[Bel-2 as a prognostic factor of breast cancers].
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Apoptosis↗
Biomedical subjects
H Tsuda
Publications and source records attributed to H Tsuda.
Antimetastatic and antitumor effects of 2,4-diamino-6-(pyridine-4-yl)-1,3,5-triazine (4PyDAT) on the high lung metastatic colon 26 tumor in mice.
The therapeutic potential of a diaminotriazine, 2,4-diamino-6-(pyridine-4-yl)-1,3,5-triazine (4PyDAT), was investigated in a metastatic model using the mouse colon 26 carcinoma variant (Co26Lu), which preferentially metastasizes to the lung of mouse. The compound had a moderate antimetastatic activity as well as antitumor activity, without toxicity to the host, when administered orally. In the cytotoxicity test in vitro, 4PyDAT showed very weak direct cytotoxicity against the Co26Lu cell line, Co26Lu(F55) (IC50 < or = 1000 microM). Less microcapiral formation on tumors were observed for the treated group with a hemorrhage than the control group under microscopy. 4PyDAT significantly inhibited the production of urokinase-type plasminogen activator (u-PA) in Co26Lu(F55) cells. These results suggest that the antimetastatic and antitumor activities of 4PyDAT are due in part to inhibition of angiogenesis, rather than direct antiproliferative action on the tumor cells. 4PyDAT may become a lead compound to develop antitumor triazine derivatives based on antiangiogenic action.
Animals↗
[Hemophagocytic syndrome: problems in diagnosis].
Hemophagocytic syndrome(HPS) is characterized by high-grade fever, pancytopenia, liver dysfunction and proliferation of benign histiocytes with hemophagocytosis. These clinical manifestations result from the overproduction of cytokines including interferon-gamma, interleukin-2, tumor necrosis factor-alpha by activated T cells(Th1 cells) and macrophages. HPS is divided into a hereditary/primary form and a secondary form. The latter is further classified into various entities by triggering factors and underlying diseases. The multiplicity of this syndrome makes it difficult to diagnose by a simple criteria. This paper gives a overview of HPS and describes the problems of diagnosing each sub-entity of HPS.
Cytokines↗
A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2.
Human chromosome 11q23.2 has been proposed to contain a tumor suppressor gene(s) whose deletion has been associated with cancer of the lung and breast and with neuroblastoma. To analyze the genomic structure and to isolate a candidate tumor suppressor gene from this region, we constructed a 2-Mb sequence-ready contig map using bacteriophage P1 (P1), bacterial artificial chromosome (BAC), and P1-derived artificial chromosome (PAC). The map comprises a contig of 24 overlapping P1, BAC, and PAC clones. To isolate gene fragments from the region, we performed direct cDNA library screening, exon trapping, EST mapping, and genomic sequencing using the P1, BAC, and PAC clones. Sequence analysis of 5 clones, which spans 23% (458,738 bp) of the region, and extensive gene scanning along the entire region revealed that the region is extraordinarily scarce in genes, but we identified one ubiquitously expressed novel gene and one testis-specific gene fragment. The novel gene, which we call IGSF4 (immunoglobulin superfamily 4), is transcribed into a 1.6- or 4.4-kb RNA encoding a 442-amino-acid protein. It shares strong homology with mouse IGSF-B12 and cell adhesion molecules NCAM1 and NCAM2 within their Ig-like C2-type domains. The IGSF4 gene, a novel gene that is shown to be located in the common loss of heterozygosity region, possesses a number of interesting features and may be good candidate for a tumor suppressor gene.
Amino Acid Sequence↗
Chemopreventive effect of dietary flavonoid morin on chemically induced rat tongue carcinogenesis.
The modifying effects of dietary exposure of the flavonoid morin on 4-nitroquinoline 1-oxide (4-NQO)-induced tongue tumorigenesis, the activities of phase II detoxifying enzymes glutathione S-transferase (GST) and quinone reductase (QR) in liver and tongue, and cell proliferation activity in tongue were investigated in male F344 rats. At 7 weeks of age, all animals except those treated with morin alone and control group were given 4-NQO (20 ppm) in drinking water for 8 weeks to induce oral neoplasms. Starting 7 days before 4-NQO exposure, experimental groups were fed experimental diets containing morin (100 and 500 ppm) for 10 weeks ("initiation feeding"). Starting 1 week after the cessation of exposure to 4-NQO, other experimental groups given 4-NQO and a basal diet were given experimental diets for 22 weeks ("post-initiation feeding"). At week 32 week, "initiation feeding" of morin caused a significant reduction in the incidence of tongue carcinoma (by 44-100%). "Post-initiation feeding" with morin also significantly decreased the frequency of tongue carcinoma (by 44%). Morin feeding elevated liver GST and QR activities and GST activity in the anterior portion of tongue. Feeding with morin significantly lowered QR activity of the posterior part of the tongue. Dietary exposure to morin significantly decreased the proliferating cell nuclear antigen-positive index in the posterior portion. Also, morin feeding lowered tongue polyamine levels, especially in the "post-initiation feeding" group. Our results indicate that morin acts as a chemopreventive agent against tongue carcinogenesis induced by 4-NQO through modification of detoxifying enzyme activities and/or cell proliferation activities.
4-Nitroquinoline-1-oxide↗
Heterocyclic amine mixture carcinogenesis and its enhancement by caffeine in F344 rats.
In order to elucidate whether mixed exposure to environmental carcinogens and caffeine increases the risk of cancer induction, we investigated the relationship between preneoplastic lesion development in the liver and colon and drug metabolizing enzyme induction and DNA adduct formation, in rats treated with a mixture of heterocyclic amines (HCAs) and caffeine. In Experiment 1, male F344 rats were administered 3 different HCAs, the food carcinogens, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), alone or in combinations of 2 or 3 at 50 ppm in the diet for 16 weeks. The numbers of hepatic glutathione-S-transferase P form positive (GST-P+) foci and colonic aberrant crypt foci (ACF) were greater in the IQ + MeIQx group than expected from simple summation and increased levels of HCA-DNA adducts were noted. However, no summation was obtained when combined with PhIP, which rather caused inhibition. In Experiment 2, the effects of concurrent caffeine administration on the PhIP carcinogenicity were assessed. Caffeine at 1000 and 500 ppm in the drinking water for 2 weeks significantly increased levels of CYP1A2. Ten weeks concurrent administration of caffeine (1000 ppm) and PhIP (400 ppm) resulted in significant increase of colon ACFs and CYP1A2 expression. Thus, concurrent administration of IQ and MeIQx caused elevation of their carcinogenicity but other mixtures with PhIP did not enhance carcinogenicity. However, a non-carcinogen, caffeine, enhanced PhIP colon carcinogenesis, possibly due to induction of CYP1A2.
Animals↗
Correlation of numerical and structural status of chromosome 16 with histological type and grade of non-invasive and invasive breast carcinomas.
Loss of heterozygosity on chromosome arm 16q frequently occurs in human breast carcinomas regardless of the histological grade or type. To reveal whether the status of chromosome 16 corresponds to the histology of breast carcinomas, we examined the signal number of 16cen, 16q breakpoints and 1;16 fusions in the interphase nuclei of 185 breast carcinomas using fluorescence in situ hybridization to detect the loci D16Z2 (16cen), D16Z3 (16q11), D16S154 (16q24) and D1Z1 (1q12). A 16q loss associated with a proximal or distal breakage was identified as a discrepancy between the modal signal counts of the D16Z2, D16Z3 and D16S154 loci in each tumor. Clonal 16cen aneusomy, proximal breakages, distal breakages and 1;16 fusion were detected in 62%, 35%, 34% and 38% of the carcinomas respectively. Each of these alterations correlated with the histology of both non-invasive and invasive carcinomas; 16cen aneusomy was more frequent in carcinomas of high histologic grade, proximal breakage was more frequent in invasive ductal carcinomas (IDCs) of the strand or solid types and in grade-2 and -3 carcinomas, and distal breakage was more frequent in tubular/cribriform type IDCs and grade-1 carcinomas. 1;16 fusion correlated with the tubular/cribriform type of non-invasive or invasive carcinomas and invasive lobular carcinomas. Proximal breakage correlated with 16cen aneusomy, whereas the distal breakage correlated with 16cen disomy. These structural and numerical chromosome alterations appeared to occur in association with each other, and their specific combinations appeared to be involved in the establishment of morphological variety among breast carcinomas. Int. J. Cancer (Pred. Oncol.) 84:381-387, 1999.
Aneuploidy↗
Heterozygous p53-deficient mice are not susceptible to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) carcinogenicity.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a very potent mutagen which induces tumors in the liver, lung and hematopoietic system of CDF1 mice and the liver, Zymbal gland and skin in F344 rats. The recent development of transgenic knockout mice allows their introduction for sensitive screening of environmental carcinogens due to the rapid development of tumors. P53 gene deficient mice (p53-/-) were found to spontaneously develop malignant lymphoma and hemangiosarcoma, whereas heterozygotes (p53+/-) mice display a high incidence of tumors of the urinary bladder when treated with N-butyl-N-(4-hydroxybutyl)nitrosamine. In the present study, to determine whether p53 gene knockout mice can be utilized in a short-term assay model for the screening of heterocyclic amines (HCAs), the effects of MeIQx, as a representative compound, at low doses were examined. Male and female p53+/- mice and wild type littermates (p53+/+) were continuously given diets containing 0, 0.1, 1, 10 and 100 ppm MeIQx for 1 year. No significant difference in tumor induction was observed other than an increase in liver adenomas in males receiving 10 ppm MeIQx treatment. The results indicate that p53+/- mice have no practical advantages for use in short-term carcinogenicity tests of HCAs.
Alleles↗
Breast Carcinoma with Osteoclast-like Giant Cells: A Case Report and Review of the Japanese Literature.
A 41-year-old premenopausal woman with a 3.5 cm freely mobile mass in the upper outer quadrant of the right breast was admitted to our hospital. Fine needle aspiration showed malignant epithelial cells and many multinucleated osteoclast-like giant cells (OGCs). Excisional biopsy revealed an invasive ductal carcinoma. A right modified radical mastectomy was subsequently performed. Macroscopically the tumor was well circumscribed with a dark brown cut surface. Microscopically, the tumor was a grade 2 invasive ductal carcinoma with many multinucleated OGCs adjacent the tumor cells and hemorrhage and infiltration of inflammatory cells in the stroma. The intra-mammary metastasis also contained OGCs and stromal reactions. By enzyme immunoassay, the tumor cells were negative for estrogen receptor but positive for progesterone receptor. The tumor cells were negative for both c-erbB-2 and p53. The OGCs showed positive immunostaining with the monoclonalantibody CD68, demonstrating a histiocytic origin. Lymph nodes were free of metastasis. We also review the Japanese literature concerning breast carcinoma withOGCs.
Journal Article↗
Enhanced quinone reductase (QR) activity correlates with promotion potential of diethyl maleate (DEM) in rat forestomach and glandular stomach carcinogenesis initiated with N-methyl-N'-nitrosoguanidine (MNNG).
The modifying effect of diethyl maleate (DEM) on gastric tumor development was studied in rats initially given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and hypertonic sodium chloride (H-NaCl 10% or 5%). Groups of animals were maintained with or without a 0.2% DEM dietary supplement after treatment with MNNG and H-NaCl and sacrificed at week 20. Forestomachs and livers cytosolic NAD(P)H:quinone-acceptor oxidoreductase (QR) activity was also analyzed. The incidences of forestomach severe hyperplasias in the MNNG + H-NaCl --> DEM groups were also significantly higher than in the MNNG + H-NaCl alone group (P < 0.01 and P < 0.05 for 5% and 10% groups, respectively). Similarly, in the glandular stomach, the numbers of preneoplastic pepsinogen 1 altered pyloric glands (PAPGs) in the MNNG + H-NaCl --> DEM groups were significantly increased (P < 0.01 for both concentrations). The QR activities in the groups treated with DEM showed 2- to 3-fold increases as compared with the control level. The results indicate that treatment with 0.2% DEM after MNNG initiation exerts enhancing effects on both forestomach and glandular stomach carcinogenesis. Induction of QR, a Phase II enzyme, activity in the rat stomach by DEM may be associated with promotion of stomach carcinogenesis rather than inhibition.
Animals↗
Bilateral Nonpalpable Breast Carcinomas in a Patient with BRCA2 Germ Line Mutation and Past History of Osteosarcoma.
A 34-year-old premenopausal woman developed asynchronous bilateral nonpalpable breast cancers at the age of 32 and 34 years. She had undergone amputation of her left lower leg because of osteosarcoma at the age of 16. Her mother had beendiagnosed with breast cancer at the age of 45. The clinicopathological features of the two breast tumors in this patient closely resembled each other; both were nonpalpable, and detectable only by helical CT scan. Histologically, they consisted mainly of an intraductal component with small grade 3 invasive foci. In addition, both tumors estrogen receptor (ER) status was negative, and both were positive for c-erbB-2 protein on immunohistochemical staining. A missense germ line mutation of BRCA2 (exon 25 codon 3118; Met3118Thr) was detected in this patient. These data may provide useful information on the carcinogenesis and biological behavior of breast cancers which develop in patients with BRCA2 germ line mutations.
Journal Article↗
Structural studies of octasaccharides derived from the low-sulfated repeating disaccharide region and octasaccharide serines derived from the protein linkage region of porcine intestinal heparin.
Four octasaccharide serines and three octasaccharides were isolated after heparinase treatment of porcine intestinal heparin. Their structures were characterized by enzymatic digestion in conjunction with HPLC and 500 MHz 1H NMR spectroscopy. Three of the four octasaccharide serines were structurally identical with those isolated previously, whereas one has the unreported structure DeltaHexA(2-sulfate)alpha1-4GlcN(N-sulfate)alpha1-4GlcAbe ta1-4GlcNAca lpha1-4GlcAbeta1-3Galbeta1-3Galbeta1-4Xylbeta 1-O-Ser (DeltaHexA, GlcN, IdceA, and GlcA represent 4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid, D-glucosamine, L-iduronic acid, and D-glucuronic acid, respectively). The other three octasaccharides were isolated for the first time as discrete structures and shared the common core hexasulfated sequence DeltaHexA(2-sulfate)alpha1-4GlcN(N-sulfate)alpha1-4IdceAa lpha1-4GlcNA calpha1-4GlcAbeta1-4GlcN(N-sulfate)alpha1-4IdceA (2-sulfate)alpha1-4Gl cN(N,6-disulfate) with one or two additional sulfate groups. The octasaccharides which were derived from the low-sulfated repeating disaccharide region of heparin contained the common trisaccharide sequence -4IdceAalpha1-4GlcNAcalpha1-4GlcAbeta1- [Yamada, S., Yamane, Y., Tsuda, H., Yoshida, K., and Sugahara, K. (1998) J. Biol. Chem. 273, 1863-1871], suggesting the programmed biosynthesis of heparin. These octasaccharides are the largest oligosaccharides isolated so far from the low-sulfated irregular region of heparin. Since oligosaccharides larger than a pentasaccharide appear to potentially exhibit binding activities toward growth factors or other functional proteins, they will be useful for investigating the structural requirement for molecular interactions between heparin and/or heparan sulfate and biologically active proteins. During the course of the present structural studies, we evaluated the NMR data accumulated thus far on heparin oligosaccharides and found several interesting rules on chemical shifts of proton signals affected by the neighboring sugar residues and their sulfation, which will be in turn useful for determining structures of unknown heparin and/or heparan sulfate oligosaccharides based on the proton resonances.
Animals↗
Prognosis of a series of 763 consecutive node-negative invasive breast cancer patients without adjuvant therapy: analysis of clinicopathological prognostic factor.
BACKGROUND AND OBJECTIVES: The objectives of this study were to confirm the favorable outcome of Japanese invasive breast cancer patients without lymph node metastasis, after treatment with surgery alone, and to evaluate clinicopathological prognostic factors in this population. METHODS: The subjects were 763 consecutive node-negative invasive breast cancer patients who underwent surgery without adjuvant therapies between 1988 and 1993 at our hospital. Disease-free survival (DFS) and overall survival (OS) rates were analyzed by clinicopathological factors. RESULTS: The median age of the patients at surgery was 52 years and the median follow-up period of patients was 74 months. At 5 years, the respective DFS and OS rates of all patients were 90.8% and 93.9%. Patients with a pathological tumor size of invasive component of more than 2 cm (319 patients) had a significantly lower DFS than those with tumors measuring 2 cm or less (361 patients) (P = 0.045). Patients with positive hormone receptor status (280 patients) (estrogen and/or progesterone receptor positive) tended to have a better OS than those negative for both hormone receptors (92 patients) (P = 0.078). Meanwhile, patients with tumors of histological grade 3 (328 patients) had a much poorer prognosis than those with tumors of histological grade 1 or 2 (413 patients) (P = 0.008 for OS and P = 0.042 for DFS). The respective 5-year DFS and OS rates of patients with histological grade 3 tumors larger than 2 cm in pathological tumor size of invasive component (195 patients) were 85.5% and 87.6%, indicating that these node-negative patients form a high risk group. CONCLUSIONS: Japanese invasive breast cancer patients without lymph node metastasis tended to show a survival advantage compared with their Caucasian counterparts. Histological grade was the most useful prognostic factor in this population.
Adult↗
der(16)t(1;16)/der(1;16) in breast cancer detected by fluorescence in situ hybridization is an indicator of better patient prognosis.
By two-color fluorescence in situ hybridization (FISH), der(16)t(1;16) or der(1;16) was frequently detected in low-grade papillary carcinoma but not in benign intraductal papilloma of the breast. In order to clarify the incidence and clinicopathological significance of der(16)t(1;16)/der(1;16) in common breast cancers, der(16)t(1;16)/der(1;16) was examined by two-color FISH in breast cancers resected from 51 patients by using DNA probes for 16cen, 16q11.2, and 1q12 labeled with biotin or digoxigenin. der(16)t(1;16)/der(1;16) was clonally detected in 16 cancers (31%), being more frequent in ductal carcinomas of lower grade and invasive lobular carcinoma than in high-grade invasive ductal carcinoma (P<0.001). der(16)t(1;16)/der(1;16) was also correlated with a higher amount of hormone receptors in the tumor (P<0.05). Disease-free and overall survival rates of the patient group with der(16)t(1;16)/der(1;16)-positive cancer were higher (88% and 94%) than those of the group with der(16)t(1;16)/der(1; 16)-negative cancer (39% and 68%) (P<0.05). Among the 16 patients with lymph node metastasis who received one of two similar forms of postsurgical adjuvant chemo-endocrine therapy, the prognosis of those with der(16)t(1;16)/der(1;16)-positive cancer was better than that of those with der(16)t(1;16)/der(1;16)-negative cancer (P<0.05). der(16)t(1;16)/der(1;16) detected by FISH is considered helpful in identifying patients with a better prognosis and for stratification of patients in randomized clinical trials of adjuvant chemo-endocrine therapies.
Breast Neoplasms↗
DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis.
To examine the significance of aberrant DNA methylation in hepatocarcinogenesis, the DNA methylation status at the D17S5 locus and mRNA expression of a candidate tumor suppressor gene, HIC-1 (hypermethylated-in-cancer), which was identified at the D17S5 locus, in primary hepatocellular carcinomas (HCCs) and their corresponding noncancerous liver tissues were assessed. DNA hypermethylation at the D17S5 locus was detected in 44% of the noncancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in noncancerous liver tissues showing no remarkable histological findings. The incidence of DNA hypermethylation at this locus was significantly higher in HCCs (90%) than noncancerous liver tissues (P <.001). Loss of heterozygosity at the D17S5 locus, which was preceded by DNA hypermethylation at the same locus, was detected in 54% of HCCs. The HIC-1 mRNA expression level of noncancerous liver tissues showing chronic hepatitis or cirrhosis was significantly lower than that of noncancerous liver tissues showing no remarkable histological findings (P <.01), and that of HCCs was even lower than that of noncancerous liver tissues (P <.05). Poorly differentiated HCCs showed lower expression levels than well- to moderately differentiated HCCs. Mutation of the p53 gene may be involved in HIC-1 inactivation. Moreover, wild-type p53 did not overcome DNA hypermethylation at the D17S5 locus to activate HIC-1 in HCCs. These data suggest that aberrant DNA methylation at this locus and reduced HIC-1 mRNA expression participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs.
Adult↗
Myoepithelial differentiation in high-grade invasive ductal carcinomas with large central acellular zones.
We hypothesized that invasive ductal carcinomas (IDCs) with large central acellular zones comprising necrosis, tissue infarction, collagen, and hyaline material on their cut surfaces are formed in association with myoepithelial differentiation of the carcinoma cells. To verify this, the expression of S100 protein, alpha-smooth muscle actin (alpha-SMA), and glial fibrillary acidic protein (GFAP) and keratin 14, which has been shown to represent the myoepithelial immunophenotype, was examined immunohistochemically in 18 IDCs with such central zones covering more than 30% of each tumor area, 18 IDCs without such areas as negative controls, and 10 metaplastic carcinomas as positive controls for myoepithelial differentiation. Expression of S100, detected with a polyclonal antibody, S100-alpha, S100-beta, alpha-SMA, GFAP, and keratin 14, was observed in 61%, 83%, 39%, 33%, 28%, and 39% of the IDCs with large central acellular zones, 17%, 44%, 6%, 6%, 0%, and 6% of the IDCs without such zones, and 80%, 70%, 50%, 100%, 80%, and 50% of the metaplastic carcinomas, respectively. We concluded that IDCs with large central acellular zones frequently contain carcinomas showing myoepithelial differentiation. Such histological and immunohistochemical features in IDCs would be expected to be clinicopathologically significant.
Actins↗
Cross-country comparisons suggest shared risk factors for carcinomas, including male lung adenocarcinoma and colon cancer development.
Smoking is clearly the major risk factor for both squamous cell carcinomas (SCCs) and adenocarcinomas (ACs) of the lung, although less so for the latter, where other influences appear to be important. In order to determine whether cross-country comparisons might provide evidence of shared risk factors with cancers in other organs of males, an examination of IARC/WHO data for cancer incidence was made for countries/registries in Europe, North America, Australia and Asia. Significant simple correlations, which persisted on partial analysis, were observed between lung SCCs and tumors of the larynx (P < 0.001), but not the buccal cavity or oesophagus, along with a link to rectal ACs (P < 0.001). Incidences of lung ACs also correlated with those for colon ACs (P < 0.001) but not lung SCCs. Oesophageal ACs were only related to colon cancers at the simple correlation level, this not persisting on partial analysis or separation into Asian and Western groups. The results suggest that blood borne factors, like hormones, may be important as determinants for the increasingly prevalent lung AC.
Adenocarcinoma↗
Contrast-enhanced computed tomography detection of occult breast cancers presenting as axillary masses.
Some non-palpable breast cancers presenting as axillary metastases (occult breast cancer, OBC) are not clinically detectable by either mammography (MMG) or ultrasonography (US). We performed contrast-enhanced computed tomography (CE-CT) in order to locate the primary tumors in five cases of OBC and succeeded in locating all of them.
Aged↗