Many faces of mixed medullary-follicular and papillary carcinoma of the thyroid.
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Biomarkers, Tumor↗
Biomedical subjects
T Monden
Publications and source records attributed to T Monden.
Cdk2/cdc2 expression in colon carcinogenesis and effects of cdk2/cdc2 inhibitor in colon cancer cells.
Cyclin dependent kinases propel the cell cycle in collaboration with cyclins. We have examined the expression of cdk2/cdc2 in adenoma and focal carcinoma in adenomatous tissue to explore their role in tumorigenesis of colorectum. Immunohistochemical study revealed that cdk2/cdc2 was overexpressed in a subsets of adenoma (14/50; 28.0%) but this overexpression was much more obvious in focal carcinoma (13/15; 86.7%). These results suggest that cdk2/cdc2 is remarkably upregulated together with a malignant change. In an effort to demonstrate a significant role for cdk2/cdc2 in colon cancer, we investigated growth and apoptosis with butyrolactone I, a specific inhibitor for cdk2/cdc2, using 4 colon carcinoma cell lines (HCT116, LoVo, HT29, Colo 320DM). Butyrolactone I inhibited proliferation of all colon carcinoma cell lines at 100 microM and it induced apoptosis in LoVo cell line with induction of p53. Our findings suggest that inhibition of cdk2/cdc2 may be a useful strategy against colon cancer.
4-Butyrolactone↗
[Liver metastases from breast cancer--clinical features and treatment].
Between 1986 and 1997, we treated 55 patients with liver metastases of breast cancer. In this study, the clinical features and effects of systemic or intra-arterial chemo-endocrine therapy for these patients were reviewed to clarify the characteristics of liver metastases and establish the optimum therapy. One of the 55 patients underwent hepatectomy, 25 were treated with systemic chemo-endocrine therapy [A] and 10 were treated with one-shot intra-arterial chemoembolization through hepatic artery [B] while the other 19 were given hepatic arterial infusion chemotherapy [C]. The response rate in the group [B] and [C] were better than in group [A], whereas there was no significant difference in survival time among the three groups. There were 14 cases (25.5%) among them showing metastasis in the thoracico-abdominal lymph nodes. In these patients, liver metastases seemed to have occurred through the lymphogenic route. In the intra-arterial chemotherapy ([B] + [C]) group, the survival time of patients with metastasis in the thoracico-abdominal lymph nodes was significantly shorter than that of patients without metastasis (p = 0.01). This study suggests that intra-arterial chemotherapy combined with MPA should be effective and useful for advanced breast cancer patients with liver metastases. And for lymphogenic liver metastases, it should be necessary to be combined with more intensive systemic chemo-endocrine therapy.
Antineoplastic Combined Chemotherapy Protocols↗
[PyNPase expression and cancer progression in the colorectum].
We analyzed PyNPase expression discriminating between cancer and tumor stroma of the colorectum by Western blotting using a newly developed extraction method from microdissected tissue sections fixed with buffered formalin. Analysis of 98 colorectal cancers revealed that PyNPase was as high as 70.2 +/- 18.5 unit/mg protein in the stroma fraction (SF), whereas it was 45.1 +/- 10.5 in the cancer fraction (CF) (p < 0.0001). Vessel density was correlated with PyNPase in the SF but not in the CF. In stage IIIb, 11 cases expressing a high level of PyNPase in the CF showed poorer prognosis than 10 cases with low-level PyNPase expression (p < 0.05), although the level of PyNPase expression in the SF did not affected the patients prognosis. Immunohistochemical examination indicated that PyNPase in the SF was mainly produced by macrophages (M phi), and therefore we investigated the profile of PyNPase production by M phi. In in vitro experiments PyNPase production by M phi was greatly enhanced by stimulation with OK-432, and the culture supernatant had the ability to convert 5'DFUR to 5-FU.
Antineoplastic Agents↗
[Results of clinical study with epirubicin hydrochloride injectable solution in hepatoma].
A 10-center cooperative clinical study with a new formulation of epirubicin hydrochloride injectable solution (Epirubicin-RTU) was conducted in patients with hepatocellular carcinoma. Epirubicin-RTU 60 mg/m2 was injected into the hepatic artery and a three-week drug-free interval followed. Of 15 patients with hepatocellular carcinoma registered in this study, 14 patients were eligible, and they all completed the entire course. The objective was to investigate the safety of treatment with Epirubicin-RTU in 14 eligible patients. The adverse drug reactions frequently observed in these 14 eligible cases were leukopenia, neutropenia, thrombocytopenia, alopecia, and fever. They were all reversible and tolerable. With these results. Epirubicin-RTU was considered to be a safe pharmaceutical product to inject into the hepatic artery.
Adult↗
Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein.
The thyroid hormone receptor (TR) regulates the expression of target genes upon binding to triiodothyronine (T3) response elements. In the presence of T3, the TR recruits coactivating proteins that both modulate and integrate the ligand response. We report here the cloning of a novel protein using the TR ligand-binding domain as bait in the yeast two-hybrid system. Analysis of a putative full-length clone demonstrates a cDNA sequence that encodes a protein of 920 amino acids with a size of 120 kDa (p120). Alignment with known sequences shows homology to a previously identified protein of unknown function, termed skeletal muscle abundant protein. Interaction studies demonstrate that p120 interacts with the TR AF-2 domain in the presence of ligand through a 111-amino acid region. Northern analysis demonstrates widespread expression in human tissues. Cotransfection assays in CV-1 cells demonstrate that p120 enhances TR-mediated transactivation on multiple T3 response elements in the presence of T3. In addition, CREB-binding protein synergizes with p120 to enhance this effect. When linked to the GAL4 DNA-binding domain, p120 is an activator of transcription alone. Thus, p120 satisfies a number of important criteria as a nuclear receptor coactivator.
ATPases Associated with Diverse Cellular Activitie↗
A unique role of the beta-2 thyroid hormone receptor isoform in negative regulation by thyroid hormone. Mapping of a novel amino-terminal domain important for ligand-independent activation.
Negative regulation by thyroid hormone is mediated by nuclear thyroid hormone receptors (TRs) acting on thyroid hormone response elements (TREs). We examine here the role of human TR-beta2, a TR isoform with central nervous system-restricted expression, in the regulation of target genes whose expression are decreased by triiodothyronine (T3). Using transient transfection studies, we found that TR-beta2 achieved significantly greater ligand-independent activation on the thyrotropin-releasing hormone (TRH) and common glycoprotein alpha-subunit genes than either TR-beta1 or TR-alpha1. A chimeric TR-beta isoform containing the TR-beta2 amino terminus linked to the TR-alpha1 DNA- and ligand-binding domains functioned like the TR-beta2 isoform on these promoters, confirming that the amino terminus of TR-beta2 was both necessary and sufficient to mediate this effect. By constructing deletion mutants of the TR-beta2 amino terminus, we demonstrate that amino acids 89-116 mediate this function. This domain, important in ligand-independent activation on negative TREs, is discrete from a previously described activation domain in the amino-terminal portion of TR-beta2. We conclude that the central nervous system-restricted TR-beta2 isoform has a unique effect on negative regulation by T3 that can be mapped to amino acids 89-116 of the amino terminus of the human TR-beta2.
Amino Acid Sequence↗
Lineage- and differentiation stage-specific expression of LSM-1 (LPAP), a possible substrate for CD45, in human hematopoietic cells.
CD45, a transmembrane tyrosine phosphatase, is found on almost all nucleated hematopoietic cells and plays a crucial role in lymphocyte activation and differentiation. We recently achieved isolation of the human LSM-1 (hLSM-1) gene, whose product is a possible substrate for CD45, and we raised antibodies against the hLSM-1 protein. hLSM-1 expression in hematopoietic cells was examined with Northern and Western blot, fluorescence-activated cell sorter, and immunocytochemical analyses. It was found that in the lymphoid lineage, T and B lymphocytes as well as NK cells expressed LSM-1, whereas terminally differentiated plasma cells did not. As for the myeloid lineage, immature myeloid cells expressed LSM-1, whereas terminally differentiated granulocytes and monocytes did not. In the erythroid lineage, normal erythroblasts expressed very low levels of LSM-1, while erythroid cell lines (K562 and HEL) did not. Megakaryocytes did not express LSM-1. Both CD34+/CD33- and CD34+/CD33+ hematopoietic progenitor cells weakly expressed LSM-1. These results showed that LSM-1 is expressed in a lineage- and differentiation stage-specific fashion.
Blotting, Western↗
Augumentation of splenic antitumor immunity by local immunotherapy in gastric cancer patients.
We previously reported that the antitumor effect of OK-432, a streptococcal preparation, was markedly augmented when this agent was injected into tumors together with fibrinogen. In order to elucidate the effect of this treatment on the spleen, we assessed splenic function in gastric cancer patients receiving preoperative local immunotherapy with OK-432 and fibrinogen. Immunohistochemical studies of the spleen at 7 days after intratumoral injection therapy revealed numerous macrophages phagocytizing OK-432 in the splenic sinuses. Phenotypic analysis of splenocytes by flow cytometry revealed an increase in the CD4/CD8 ratio and in the expression of HLA-DR, CD25, and Leu M3 by splenic T cells of the patients treated with OK-432 plus fibrinogen when compared to patients treated with OK-432 alone or untreated patients. Splenic T cells from patients treated with OK-432 plus fibrinogen showed significantly higher cytotoxicity against Daudi and K562 cells than T cells from control patients (p < 0.05), and culture of these splenic T cells with recombinant IL-2 induced the expansion of lymphokine-activated killer cells. These results demonstrate that local immunotherapy with a mixture of OK-432 and fibrinogen effectively augumented splenic antitumor immunity in gastric cancer patients.
Antineoplastic Agents↗
Midkine expression in human breast cancers: expression of truncated form.
The expression of midkine (MK), a growth/differentiation factor, was assessed in 34 surgically resected specimens of primary breast cancer or mastopathy. Using reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, all of the non-cancerous and cancerous tissues were found to express MK except for one breast cancer specimen. Northern blot analysis revealed that MK mRNA was also expressed in the normal breast tissues examined. Immunohistochemical analysis of the MK protein was performed on a limited number of the specimens, showing that some cancerous tissues were immunoreactive with anti-MK antibodies. Furthermore, using RT-PCR analysis, expression of not only the wild-type but also a truncated form of MK, which was recently found in various human tumor cell lines, was detected in 6 of 26 cancerous tissues but not in non-cancerous tissues.
Blotting, Northern↗
A detailed analysis of the role of K-ras gene mutation in the progression of colorectal adenoma.
To elucidate the role of ras gene mutations during the early stage of colorectal tumour progression, K-ras gene mutations were analysed in 32 benign adenomas and 36 adenomas with focal carcinoma in the colorectum by microscraping of histologically pure regions from tissue sections, polymerase chain reaction-restriction fragment length polymorphism and in part by direct sequencing. Several regions were scraped out and analysed when an adenoma contained areas with different grades of dysplasia. The frequencies of K-ras gene mutation in mild dysplasia, moderate dysplasia and focal carcinoma were 19% (7/36), 51% (25/49) and 39% (14/36) respectively. The K-ras gene status was heterogeneous in 4 of the 11 benign adenomas from which multiple samples were obtained, and mutations were always found in the regions with more advanced dysplasia in these adenomas. Thirteen of the 36 adenomas with focal carcinoma showed heterogeneity of mutations between the adenoma region and the focal carcinoma. Seven of which had mutations only in the adenoma region. These findings indicated that the K-ras gene mutations occur during the late stage of adenoma progression and may confer a more advanced morphological phenotype of adenoma, but these mutations are not mainly involved in malignant transformation from adenoma to carcinoma.
Adenoma↗
p21(Waf1/Cip1) and p53 protein expression in breast cancer.
p21/Cip1/Waf1 (wild-type p53 activated fragment 1/cyclin-dependent kinase [Cdk]-interacting protein 1) is a prominent Cdk inhibitor and has been shown to be a downstream mediator of p53. In this study, we sought to clarify the clinical significance of Waf1 and the relationship between Waf1 and p53 in breast cancer. For this purpose, the expressions of Waf1 and p53 were evaluated immunohistochemically in a series of 104 patients. Waf1 was expressed in 51 (49%) of 104 tumors tested, and p53 in 33 tumors (32%). Inverse expression of these two proteins was seen in 76 cases (73%); 47 were Waf1-positive and p53-negative, and 29 were Waf1-negative and p53-positive. A comparison with clinicopathologic parameters showed that Waf1 expression correlated with negative lymph nodes (P<.01), a low histologic grade (P<.0001), and positive estrogen receptor status (P<.01). Recurrence-free survival was lower for patients with Waf1-negative tumors than for those with Waf1-positive tumors (P<.0001). In multivariate analysis, Waf1 expression and low histologic grade (1 or 2) tumors had an independent prognostic significance for recurrence-free survival. These results suggest that Waf1 is induced mainly by a p53-dependent pathway and could be a reliable indicator of recurrence in breast cancer.
Adult↗
Analysis of phosphorylation of pRB and its regulatory proteins in breast cancer.
AIM: In order to study the role of retinoblastoma protein (pRB) in breast cancer, the phosphorylation of pRB and the expression of its related proteins-such as cyclin E, cyclin dependent kinase 2 (Cdk2), and p21/Cdk interacting protein 1 (Cip1)-were examined in 30 breast cancers in which pRB overexpression was confirmed immunohistochemically. METHODS: The phosphorylation of pRB for 30 tumours was investigated with western blotting. The expression of pRB, Cdk2/Cdc2, cyclin E, and p21/Cip1 was identified by immunohistochemistry and western blotting. RESULTS: The expression of pRB was confirmed in 52 of 70 tumours (74%) by immunostaining. Western blotting for pRB showed that 25 of 30 representative cancers (83%) were underphosphorylated, while only five tumours showed the hyperphosphorylated form of pRB. However, cyclin E and Cdk2-which promote phosphorylation of pRB-were expressed in all tumours. On the other hand p21/Cip1, a Cdk2 inhibitor, was expressed in 18 of 25 tumours with underphosphorylated pRB, while four of the five tumours with hyperphosphorylated pRB showed no expression of p21/Cip1. Examination of the relation between pRB phosphorylation and clinicopathological variables showed that the underphosphorylated group was characterised by low risk of lymph node metastasis (p < 0.01). CONCLUSIONS: The phosphorylation of pRB appears to be regulated mainly by p21/Cip1 through the suppression of cyclin E and Cdk2 in breast cancer. The underphosphorylated form of pRB may be useful as a prognostic factor.
Adult↗
Isoform variable action among thyroid hormone receptor mutants provides insight into pituitary resistance to thyroid hormone.
Resistance to thyroid hormone (RTH) is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). The mutant TR interferes with the action of normal TR to cause the clinical syndrome. Selective pituitary resistance to thyroid hormone (PRTH) results in inappropriate TSH secretion and peripheral sensitivity to elevated thyroid hormone levels. Association of the PRTH phenotype with in vitro behavior of the mutant TR has proved elusive. Alternative exon utilization results in two TR-beta isoforms, TR-beta 1 and TR-beta 2, which differ only in their amino termini. Although the TR-beta 1 isoform is ubiquitous, the TR-beta 2 isoform is found predominantly in the anterior pituitary and brain. To date, in vitro evaluation of RTH mutations has focused on the TR-beta 1 isoform. Site-directed mutagenesis was used to create several PRTH (R338L, R338W, V349M, R429Q, I431T) and generalized RTH (delta 337T, P453H) mutations in both TR-beta isoforms. The ability of mutant TRs to act as dominant negative inhibitors of wild type TR-beta function on positive and negative thyroid hormone response elements (pTREs and nTREs, respectively) was evaluated in transient transfection assays. PRTH mutants had no significant dominant negative activity as TR-beta 1 isoforms on pTREs found in peripheral tissues or on nTREs found on genes regulating TSH synthesis. PRTH mutants, in contrast, had strong dominant negative activity on these same nTREs as TR-beta 2 isoforms. Cotransfected retinoid X receptor-alpha was required for negative T3 regulation via the TR-beta 1 isoform but was not necessary for negative regulation via the TR-beta 2 isoform in CV-1 cells. The differing need for retinoid X receptor cotransfection demonstrates two distinct negative T3-regulatory pathways, one mediated by the TR-beta 1 and the other mediated by TR-beta 2. The selective effect of PRTH mutations on the TR-beta 2 isoform found in the hypothalamus and pituitary vs. the TR-beta 1 isoform found in peripheral tissues suggests a molecular mechanism for the PRTH disorder.
Alleles↗
[Molecular-pathological problems of genetic diagnosis for colorectal cancer].
Recent advances in molecular biology have revealed that the alteration of multiple genes, eg., APC, K-ras, p53, DCC, are involved in multistep colorectal carcinogenesis. Some of these alterations can be used as molecular markers in genetic diagnosis. Genetic diagnoses for colorectal cancer are classified into three categories, eg., 1. identification of the career in the family of patient with hereditary disease such as FPC (Familial Polyposis Coli) or HNPCC (Hereditary Non-Polyposis Colorectal Cancer), 2. early diagnosis of colorectal cancer by identifying gene mutations in the stool, 3. assist for histopathological diagnosis, or risk assessment of the metastasis, recurrence or secondary cancer by molecular means. However, there are several problems in these genetic diagnoses. These consist of two categories, eg., 1. problems in the method of gene analyses or assay system and 2. problems in performing genetic diagnoses itself. The former includes the problem of contamination of different tissue, false positive or negative result in PCR-based analyses, heterogeneity of gene mutation in tumor tissue, and the latter includes the social, ethical or economical problems mainly related to the genetic diagnosis for hereditary colorectal cancers. In this paper, we describe the possibility of genetic diagnosis for colorectal cancers and the current problems, especially from the molecular pathological aspect, in genetic diagnosis.
Colorectal Neoplasms↗
Expression of occludin, tight-junction-associated protein, in human digestive tract.
The tight junction seals cells together at a subapical location and functionally separates the plasma membrane into an apical and a basolateral domain. This junction is one of the most characteristic structural markers of the polarized epithelial cell. Recently, occludin has been identified as an integral transmembrane protein localizing at the tight junction and directly associated with ZO-1, an undercoat-constitutive cytoplasmic protein. We have investigated occludin expression in conjunction with ZO-1 in normal epithelia and cancers of human digestive tract by immunostaining with a new antibody raised against human occludin. In the normal simple columnar epithelium, occludin was expressed together with ZO-1 as a single line at the apical cell border. However, in the esophagus, which has a stratified squamous epithelium, no occludin expression could be detected, but ZO-1 was expressed in the spinous layer. As for cancers, both occludin and ZO-1 showed the same expression in differentiated adenocarcinoma cells as in normal epithelium, but in poorly differentiated adenocarcinomas, the expression of these two proteins was reduced. There was significant correlation between tumor differentiation and expression of these proteins. These results suggest that occludin, together with ZO-1, is involved in the formation of gland-like structures. In addition, occludin expression can serve as a histopathological indicator for differentiation in gastrointestinal adenocarcinomas.
Adenocarcinoma↗
[Transarterial immuno-embolization therapy in patients with hepatocellular carcinoma].
Surgical resection, transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) are effective for hepatocellular carcinoma (HCC), but the recurrence rate is high. We have devised a new therapy of transarterial immuno-embolization (TIE) with OK-432, fibrinogen and thrombin, and 2 cases are reported. Case 1: A 78-year-old Japanese male with HCC (diameter, 4 cm in subsegment 5) received TIE. The tumor size was markedly decreased, and the patient survived for more than 3 years without recurrence. Case 2: A 61-year-old Japanese male with HCC (diameter, 4.5 cm in segment 5) received hepatic subsegmentectomy following TIE. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells in the main tumor. Tumor recurrence had developed three times thereafter, but was effectively treated by TIE. TIE may be an effective therapy for HCC.
Aged↗
[A case of local recurrence of rectal cancer that achieved a complete response with high-dose interstitial brachytherapy].
We report a case of local recurrence of rectal cancer that achieved complete response with high-dose interstitial brachytherapy. The patient was a forty-nine-year-old woman. In September 1995, she underwent abdominoperineal resection of rectum for rectal cancer (T4 N2 M0, moderately differentiated adenocarcinoma). In February 1996, she complained of genital bleeding. MRI examination revealed a mass of 70 x 22 x 20 mm in the pelvis, which was diagnosed to be recurrent rectal cancer with needle biopsy. Interstitial brachytherapy (60 Gy/twelve fractions/six days) was performed, and a complete response was achieved. One year after the treatment, no tumor was detected in the pelvis. No skin erosion, skin ulcer, urinary cystitis, nor ileitis occurred. High-dose interstitial brachytherapy delivers high-dose irradiation to a tumor while keeping the dose to the surrounding normal organs at a low level. This procedure may be an effective modality for local recurrence of rectal cancer.
Adenocarcinoma↗