turnover accelerated by OVX, and the data indicated that both bisphosphonates recovered BMD by means of inhibition of bone resorption. These data suggested that clodronate and etidronate reversed osteopenia induced by ovariectomy in rats. As judged from the dose response of BMD and histomorphometric findings, clodronate showed a wider safety margin than etidronate.
Amino Acids↗