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Biomedical subjects

Y Shimosato

Publications and source records attributed to Y Shimosato.

At least 109 records · Page 6Linked to original sources
PubMed1989

Amplification of protooncogenes in surgical specimens of human lung carcinomas.

The possible existence of amplification or rearrangement of protooncogenes was examined in more than 100 surgical specimens of human lung carcinoma. Protooncogenes were amplified in 28% of the carcinomas. About 90% of the amplified genes were of the myc, ras, or erbB family. Of the myc family genes, myc was amplified in 14 of 137 tumors and L-myc in four of 108 tumors, but N-myc was not amplified. A high frequency of amplification of myc was observed in squamous cell carcinomas (seven of 37) and of L-myc in small cell carcinomas (two of six). Of the ras family genes, K-ras-2 was amplified in six of the 137 tumors and N-ras in two of the 137 tumors, but no amplification of H-ras-1 was detected. Seven of the eight cases of amplified ras genes were in advanced pathological stages. Of the erbB family genes, erbB-1 (epidermal growth factor receptor) was amplified in 10 of 114 tumors and erbB-2 (HER-2/neu) in one of 51 tumors. Amplifications of the myc, ras, and erbB family genes might be one of the crucial DNA abnormalities involved in the development of human lung carcinomas.

DNA, Neoplasm↗
PubMed1989

DNA cytofluorometric and nuclear morphometric analyses of lung adenocarcinoma.

The nuclear DNA content of tumor cells in imprint smears prepared from 72 surgically resected adenocarcinomas of the lung was determined prospectively by means of cytofluorometry, and its relationship to pathologic stage, degree of histologic differentiation, and nuclear atypia represented by the mean nuclear area (MNA) and standard deviation of the nuclear area (SDNA) was studied. The mean nuclear DNA content (MNDC) of poorly differentiated adenocarcinomas was significantly larger than that of well-differentiated adenocarcinomas both in Stages I + II and III + IV (P less than 0.001, each), and the MNDC of Stages III + IV was significantly larger than that of I + II in poorly differentiated adenocarcinomas (P less than 0.01). There was a tendency for histogram Patterns III and IV, in which more aneuploid cells were present than in I and II, to be more common and for the incidence of the aneuploid stem cell line to be higher in less differentiated and more advanced adenocarcinomas, although the differences were not significant statistically. Furthermore, there were significant positive correlations between MNDC and MNA (P less than 0.01) and between MNDC and SDNA (P less than 0.05). The averages of the MNA according to the histogram pattern increased significantly in the increasing order of Patterns I to IV. These results indicate that the nuclear DNA content increases in less differentiated and more advanced adenocarcinomas, and that the nuclear atypia is reflected in abnormal nuclear DNA content (DNA aneuploidy).

Adenocarcinoma↗
PubMed1989

Concordant deletions of chromosome 3p and loss of heterozygosity for chromosomes 13 and 17 in small cell lung carcinoma.

Common regions of loss of heterozygosity on chromosomes 3, 13, and 17 were determined by restriction fragment length polymorphism analysis in 34 tumors and nine cell lines from 27 patients with small cell lung carcinoma. The common regions of loss of heterozygosity on chromosomes 3, 13, and 17 reside between D3S2 (3p14-p21) and ERBA beta (3p22-p24.1), between D13S1 (13q12) and D13S2 (13q22), and distal to MYH2 (17p13.1), respectively. Allele loss in each of these regions has been previously shown in several human tumors. Thus, the present findings indicate the pleiotropy of recessive genetic lesions in these genomic areas. Cytogenetic analysis was performed on three small cell lung carcinoma cell lines which had allele loss on all three chromosomes, and although chromosome 3p deletions were observed in two of three cell lines, no obvious structural abnormalities involving chromosomes 13 and 17 were detected. Mitotic recombination or mitotic nondisjunction rather than deletion may thus be the frequent chromosomal mechanism for attaining homozygosity of chromosomes 13 and 17 in small cell lung carcinoma.

Alleles↗
PubMed1989

Loss of heterozygosity on the short arm of chromosome 3 in carcinoma of the uterine cervix.

Loss of genes at specific chromosomal loci is a common genetic alteration in human tumors and is thought to be critical for unmasking the recessive genetic changes for tumorigenesis. To learn whether such recessive mutations are involved in the development of carcinoma of the uterine cervix, 18 fresh tumors were analyzed by Southern blot hybridization using 34 polymorphic DNA markers covering 19 different chromosomes. We found loss of heterozygosity at the D3S2 locus on chromosome 3p in all nine patients who could be evaluated. Human papillomavirus type 16 and type 18 were present in seven and three of 18 tumors, respectively, while no amplification of 13 oncogenes, including c-myc and H-ras, was detected in these tumors. These results suggest that recessive genetic changes on chromosome 3p are one of the important genetic alterations for the development of carcinoma of the uterine cervix. Since this locus is also lost commonly in lung cancer and in renal cell carcinoma, it is possible that these three different types of adult tumors result from mutations of the same recessive gene on chromosome 3p.

Blotting, Southern↗
PubMed1989

Deregulation of alternative splicing of fibronectin pre-mRNA in malignant human liver tumors.

Alternative splicing of fibronectin pre-mRNA at the ED-A region has been shown to be regulated in a tissue- and developmental stage-specific manner. We investigated the splicing pattern at this region in malignant and nonmalignant human liver tissues and found that the relative population of the fibronectin mRNA containing the ED-A sequence is markedly increased in malignant liver tumors. Nontumorous liver tissues including those with chronic hepatitis and cirrhosis did not show any significant change in the alternative splicing at the ED-A region. It was also found that the increased expression of the ED-A-containing fibronectin mRNA closely correlates with the occurrence of portal vein tumor thrombus and intrahepatic metastasis, which are two characteristic features of invasive liver tumors. These results indicate that tissue-specific alternative splicing of fibronectin mRNA is modified in human liver cancer and raise a possibility that the putative molecular machinery governing alternative RNA splicing of not only fibronectin but also other cellular proteins is deregulated in malignant human tumors.

Carcinoma, Hepatocellular↗
PubMed1989

Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units: hst-1/int-2 and c-erbB-2/ear-1.

The incidence and association with 10-year survival of amplification in five protooncogenes or transforming genes were retrospectively examined using DNAs extracted from formalin-fixed, paraffin-embedded blocks of tissues obtained from 176 consecutive patients surgically treated for primary breast carcinoma. The incidences of greater than threefold amplification of hst-1, int-2, c-erbB-2, ear-1 (one of c-erbA), and c-myc were 12, 13, 16, 10, and 4.0%, respectively. hst-1 and int-2 were almost always coamplified (21/22), while c-erbB-2 and ear-1 were frequently coamplified (18/28) with almost the same copy number. The hst-1 and int-2 pair and the c-erbB-2 and ear-1 pair, localized on chromosomes 11q13 and 17q21-22, respectively, in normal cells, were inferred to be constituents of different amplification units. Amplification of hst-1 and/or int-2 was detected preferentially in the younger age group, and was correlated with poorer prognosis in cases carrying four or more copies of the genes. Amplification of c-erbB-2 and/or ear-1 was strongly correlated with poor prognosis in all 176 patients, especially those with lymph node metastasis. Amplification of c-myc was also correlated with poor prognosis. Cox's life-table regression analysis showed that amplification of c-erbB-2 had a prognostic value, which was independent of other known prognostic factors such as lymph node status and tumor size.

Breast Neoplasms↗
PubMed1989

Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas.

Two distinct calcium-sensitive cell-cell adhesion molecules were identified in human epithelial tissues and carcinomas using two monoclonal antibodies raised against vulvar epidermoid carcinoma A-431 and human mammary carcinoma MCF-7 and selected on the basis of their activities to disrupt cell-cell adhesion. In immunoblot analysis, these antibodies, designated NCC-CAD-299 and HECD-1, detected main bands of Mr 118,000 and 124,000, respectively. Purified tryptic fragments of the antigen recognized by NCC-CAD-299 showed cross-reactivity with a rabbit antiserum against mouse P-cadherin, indicating that this molecule was the human homologue of P-cadherin. On the other hand, the antigen recognized by HECD-1 showed essentially the same tissue distribution pattern as E-cadherin in the mouse, suggesting that this molecule is the human homologue of E-cadherin. Availability of these monoclonal antibodies to human P- and E-cadherin allowed us to examine their distributions in human tissues immunohistochemically. Both antigens were detected in epithelial tissues, but they showed distributions that were distinct from each other. The antigen recognized by HECD-1 was expressed in almost all epithelial tissues, while distribution of the other one recognized by NCC-CAD-299 was restricted to the basal or lower layers of stratified epithelia in which both antigens were coexpressed. Moreover, immunohistochemical examination of 44 lung carcinomas showed that both molecules were coexpressed in all of them, and suggested that expression of P-cadherin was closely related to the differentiation of carcinoma cells.

Antibodies, Monoclonal↗
PubMed1989

Immunoreactive gastrin-releasing peptide as a specific tumor marker in patients with small cell lung carcinoma.

Gastrin-releasing peptide (GRP) is now known to be a very common product of small cell lung carcinoma (SCLC). With the aim of investigating the possible role of this peptide as a tumor marker of SCLC, we have developed a sensitive radioimmunoassay system for plasma immunoreactive GRP using immune-affinity chromatography for plasma extraction. Plasma immunoreactive GRP levels in control subjects were determined by using 15 ml of plasma as the starting material (minimum concentration detectable, 0.8 pg/ml). The levels in 10 control subjects were (mean +/- SD) 1.2 +/- 0.27 pg/ml; range, 0.86-1.7 pg/ml. This assay system was applied for the clinical use by using 3 ml of plasma as the starting material (minimum concentration detectable, 4.0 pg/ml). Plasma immunoreactive GRP levels were elevated in SCLC patients at frequencies of 71% in patients with limited disease and 80% in those with extensive disease. Furthermore, a change in the level showed excellent correlation with the therapeutic response. In six patients with complete response who had had elevated levels before treatment, the levels decreased to an undetectable range when the tumor disappeared, and they remained undetectable until 1 month later, when the patients were judged to have achieved complete response. In the partial response group, plasma immunoreactive GRP levels had decreased to an undetectable level in two of three patients, when the patients achieved partial response. In four patients with progressive disease, plasma immunoreactive GRP levels were elevated at the time of the progressive disease judgment, when compared with levels before treatment. The levels in 21 patients with non-SCLC (10 with adenocarcinoma, seven with squamous cell carcinoma and four with large cell carcinoma) were not elevated. These results indicate the plasma immunoreactive GRP level as a useful tumor marker in SCLC patients. It is now believed that GRP can function as an autocrine growth factor for SCLC. The present study suggests that the possible autocrine growth factor could serve as a reliable tumor marker for cancer patients.

Adenocarcinoma↗
PubMed1989

Establishment of an anti-A human monoclonal antibody from a blood group A lung cancer patient: evidence for the occurrence of autoimmune response to difucosylated type-2 chain A.

A human monoclonal antibody, NCC-HAL-27, has been established by a combination of transformation by Epstein-Barr virus (EBV) and a newly devised "micro cell fusion" technique. Lymphocytes used were derived from a blood group A lung cancer patient. Cancer cells, as well as normal epithelial cells of lung, stomach and colon (including autologous tissue) from blood group A individuals, fixed in formalin, were immunohistochemically stained by the antibody. A higher concentration (greater than 140 mg/ml) of the antibody agglutinated only type-A (not B or 0) erythrocytes. The structural specificity of NCC-HAL-27 was determined by particle-concentrated fluorescence immunoassay and thin-layer chromatography immunostaining using purified, well-defined glycolipids. The antibody was found to be directed against type-2 chain A and difucosylated type-2 chain A antigens with no cross-reactivity with known A-like antigens, such as Tn and Forssman antigen, generally expressed irrespective of ABO status. Interestingly, however, the antibody detected the expression of incompatible A antigen in colon cancers of B and 0 individuals with high incidence (30%-40%). The finding that a monoclonal antibody generated from a blood group A cancer-bearing host is directed against autologous A antigen is novel because the ABO blood group antigens are the major alloantigens in man, with strictly controlled immunotolerance. The induction of anti-A in this patient could, therefore, be directly associated with the lung cancer.

ABO Blood-Group System↗
PubMed1989

Conformational epitopes specific to carcinoembryonic antigen defined by monoclonal antibodies raised against colon cancer xenografts.

Four monoclonal antibodies (MoAbs) reactive with carcinoembryonic antigen (CEA) were obtained by hybridizing mouse myeloma cells (P3-X63-Ag8-U1) with spleen cells from nude mice (BALB/c, nu/nu) that had rejected transplanted human colonic adenocarcinomas Co-3 and Co-4 following intraperitoneal injection of spleen cells from immunocompetent mice (BALB/c). By solid-phase RIA with purified CEA and its related antigens, NCC-CO-413 (IgG2a, kappa) was shown to react with NCA and BGP-I as well as with CEA, whereas the reactivities of three other MoAbs, NCC-CO-308 (IgG1, kappa), -432 (IgG1 lambda), and -411 (IgG1, kappa) were limited to CEA. Immunohistochemical reactivities of these MoAbs to colonic carcinomas, granulocytes, and liver bile canaliculi on acetone-fixed paraffin-embedded sections ("AMeX" sections) confirmed the specificities of these MoAbs shown by the solid-phase RIA. By competition solid-phase RIA, the epitopes recognized by NCC-CO-308 and -432 were shown to be shared or located close to each other, whereas the other MoAbs were shown to recognize different epitopes. Thus, two epitopes specific to CEA and one shared by NCA and BGP-I as well as CEA were identified. Furthermore, reactivities of MoAbs with the two CEA-specific epitopes were easily abolished by heat denaturation or reduction of CEA, as revealed by solid-phase RIA and SDS-PAGE-immunoblotting, indicating that these two CEA-specific epitopes are based on the conformational structure of the CEA molecule.

Animals↗
PubMed1989

Immunohistochemical distinction of malignant mesothelioma from pulmonary adenocarcinoma with anti-surfactant apoprotein, anti-Lewisa, and anti-Tn antibodies.

Nine cases of malignant mesothelioma of pure epithelial and biphasic types (five pleural, three peritoneal, and one pericardial mesotheliomas), seven cases of benign adenomatoid tumor of the uterus, and 21 cases of peripheral pulmonary adenocarcinoma of non-mucus-producing type were examined immunohistochemically for expression of keratin, vimentin, carcinoembryonic antigen (CEA), surfactant apoprotein, Lewis blood group antigens, and Tn antigen. The majority (78%) of the malignant mesotheliomas expressed keratin, but CEA and surfactant apoprotein were not detected in any mesotheliomas. On the other hand, pulmonary adenocarcinomas expressed not only keratin (100%), but also CEA (62%) and surfactant apoprotein (62%). The expression of Lewisa blood group antigen and Tn antigen was detected in 76% and 62% of the pulmonary adenocarcinomas, respectively, but only one mesothelioma was stained for Lewisa antigen. This study reveals that the majority of malignant mesotheliomas can be distinguished from pulmonary adenocarcinomas by immunohistochemcial staining for CEA, surfactant apoprotein, Lewisa antigen, and Tn antigen. Immunohistochemically, adenomatoid tumors behaved similarly to malignant mesotheliomas.

Adenocarcinoma↗
PubMed1989

Molecular cloning of a human Ca2+-dependent cell-cell adhesion molecule homologous to mouse placental cadherin: its low expression in human placental tissues.

P-cadherin is a subclass of Ca2+-dependent cell-cell adhesion molecules present in mouse placenta, where its localization suggests a function of connecting the embryo to the uterus (Nose, A., and M. Takeichi. 1986. J. Cell Biol. 103:2649-2658). We recently identified a human cadherin detected by an mAb capable of disrupting cell-cell adhesion of A-431 cells, and found that it was closely related immunochemically to mouse P-cadherin. Curiously, this cadherin was undetectable in human placenta by immunohistochemical examination (Shimoyama, Y., S. Hirohashi, S. Hirano, M. Noguchi, Y. Shimosato, M. Takeichi, and O. Abe. 1989. Cancer Res. 49:2128-2133). We here report the cloning and sequencing of cDNA clone encoding the human homologue of mouse P-cadherin. The deduced amino acid sequence of the human P-cadherin consists of 829 amino acid and shows striking homology with mouse P-cadherin. On Northern blot analysis, human P-cadherin was scarcely expressed in human placenta in contrast to mouse P-cadherin, which was abundantly expressed in mouse placenta throughout pregnancy, and it was shown that E-cadherin, but not P-cadherin, was the major cadherin molecule in human placenta. Moreover, NIH3T3 cells transfected with human P-cadherin cDNA expressed the functional cadherin molecule, which was identical to the cadherin we had previously identified using the mAb, showing that this molecule really does mediate cell-cell adhesion and that the cadherin we detected immunochemically is undoubtedly human P-cadherin. The results obtained in this study support the idea that P-cadherin plays little role, if any, in Ca2+-dependent cell-cell binding in human placental tissue at least after several weeks of pregnancy.

Amino Acid Sequence↗
PubMed1989

Multicentric independent development of hepatocellular carcinoma revealed by analysis of hepatitis B virus integration pattern.

Two separate nodular lesions of hepatocellular carcinoma (HCC) were surgically removed from a patient with positive serum hepatitis B surface antigen. Southern blot analysis of DNA from the two separate HCC lesions showed different restriction patterns of integrated hepatitis B virus DNA, indicating their independent origins. The two lesions were composed mainly of poorly differentiated HCC; however, well-differentiated HCC was also observed in the periphery of the lesions. This histological finding is consistent with the multistep and independent development of HCC in each site of the liver.

Aged↗
PubMed1989

Leydig cell tumor of the ovary associated with endometrial carcinoma and containing 17 beta-hydroxysteroid dehydrogenase.

A case of ovarian Leydig cell tumor associated with adenocarcinoma of the endometrium in a 66-year-old woman is described herein, the eighth such case published. Clinically, both masculinizing and feminizing symptoms were observed: an increase in facial hair growth, slight baldness, clitoromegaly, and postmenopausal genital bleeding. Three biopsies of the endometrium during a 5-month preoperative period showed atypical hyperplasia. Surgically resected material contained a Leydig cell tumor of the left ovary and focal adenocarcinoma in atypical hyperplasia of the endometrium. Serum levels of androgens and estrogens measured by radioimmunoassay decreased after removal of the tumor. Immunohistochemical studies revealed that the Leydig cell tumor contained testosterone, estrogens, and 17 beta-hydroxysteroid dehydrogenase (HSD) in the cytoplasm. This is the first report of a Leydig cell tumor in which the localization of 17 beta-HSD was demonstrated immunohistochemically.

17-Hydroxysteroid Dehydrogenases↗
PubMed1989

Detection of increased fecal carcinoembryonic antigen and its characterization as a membrane-bound form in colorectal carcinoma and other gastrointestinal disorders.

The levels and character of carcinoembryonic antigen (CEA) in feces were investigated by sandwich radioimmunometric assay using anti-CEA monoclonal antibodies NCC-CO-411 and NCC-CO-432. Mean CEA concentration was significantly higher (P less than 0.001) in the feces from patients with colorectal carcinoma and other gastrointestinal disorders as compared to normal adults. More than 90% of the fecal CEA was trapped by a 0.22 micron membrane filter and solubilized by treatment with 1% Triton X-100 or phosphatidyl-inositol specific phospholipase C. In hydrophobic chromatography, most of the fecal CEA was eluted at the lowest (NH4)2SO4 concentration while serum CEA appeared in the more hydrophilic fractions. These results suggest that the majority of CEA exists in feces as an amphiphilic molecule or a membrane-bound form. The increase of fecal CEA may reflect the destruction and abrasion of epithelial cells in various gastrointestinal disorders.

Antibodies, Monoclonal↗
PubMed1989

Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma.

We examined the incidence of point mutation in codons 12, 13 and 61 of c-Ki-ras and N-ras genes in human hepatocellular carcinoma (HCC) using the polymerase chain reaction and oligonucleotide hybridization techniques. Among 34 tissues specimens surgically resected from 30 patients and 5 cell lines of human HCC, only two had ras point mutations; in one case, codon 12 of c-Ki-ras was altered from GGT, coding glycine, to GTT, coding valine; in the other case, codon 61 of N-ras was altered from CAA, coding glutamine, to AAA, coding lysine. Thus, point-mutational activation of ras oncogenes is an uncommon event in human HCC.

Carcinoma, Hepatocellular↗
PubMed1989

Quantitative distribution of cluster 1 small cell lung cancer antigen in cancerous and non-cancerous tissues, cultured cells and sera.

Three monoclonal antibodies (mAbs), NCC-LU-243, -244 and -246, detected three different epitopes on a 145-kDa cell membrane antigen, which had been designated as the cluster 1 antigen at the First International Workshop on Small Cell Lung Cancer (SCLC) Antigens. The distribution of the antigen in various tissues, cultured cells and sera was examined by immunohistochemistry and sandwich radioimmunoassay using these mAbs. The antigen is a normal differentiation antigen and is present in neuronal, neuroendocrine and cardiac muscle cells. The level of the antigen was highest in central nervous tissues, while it was undetectable in the liver, kidney and peripheral lung. Among tumor tissues, the antigen was detected only in SCLC, carcinoid tumor and neuroblastoma, indicating its usefulness as a marker for discriminating SCLC from non-SCLC. The level of the antigen varied among SCLC tissues and tended to be lower in variant-type cultured SCLC cells. Although an increase in the antigen level was observed in sera of some patients with advanced SCLC, the antigen did not possess any additional value over neuron-specific enolase as a serum tumor marker for monitoring SCLC patients.

Animals↗