The sequential accumulation of genetic alterations characteristic of the colorectal adenoma-carcinoma sequence does not occur between gastric adenoma and adenocarcinoma.
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Adenocarcinoma↗
Biomedical subjects
E Tahara
Publications and source records attributed to E Tahara.
Expression of cyclin-dependent kinase inhibitor p21WAF1/CIP1 in non-neoplastic mucosa and neoplasia of the stomach: relationship with p53 status and proliferative activity.
The expression of the p53-inducible cyclin-dependent kinase inhibitor p21WAF1/CIP1 in non-neoplastic mucosa, adenoma, and adenocarcinoma of the stomach was examined immunohistochemically and its relationship with p53 expression and proliferative activity was analysed. In normal gastric mucosa as well as in intestinal metaplasia the epithelial cells at the surface which showed no proliferative activity expressed p21WAF1/CIP1, whereas the cells in the deep area of the glands expressing Ki-67 did not. In the neoplastic lesions, the expression of p21WAF1/CIP1 was detected in 78 per cent (112/144) of the adenomas and 76 per cent (262/343) of the adenocarcinomas. The incidence of p21WAF1/CIP1 expression did not differ among histological types of gastric carcinoma. The strong expression of p21WAF1/CIP1 was more frequently observed in carcinomas invading into submucosa or in cases of stages 2, 3, and 4 than in carcinomas limited to the mucosa or in stage 1 cases. The incidence of strongly positive cases was higher in carcinomas with lymph node metastasis than in those without metastasis. There was no apparent correlation between the expression of p21WAF1/CIP1 and the abnormal accumulation of p53 or with proliferative activity measured by Ki-67 expression. These findings overall suggest that p21WAF1/CIP1 might be associated with the senescence of non-neoplastic gastric epithelial cells; that a p53-independent pathway might be substantially involved in the induction of p21WAF1/CIP1 in gastric neoplasia; and that the proliferative activity of gastric cancer might not be solely dependent on control of the cell cycle by p21WAF1/CIP1.
Adenocarcinoma↗
Expression of cripto in human gall bladder lesions.
The expression of cripto, a member of the epidermal growth factor (EGF) family, was examined by immunohistochemistry in benign lesions and carcinomas of the gall bladder. Cripto expression was detected in 6 (67 percent) of 9 hyperplasias, 4 (58 percent) of 7 adenomas, and 89 (68 percent) of 132 adenocarcinomas of the gall bladder. The degree of cripto expression was not correlated with depth of tumour invasion, tumour stage or patient prognosis. The incidence of cases with cripto expression was significantly higher in papillary and well-differentiated adenocarcinomas (positive 73 percent; strongly positive 38 percent) than in moderately and poorly differentiated adenocarcinomas (positive 54 percent; strongly positive 17 percent) (P < 0.05). These results suggest that cripto expression may not relate to progression in gall bladder carcinomas, but may be associated with tumour differentiation.
Adenocarcinoma↗
Expression of cyclin E in colorectal adenomas and adenocarcinomas: correlation with expression of Ki-67 antigen and p53 protein.
The expression of cyclin E in human colorectal adenomas and adenocarcinomas was examined immunohistochemically to elucidate the role of cyclin E in the colorectal carcinogenesis. The expression of cyclin E was detected in 25% (91/358) of the adenomas and 56% (149/267) of the adenocarcinomas. The incidence of strongly positive cases was significantly higher in the adenocarcinomas (20%) than in the adenomas (5%) (P < 0.01). Among adenomas, a significant correlation was noticed between the expression of cyclin E and the grade of atypia. The incidence of cyclin E expression was significantly higher in the adenocarcinomas without an adenoma component (62%; 104/169) than in those with this component (46%; 45/98) (P < 0.05). Furthermore, the incidence of the cyclin E expression was higher in stages 1 and 2 carcinoma than in stage 0 and stages 3 and 4 carcinoma. The expression of cyclin E was the most prominent in tumors invading the submucosa and muscularis propria. The expression of cyclin E was significantly correlated with the proliferative activity of the tumor cells measured by Ki-67 antigen expression (P < 0.01). It was also correlated with the expression of p53 protein in the tumor cells (P < 0.01). Overexpression of cyclin E and subsequent deregulation of cell cycle may contribute to the development and early progression of the colorectal carcinomas.
Adenocarcinoma↗
Telomerase and cancer. The Fifth International Symposium of the Hiroshima Cancer Seminar October 1995, Hiroshima, Japan.
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Humans↗
Molecular-pathological analysis of a patient with three synchronous squamous cell carcinomas in the aerodigestive tract.
A case of synchronous squamous cell carcinomas in the soft palate, larynx and esophagus is reported, along with findings of molecular-pathological analysis. A biopsy sample from the aryngeal carcinoma revealed well differentiated squamous cell carcinoma harboring two point mutations at codons 144 and 148 of the p53 gene but not at codon 299, and more than 50% of the cancer cells showed accumulation of p53 protein immunohistochemically. The esophageal tumor, which was moderately differentiated squamous cell carcinoma, showed immunoreactivity for p53 within the nuclei of 25-50% of cancer cells with a missense mutation at codon 299 but not at codon 144 or 148. This cancer also showed immunoreactivity for transforming growth factor alpha. On the other hand, the poorly differentiated squamous cell carcinoma in the soft palate showed negative immunoreactivity for p53 and no point mutation in exons 5 to 8 of the gene. These results suggest that the three synchronous squamous cell carcinomas arose as independent events.
Aged↗
Inhibition of cell growth by transforming growth factor beta 1 is associated with p53-independent induction of p21 in gastric carcinoma cells.
Cell cycle regulators such as cyclins, cyclin-dependent kinases (cdks) and their inhibitors control the growth of cells. SDI1/CIP1/WAF1/p21 is a potent inhibitor of G1 cdks, whose expression is induced by wild-type p53. To elucidate the mechanism of growth inhibition by transforming growth factor beta 1 (TGFbeta 1), we examined the effect of TGFbeta 1 on the expression of p21, G1 cyclins and cdks by human gastric cancer cell lines. TGFbeta 1 induced p21 expression and subsequently suppressed cdk2 kinase activity, followed by a reduction in phosphorylation of the product of the retinoblastoma tumor suppressor gene in TMK-1 cells, which are responsive to TGFbeta 1. Coimmunoprecipitation analysis demonstrated that TGFbeta 1 increased the level of p21 protein present in complexes with cdk2. In contrast, TGFbeta 1 did not induce p21 in TGFbeta 1-resistant MKN-28 cells. TGFbeta 1 did not affect the levels of p53 mRNA and protein in TMK-1 and MKN-28 cells, which contain mutated p53 genes. These mutated p53 complementary DNAs, when overexpressed, failed to activate transcription from the p21 promoter. Furthermore, TGFbeta 1 caused a reduction in the steady-state level of cyclin A protein concomitantly with inhibition of cdk2 kinase activity in TMK-1 cells. These results suggest that the growth inhibition of tumor cells by TGFbeta 1 is associated with p53-independent induction of p21, subsequent suppression of cdk activity and a decrease in cyclin A protein in TMK-1 cells.
Adenocarcinoma↗
Genetic status and expression of the cyclin-dependent kinase inhibitors in human gastric carcinoma cell lines.
Deregulation of cyclin, cyclin-dependent kinases (CDKs) and their inhibitors could have a pivotal role in the development of diverse human cancers. We examined the genetic status and the expression of CDK inhibitors (p21, p27, p16 and p15), CDK2 and cyclins (A, D1 and E) in eight gastric carcinoma cell lines, in comparison with the status of p53 gene alterations. All the cell lines (except MKN-28) that contained a p53 gene abnormality expressed very low or undetectable levels of p21 mRNA, while the cell lines (MKN-45 and -74) with wild-type p53 gene expressed high levels of p21 mRNA. An inverse correlation was found between the level of p21 mRNA and the expression of mRNAs for CDK2 and G1 cyclins. MKN-28 was an exception; it contained mutated p53, and expressed mRNAs for p21, CDK2 and G1 cyclins at high levels. Only MKN-45 and -74, with wild-type p53, expressed considerable levels of p21 protein. Homozygous deletion of the p16 and p15 genes was detected in two (MKN-45 and HSC-39) of the eight gastric carcinoma cell lines, p16 protein was not expressed in three cell lines (MKN-28, MKN-74 and KATO-III), as well as MKN-45 and HSC-39. Rearrangement of the p15 gene was found in TMK-1. Rearrangement of the p27 gene was detected in MKN-45, although the expression of p27 protein was well preserved in all the gastric carcinoma cell lines. The expression of pRb was also preserved in all the cell lines except KATO-III. No obvious correlation was observed between the p53 gene status and the expression of p27 and p16. These findings suggest that abnormal regulation of CDK2/cyclins and CDK inhibitors might be involved in deregulated growth of gastric carcinomas.
Adenocarcinoma↗
Hepatoblastoma in an adult associated with c-met proto-oncogene imbalance.
A rare case of hepatoblastoma in a 61-year-old Japanese housewife is described. This liver tumor mainly consisted of two tissue components: embryonal hepatocytes and primitive mesenchymal tissue. Fetal hepatocytes with alpha-fetoprotein production, gland formation, cartilage and osteoid were also found in a small portion. Molecular analysis by slot blot method revealed increased copy numbers of c-met and K-sam proto-oncogenes and cyclin D1 genes. These findings suggest that alterations of these oncogenes might play a role in the development of adult hepatoblastoma.
Cyclin D1↗
Comparison of proliferative activities and metastases between two subtypes classified at the deeply infiltrating sites of colorectal moderately differentiated adenocarcinomas.
Twenty-eight moderately differentiated adenocarcinomas invading beyond the muscularis propria of the colorectum were subclassified as 13 moderate- and 15 poor-subtype tumors based on the histology at the deeply infiltrating sites. Moderately differentiated cancer cells were correlated with liver metastasis and p53 immunoreactivity. Poorly differentiated cancer cells were correlated with lymph node metastases but not to p53 immunoreactivity. The proliferative cell nuclear antigen (PCNA) labeling index (LI), Ki-67 LI and agyrophilic nuclear organizer regions (AgNOR) values determined for the poorly differentiated cancer cells in the poor-subtype tumors were significantly lower than those of moderately differentiated cancer cells in the moderate-subtype tumors. In cells from tumors classified as poor-subtype, poor differentiation was associated with decreased PCNA LI levels, but with unchanged Ki-67 LI and AgNOR values. These results indicate that colorectal adenocarcinoma cells that are histologically subclassified as moderately differentiated have different proliferative and metastatic activities from cancer cells that are poorly differentiated. Moderately differentiated cancer cells are associated with hematogenous metastasis to liver and high proliferative activity, and loss of tubular formation of cancer cells may be fundamentally related to lymph node metastasis and infiltrative growth.
Adenocarcinoma↗
Detection of exfoliated carcinoma cells in colonic luminal washings by identification of deranged patterns of expression of the CD44 gene.
AIMS: To investigate whether colonic cancer cells exfoliated into the lumen of the organ can be detected by identification of their abnormal CD44 gene products. METHODS: Exfoliated cells were obtained by centrifugation of saline wash-outs of 27 surgically resected colon specimens obtained from 15 patients with carcinoma, seven with ulcerative colitis and five with Crohn's disease. After extracting cellular mRNA, amplification by the reverse transcription-polymerase chain reaction (RT-PCR) technique and analysis by Southern blot hybridisation was carried out to examine the levels and patterns of transcription of exons 11(v6), and 12(v7) and intron 9 of the CD44 gene. The transcription of these CD44 components was also examined by RT-PCR of snap-frozen solid tissue specimens from 11 of the above patients with colorectal carcinoma, seven with ulcerative colitis and five with Crohn's disease. RESULTS: Abnormal expression of exons 11(v6) and 12(v7) was detected in exfoliated cells from 11 (73%) of 15 patients with carcinoma, but not in any patients with inflammatory bowel disease (IBD). The retention of intron 9 in CD44 mRNA transcripts was detected in washings from four (27%) carcinoma specimens but not in washings from non-malignant specimens. It was confirmed that in solid tissue samples from the same carcinomas there was abnormal over-expression of numerous alternatively spliced CD44 species containing transcripts of exons 11 and 12 and retention of intron 9. Low level expression of these exons was detected in tissue from inflammatory lesions from five of seven patients with ulcerative colitis and four of five with Crohn's disease. The retention of intron 9 was not seen in normal mucosa nor IBD. CONCLUSION: Abnormal expression of the variant exons and of intron 9 of the CD44 gene in tumour cells exfoliated into the colonic lumen may be helpful markers for the early, non-invasive, diagnosis of colorectal cancer.
Aged↗
Molecular biological observations in gastric cancer.
Alterations in the structure and function of oncogenes and tumor suppressor genes, as well as genetic instability at several other genetic foci may be responsible for stomach carcinogenesis. The particular combination of multiple gene changes found in gastric cancer differs depending on the two histological types, strongly indicating that different genetic pathways exist for well differentiated or intestinal type and poorly differentiated or diffuse type gastric cancers. In general, genetic instability, telomerase activity, CD44 abnormal transcripts, and p53 mutation, all of which are common events of two types of gastric cancer, may be involved mainly in the early stage of stomach carcinogenesis, whereas activation of oncogenes and overexpression of the epidermal growth factor-related growth factor system may chiefly confer progression on gastric cancer. A new strategy of molecular diagnosis of gastrointestinal cancer, which has been implemented as a routine service in the Hiroshima University Clinical Laboratory, may provide new opportunities for early cancer diagnosis and more accurate evaluation of prognosis or grade of malignancy.
Disease Progression↗
[Genetic alterations in stomach cancer].
The scenario of multistep of stomach carcinogenesis differs depending on the two histological types, well differentiated adenocarcinoma and poorly differentiated adenocarcinoma, because the two types may have different genetic pathways. Genetic instability, reactivation of telomerase and abnormal transcript of CD44 including intron 9 are common events of both well and poorly differentiated type carcinomas. These occur at early stage of carcinogenesis, even in precancerous lesions such as intestinal metaplasia and adenoma. Inactivation of APC, activation of K-ras, amplification of c-erbB2, and allelic loss of DCC locus are associated with well differentiated type, while amplification of K-sam and functional loss of cadherin/catenin are characteristics of poorly differentiated type. HGF/c-met system plays a pivotal role in morphogenesis of both histological types through interaction with cell-cell adhesion molecules. Reactivation of telomerase or genetic instability may be an initial event for accumulation of multiple genetic alterations during the progression of stomach carcinogenesis.
Adenocarcinoma↗
Analysis of the hepatocyte growth factor receptor in regeneration and oncogenesis of the liver.
The c-met proto-oncogene product is the tyrosine kinase receptor for hepatocyte growth factor. To gain insights into its functions in the liver, we carried out a study of the expression and tyrosine phosphorylation status of the Met protein during hepatic regeneration and in human hepatocellular carcinomas. Following partial hepatectomy of rats, decreased expression of the proreceptor p170MET and reduced levels of tyrosine phosphorylation were seen within 12 h. These changes were still evident 7 days later. By contrast, there was no significant alteration of the Met beta subunit. The analysis of samples from 18 patients with hepatocellular carcinoma revealed that the expression of p160MET proreceptor was increased in non-cancerous areas, while that of the p145 beta MET proreceptor was significantly greater in the tumor tissue than in the non-tumor areas (p < 0.05). These findings suggest that processing of the Met proreceptor is closely associated with regeneration and carcinogenesis of the liver.
Adult↗
High frequency of p53 gene mutation in adenocarcinomas of the gallbladder.
p53 mutations in adenocarcinomas of the gallbladder were analyzed by deoxynucleotide sequencing of the gene. Of 23 cases, 16 (70%) harbored 18 missense mutations in exon 5, 6, or 8 of the p53 gene. The characteristics of the p53 mutation spectrum observed in gallbladder carcinomas were (a) frequent mutations at an A:T pair [10 (55%) of 18 mutations], (b) high transversion incidence [12 (66%) of 18 mutations], and (c) only one mutation at the CpG site. The immunohistochemical study revealed that 36 (55%) of 65 cases showed an abnormal accumulation of p53 immunoreactivity, and 12 (52%) of 23 cases had p21 expression. No statistical correlation was observed between p53 and p21 immunoreactivity. These results suggest that p53 mutations may confer the carcinogenesis of the adenocarcinoma of the gallbladder with the specific mutation spectrum of p53.
Adenocarcinoma↗
Regulation of carcinoembryonic antigen expression in human colon carcinoma cells by the organ microenvironment.
The expression of carcinoembryonic antigen (CEA) is thought to be involved in homotypic adhesion and has been associated with the progression of human colon carcinomas (HCC) to the metastatic state. Three cell lines established from surgical specimens of Dukes' stage D (KM20) or Dukes' stage B (KM12C, KM12SM) with high and low preoperative CEA serum levels, respectively, were studied subsequent to growth in culture, in the subcutis (ectopic) or cecal wall (orthotopic) of nude mice. In all cell lines, CEA expression was higher in cecal tumors than in subcutaneous lesions. The degree of differentiation and CEA expression by HCC growing in the cecal wall of nude mice correlated with the pathological diagnosis and preoperative CEA level of the original patients. To better understand the regulation of CEA expression, the HCC cells were grown in culture as sparse and confluent monolayers or as multicell spheroids. The CEA expression level increased in all three cell lines growing as confluent monolayers and was highest in multicell spheroids. Treatment of sparse monolayer cultures of KM12SM cells with mitomycin-C inhibited cell division and was associated with higher production of CEA protein. Moreover, conditioned media from confluent monolayer cultures or from spheroids up-regulated CEA production in sparse monolayer cells. These data show that CEA expression in HCC cells may be regulated by cell density and by factors from the organ environment.
Animals↗
Multiparametric in situ mRNA hybridization analysis to predict disease recurrence in patients with colon carcinoma.
We examined the expression level of several genes that regulate different steps of metastasis in formalin-fixed, paraffin-embedded archival specimens of primary human colon carcinomas from patients with at least 5 years of follow-up. The expression of epidermal growth factor receptor, basic fibroblast growth factor, type IV collagenase, E-cadherin, and multidrug resistance (mdr-1) was examined by a colorimetric in situ mRNA hybridization technique concentrating on reactivity at the periphery of the neoplasms. The in situ hybridization technique revealed inter- and intratumor heterogeneity for expression of the metastasis-related genes. The expression of basic fibroblast growth factor, collagenase type IV, epidermal growth factor receptor, and mdr-1 mRNA was higher in Dukes's stage D than in Dukes' stage B tumors. Among the 22 Dukes' stage B neoplasms, 5 specimens exhibited a high expression level of epidermal growth factor receptor, basic fibroblast growth factor, and collagenase type IV. Clinical outcome data (5-year follow-up) revealed that all 5 patients with Dukes' stage B tumors developed distant metastasis (recurrent disease), whereas the other 17 patients with Dukes' stage B tumors expressing low levels of the metastasis-related genes were disease-free. Multivariate analysis identified high levels of expression of collagenase type IV and low levels of expression of E-cadherin as independent factors significantly associated with metastasis or recurrent disease. More specifically, metastatic or recurrent disease was associated with a high ratio (> 1.35) of expression of collagenase type IV to E-cadherin (specificity of 95%). Collectively, the data show that multiparametric in situ hybridization analysis for several metastasis-related genes may predict the metastatic potential, and hence the clinical outcome, of individual lymph-node-negative human colon cancers.
Carcinoma↗
[Mutations of hMSH2 gene and hMLH1 gene in human colovectal carcinomas].
Mutations of the hMSH2 and hMLH1 mismatch repair system genes in hereditary non-polyposis colorectal cancer (Lynch) syndrome as well as sporadic colorectal cancers with microsatellite instabilities are overviewed. Alterations of genes involved in DNA repair would be the cause of genetic instability, increase of mutation rate as well as elevation of cancer risk. In addition, the recent topics of frequent association of TGF-beta type II receptor gene insertion/deletion mutation and replication error positive colorectal cancers are also discussed.
Colorectal Neoplasms, Hereditary Nonpolyposis↗