Japanese Journal Of Cancer Research[JOURNAL]
Sun
200 papers
DNA hypermethylation status of multiple genes in prostate adenocarcinomas.
Konishi N, Nakamura M, Kishi M … +3 more , Nishimine M, Ishida E, Shimada K
Jpn J Cancer Res · 2002 Jul · PMID 12149142 · Full text
Multiple genetic mutations and epigenetic methylation are believed to be involved in prostate carcinogenesis, but it is not known whether these events are independent or correlated in some fashion. We therefore studied 3...
Multiple genetic mutations and epigenetic methylation are believed to be involved in prostate carcinogenesis, but it is not known whether these events are independent or correlated in some fashion. We therefore studied 32 prostate adenocarcinomas not only for deletions and / or mutations of multiple suspect genes, but also for aberrant DNA methylation using methylation-specific PCR (MSP). Of those genes examined, p16(INK4a), O(6)-MGMT, and GST-P were found to be the most frequently methylated (66%, 25% and 75% of cases, respectively), while methylations of p14(ARF), RB1, p21(Waf1), and p27(Kip1) were far less common (3%, 6%, 6% and 6% of cases, respectively). Methylation of O(6)-MGMT and GST-P genes was defective in about 19% of the cases and there were occasional simultaneous deletions and methylations of p14(ARF) and p16(INK4a) genes (13% and 3% of cases, respectively). In p16(INK4a), methylation occurred in the promoter region in 9% of samples and in exon 2 in 66% of tumors. Hypermethylation of O(6)-MGMT with concurrent p53 and ras gene mutations were found in 6% and 13% of specimens, respectively; among those tumors with high Gleason scores were 2 carcinomas showing hypermethylated O(6)-MGMT with G-to-A transitions in K-ras. Our results demonstrate that multiple genes of a subset common in prostate carcinomas are methylated and not infrequently show concurrent deletions. Further, there is a suggestion that specific combinations of hypermethylation and mutation correlate to tumor malignancy.
Cell-free human T-cell leukemia virus type 1 binds to, and efficiently enters mouse cells.
Sun B, Nitta T, Shoda M … +4 more , Tanaka M, Hanai S, Hoshino H, Miwa M
Jpn J Cancer Res · 2002 Jul · PMID 12149141 · Full text
Human T-cell leukemia virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia / lymphoma and other HTLV-1-associated diseases. However, the interaction between HTLV-1 and T cells in the pathogenesis of these...
Human T-cell leukemia virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia / lymphoma and other HTLV-1-associated diseases. However, the interaction between HTLV-1 and T cells in the pathogenesis of these diseases is poorly understood. Mouse cells have been reported to be resistant to cell-free HTLV-1 infection. However, we recently reported that HTLV-1 DNA could be observed 24 h after cell-free HTLV-1 infection of mouse cell lines. To understand HTLV-1 replication in these cells in detail, we concentrated the virus produced from c77 feline kidney cell line and established an efficient infection system. The amounts of adsorption of HTLV-1 are larger in mouse T cell lines, EL4 and RLm1, than those in human T cell lines, Molt4 and HUT78, and are similar to that in human kidney cell line, 293T. Unexpectedly, however, the amounts of entry of HTLV-1 are about 10-fold larger in the two mouse cell lines than those in the three human cell lines employed. Moreover, viral DNA was detectable from 1 h in EL4 and RLm1 cells, but only from 2 - 3 h in 293T, Molt4 and HUT78 cells. However, the amount of viral DNA in EL4 cells became smaller than that in Molt4 cells. HTLV-1 expression could be detected until day 1 - 2 in RLm1 and EL4 cells, and until day 4 in Molt4 cells. Our results suggest that mouse cell experiments would give useful information to dissect the early steps of cell-free HTLV-1 infection.
Enhancing effects of beta-estradiol 3-benzoate but not methoxychlor on the promotion/progression stage of chemically-induced mammary carcinogenesis in ovariectomized rats.
Ueda M, Takagi H, Onodera H … +6 more , Yasuhara K, Takizawa T, Imai T, Mitsumori K, Matsui T, Hirose M
Jpn J Cancer Res · 2002 Jul · PMID 12149140 · Full text
Modifying effects of beta-estradiol 3-benzoate (EB) and methoxychlor (MXC), a pesticide which possesses weak estrogenic activity, on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis were investigated...
Modifying effects of beta-estradiol 3-benzoate (EB) and methoxychlor (MXC), a pesticide which possesses weak estrogenic activity, on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis were investigated in ovariectomized or intact female Sprague-Dawley rats. Twenty-eight weeks after a single DMBA (100 mg / kg body weight) initiation, when the incidence of mammary tumor-bearing rats had reached 75%, a number of the animals were subjected to ovariectomy in order to obtain 3 groups: i) tumor-bearing, ovariectomized group; ii) tumor-bearing, intact group; iii) no-tumor, ovariectomized group. Subsequently animals of each group were subjected to subcutaneous implantation of 0.5 mg EB or given diet containing 1000 ppm MXC for 13 weeks. Although the incidences, multiplicities and volumes of the palpable tumors gradually decreased after ovariectomy, EB treatment stimulated tumor growth in the tumor-bearing, ovariectomized group thereafter. A similar effect of EB treatment was also observed in the no-tumor, ovariectomized group. However, MXC did not show any effect in the tumor-bearing, or no-tumor ovariectomized groups, except that the multiplicity of tumors was significantly decreased by MXC treatment in the tumor-bearing, intact group. The results of our study suggest that MXC has no promotion / progression effect, but rather possesses a weak inhibitory effect, whereas the strongly estrogenic substance EB clearly enhanced DMBA-induced mammary tumorigenesis.
Transgenic rats carrying human c-Ha-ras proto-oncogene are highly susceptible to N-nitrosomethylbenzylamine induction of esophageal tumorigenesis.
Asamoto M, Toriyama-Baba H, Ohnishi T … +5 more , Naito A, Ota T, Ando A, Ochiya T, Tsuda H
Jpn J Cancer Res · 2002 Jul · PMID 12149139 · Full text
A transgenic rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, has been established in our laboratory (Hras128 rats), and shown to be highly susceptible to induction...
A transgenic rat line carrying three copies of the human c-Ha-ras proto-oncogene, including its own promoter region, has been established in our laboratory (Hras128 rats), and shown to be highly susceptible to induction of mammary and urinary bladder tumors. Mutation analysis of induced lesions indicated the majority to contain some but not all cells with transgene mutation. In the present study, the susceptibility of Hras128 rats to N-nitrosomethylbenzylamine (NMBA) induction of esophageal tumors was examined with a similar mutation analysis of the transgenes. Male 6-week-old Hras128 and wild littermate rats were treated with NMBA, 0.5 mg / kg subcutaneously, 3 times a week for 5 weeks and then maintained for 5 weeks without any further treatment. Multiple esophageal tumors, squamous cell papillomas and carcinomas, rapidly developed within this 10-week experimental period in Hras128 rats (11.05 +/- 7.83 / rat). In contrast, wild-type littermates had only small numbers of mostly benign tumors (1.67 +/- 2.06 / rat). The Hras128 rats had no other tumors or abnormalities. In their esophageal lesions, codon 12 GGC to GAC mutations of the transgene were frequently detected by restriction fragment length polymorphisms (RFLP) and subsequent direct sequencing analysis (19 / 25, 76%). In the endogenous rat c-Ha-ras gene they were less frequent (2 / 25, 8%), than in wild-type rats (8 / 14, 57.1%). The densities of mutated bands in the RFLP analysis indicated that mutated cells were major populations in tumors, in contrast to the case with mammary and urinary bladder lesions. Furthermore, activated ras protein, detected by binding to raf protein, was clearly increased in tumors as compared to surrounding epithelium or the normal esophagus of untreated rats. The results show that Hras128 rats are highly susceptible to NMBA esophageal carcinogenesis, as well as induction of mammary and urinary bladder tumors, but that tissue-specific characteristics exist for the roles of transgene ras mutations.
Oxidative DNA damage induced by a metabolite of 2-naphthylamine, a smoking-related bladder carcinogen.
Ohnishi S, Murata M, Kawanishi S
Jpn J Cancer Res · 2002 Jul · PMID 12149138 · Full text
2-Naphthylamine (2-NA), a bladder carcinogen, is contained in cigarette smoke. DNA adduct formation is thought to be a major cause of DNA damage by carcinogenic aromatic amines. We have investigated whether a metabolite...
2-Naphthylamine (2-NA), a bladder carcinogen, is contained in cigarette smoke. DNA adduct formation is thought to be a major cause of DNA damage by carcinogenic aromatic amines. We have investigated whether a metabolite of 2-NA, 2-nitroso-1-naphthol (NO-naphthol) causes oxidative DNA damage, using (32)P-labeled DNA fragments. We compared the mechanism of DNA damage induced by NO-naphthol with that by N-hydroxy-4-aminobiphenyl (4-ABP(NHOH)), a metabolite of 4-aminobiphenyl, another smoking-related bladder carcinogen. NO-naphthol caused Cu(II)-mediated DNA damage at T > C > G residues, with non-enzymatic reduction by NADH. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). Some free. OH scavengers also attenuated NO-naphthol-induced DNA damage, while free. OH scavengers had no effect on the DNA damage induced by 4-ABP(NHOH). This difference suggests that the reactive species formed by NO-naphthol has more free. OH-character than that by 4-ABP(NHOH). A high-pressure liquid chromatograph equipped with an electrochemical detector showed that NO-naphthol induced 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in the presence of NADH and Cu(II). The oxidative DNA damage by these amino-aromatic compounds may participate in smoking-related bladder cancer, in addition to DNA adduct formation.
Psychosocial stress augments tumor development through beta-adrenergic activation in mice.
Hasegawa H, Saiki I
Jpn J Cancer Res · 2002 Jul · PMID 12149137 · Full text
Housing conditions affect behavioral and biological responses of animals. We investigated the effect of same-sex-grouped (G), crowded (GC) and isolated (I) conditions on the growth of B16 melanoma or Meth A fibrosarcoma...
Housing conditions affect behavioral and biological responses of animals. We investigated the effect of same-sex-grouped (G), crowded (GC) and isolated (I) conditions on the growth of B16 melanoma or Meth A fibrosarcoma implanted in the footpad of syngeneic male C57BL / 6 or BALB / c mice. Differential housing altered host resistance to tumor growth. The host responses to stress were reflected in thymic atrophy, which was lowest in the G mice, highest in the GC mice and intermediate in the I mice. The GC condition was a more stressful social environment than the I condition in both male C57BL / 6 and BALB / c mice. Reflecting the extent of psychosocial stress, tumor growth was augmented in the order of GC, I and G condition, and a negative mass correlation between tumor and thymus was observed, thus clearly indicating that the host resistance to tumors was attenuated by psychosocial stress. Furthermore, the stress-enhanced tumor growth and thymus atrophy were completely abrogated by the oral administration of the non-selective beta-adrenergic antagonist, propranolol. On the contrary, the chronic administration of corticosterone significantly induced the atrophy of thymus and spleen without affecting tumor growth. These results suggest an interrelationship among psychosocial stress, tumor growth and beta-adrenergic activation.
Sensitivity to anticancer agents and resistance mechanisms in clear cell carcinoma of the ovary.
Itamochi H, Kigawa J, Sultana H … +5 more , Iba T, Akeshima R, Kamazawa S, Kanamori Y, Terakawa N
Jpn J Cancer Res · 2002 Jun · PMID 12079522 · Full text
We conducted the present study to determine the chemoresistance mechanisms in clear cell carcinoma of the ovary (CCC). Five human CCC cell lines (HAC-2, RMG-I, RMG-II, KK, and KOC-7c) were used in this study. The sensiti...
We conducted the present study to determine the chemoresistance mechanisms in clear cell carcinoma of the ovary (CCC). Five human CCC cell lines (HAC-2, RMG-I, RMG-II, KK, and KOC-7c) were used in this study. The sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and we assessed drug sensitivity by calculating assay area under the curve (AUC) for each agent. The expression of multi-drug resistance genes (MDR-1, MRP-1, MRP-2) was detected by reverse transcription-polymerase chain reaction (RT-PCR). Glutathione (GSH) concentration was measured by an enzymatic assay. Topoisomerase (topo) I activity was assayed in terms of relaxation of supercoiled plasmid substrate DNA. The IC(50) to anticancer agents ranged widely. The assay AUC indicated that 3 of 5 cell lines (RMG-I, RMG-II, and KK) were sensitive to paclitaxel (PTX), 3 (HAC-2, RMG-I, and RMG-II) were sensitive to 7-ethyl-10-hydroxycamptothecin (SN-38), which is an active metabolite of camptothecin (CPT-11), and only one (HAC-2) was sensitive to cisplatin (CDDP). All cell lines were resistant to mitomycin-C (MMC) and etoposide (VP-16). The MRP-1 gene was detected in all cell lines. Only one cell line showed both MRP-2 and MDR-1 gene expression. Except for HAC-2 cells, expression of MRP genes was related to CDDP resistance, and MDR-1 gene expression was associated with PTX resistance. GSH concentrations increased after exposure to CDDP or MMC in all cell lines. There was a significant correlation between topo-I enzymatic activity and the response to SN-38. The present study revealed several resistance mechanisms in CCC and the results suggested that PTX and CPT-11 might be effective agents to treat CCC.
Hammerhead ribozyme against gamma-glutamylcysteine synthetase attenuates resistance to ionizing radiation and cisplatin in human T98G glioblastoma cells.
Tani M, Goto S, Kamada K … +7 more , Mori K, Urata Y, Ihara Y, Kijima H, Ueyama Y, Shibata S, Kondo T
Jpn J Cancer Res · 2002 Jun · PMID 12079521 · Full text
Glioblastoma cells are highly malignant and show resistance to ionizing radiation, as well as anti-cancer drugs. This resistance to cancer therapy is often associated with a high concentration of glutathione (GSH). In th...
Glioblastoma cells are highly malignant and show resistance to ionizing radiation, as well as anti-cancer drugs. This resistance to cancer therapy is often associated with a high concentration of glutathione (GSH). In this study, the effect of continuous down-regulation of gamma-glutamylcysteine synthetase (gamma-GCS) expression, a rate-limiting enzyme for GSH synthesis, on resistance to ionizing radiation and cisplatin (CDDP) was studied in T98G human glioblastoma cells. We constructed a hammerhead ribozyme against a gamma-GCS heavy subunit (gamma-GCSh) mRNA and transfected it into T98G cells. (1) The transfection of the ribozyme decreased the concentration of GSH and resulted in G1 cell cycle arrest of T98G cells. (2) The transfection of the ribozyme increased the cytotoxicity of ionizing radiation and CDDP in T98G cells. Thus, hammerhead ribozyme against gamma-GCS is suggested to have potential as a cancer gene therapy to reduce the resistance of malignant cells to ionizing radiation and anti-cancer drugs.
Dose of adenoviral vectors expressing interleukin-2 plays an important role in combined gene therapy with cytosine deaminase/5-fluorocytosine: preclinical consideration.
Nakamori M, Iwahashi M, Ueda K … +4 more , Tsunoda T, Terasawa H, Hamada H, Yamaue H
Jpn J Cancer Res · 2002 Jun · PMID 12079520 · Full text
Using a syngeneic murine model, we investigated the therapeutic efficacy of combined gene therapy using adenoviral vectors expressing murine interleukin-2 (AdmIL-2) and Escherichia coli cytosine deaminase (AdCD). In a su...
Using a syngeneic murine model, we investigated the therapeutic efficacy of combined gene therapy using adenoviral vectors expressing murine interleukin-2 (AdmIL-2) and Escherichia coli cytosine deaminase (AdCD). In a subcutaneous tumor model, tumor-bearing mice were treated with an intratumoral injection of adenoviral vectors and received an intraperitoneal administration of 5-fluorocytosine (5-FC). Only the mice treated with AdCD (2 x 10(8) pfu) and an intermediate dose of AdmIL-2 (1 x 10(6) pfu) survived significantly longer than mice treated with AdCD alone (P < 0.01). Moreover, 40% of these treated mice obtained complete remission from tumor-bearing status. The cytotoxicity of splenocytes obtained from the treated mice was related to the survival period. Tumor-specific cytotoxic T lymphocyte assay showed that the cell-mediated cytotoxic response was specific for parental tumor cells. In a hepatic metastasis model, mice treated with an intravenous administration of both AdCD (2 x 10(8) pfu) and an intermediate dose of AdmIL-2 (1 x 10(6) pfu) demonstrated the most significant reduction of metastatic foci and the longest survival following a 5-FC administration. These results suggest that gene therapy combined with AdmIL-2 and AdCD may be a promising strategy for clinical application and, in addition, that translation of combined gene therapy from murine models into the clinical setting will require careful attention to the variables of cytokine expression levels in the design of clinical trials and in the evaluation of treatment efficacy.
Immunocytochemical expression of microtubule-associated protein-2 (MAP-2) in small cell lung cancer cell lines with neuronal-like processes.
Tanaka K, Terasaki T
Jpn J Cancer Res · 2002 Jun · PMID 12079519 · Full text
Five of six human small cell lung cancer (SCLC) cell lines changed morphologically into cells with neuronal-like processes on the extracellular matrix of human lung adenocarcinoma cell line PC-9 cells (PC-9 / ECM substra...
Five of six human small cell lung cancer (SCLC) cell lines changed morphologically into cells with neuronal-like processes on the extracellular matrix of human lung adenocarcinoma cell line PC-9 cells (PC-9 / ECM substrate). The features of the neuronal-like processes of these SCLC cell lines were examined immunocytochemically using monoclonal antibodies against beta-chains of tubulin and microtubule-associated protein-2 (MAP-2), which is somatodendritic MAP of neurons. It was observed that beta-chains of tubulin and MAP-2 were expressed along the neuronal-like processes of SCLC cell lines. These findings suggest that the beta-chains of tubulin and MAP-2 are expressed functionally in SCLC cell lines in association with the development of dendrite-like processes on PC-9 / ECM substrate.
Clinical significance of occult micrometastases in axillary lymph nodes in "node-negative" breast cancer patients.
Umekita Y, Ohi Y, Sagara Y … +1 more , Yoshida H
Jpn J Cancer Res · 2002 Jun · PMID 12079518 · Full text
The most important subgroup of breast cancer patients for whom reliable prognostic indicators are needed is women without axillary lymph node metastases. We evaluated the clinical significance of occult micrometastases i...
The most important subgroup of breast cancer patients for whom reliable prognostic indicators are needed is women without axillary lymph node metastases. We evaluated the clinical significance of occult micrometastases in axillary lymph nodes in 148 consecutive "node-negative" breast cancer patients. The median age of the patients at surgery was 52 years and the median follow-up period after surgery was 98.5 months. Occult micrometastases were detected in 21 of 148 patients (14.2%) by means of immunohistochemical analysis using AE1 / 3 antibody and a single unstained section after routine histopathological examination. Log-rank tests indicated that the 7-year disease-free survival (DFS) and overall survival (OS) rates by Kaplan-Meier methods were significantly better in patients without occult micrometastases than in patients with occult micrometastases [DFS, 93% versus 71% (P = 0.0009); OS, 96% versus 76% (P = 0.0001)]. According to Cox's multivariate analysis, the presence of occult micrometastases had the most significant effect on DFS (P = 0.0053) and OS (P = 0.0035). These findings suggest that the presence of occult micrometastases is an independent and significant predictor of clinical outcome, and that their immunohistochemical detection after routine histopathological examination is useful for selecting the "node-negative" breast cancer patient subgroup at high risk for relapse and death.
MUM1/IRF4 expression is an unfavorable prognostic factor in B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Ito M, Iida S, Inagaki H … +9 more , Tsuboi K, Komatsu H, Yamaguchi M, Nakamura N, Suzuki R, Seto M, Nakamura S, Morishima Y, Ueda R
Jpn J Cancer Res · 2002 Jun · PMID 12079517 · Full text
B-Cell chronic lymphocytic leukemia (B-CLL) / small lymphocytic lymphoma (SLL) consists of heterogeneous diseases that are distinguished by morphological, immunophenotypic and molecular features. MUM1 (multiple myeloma o...
B-Cell chronic lymphocytic leukemia (B-CLL) / small lymphocytic lymphoma (SLL) consists of heterogeneous diseases that are distinguished by morphological, immunophenotypic and molecular features. MUM1 (multiple myeloma oncogene 1) is a protooncogene that is deregulated as a result of (6;14)(p25;q32) chromosomal translocation in multiple myeloma, and is also expressed in a variety of malignant lymphoma entities. We examined the expression of MUM1 in B-CLL / SLL, and found that 2 of 4 B-CLL-derived cell lines and 14 of 29 patients' specimens expressed MUM1 by immunohistochemical analysis. MUM1 expression was not associated with CD38 expression, somatic hypermutation of immunoglobulin heavy chain gene variable region (IgV(H)), or any other clinical characteristics of the patients. Interestingly, the patients who were positive for MUM1 showed shorter overall survival times than those who were negative for MUM1 (50% survival: 22 months vs. 82 months) (P = 0.0008, log-rank test). Multivariate analysis by Cox's proportional-hazards regression model showed that MUM1 expression and unmutated IgV(H) status were independent unfavorable prognostic factors in patients with B-CLL / SLL. These findings suggest that MUM1 expression is a useful prognostic factor in B-CLL / SLL. The biological role and mechanism of action of MUM1 in B-CLL / SLL need to be clarified for the development of therapies for patients with the poor prognostic subtype.
Clinicopathologic comparison between the API2-MALT1 chimeric transcript-positive and -negative gastric low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type.
Nakamura T, Nakamura S, Yokoi T … +3 more , Suzuki H, Ohashi K, Seto M
Jpn J Cancer Res · 2002 Jun · PMID 12079516 · Full text
Little is known about the clinicopathological differences between API2-MALT1 chimeric transcript-positive and -negative gastric low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type. The aim of this...
Little is known about the clinicopathological differences between API2-MALT1 chimeric transcript-positive and -negative gastric low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type. The aim of this study was to clarify those differences in gastric MALT lymphoma. Twenty-three patients with gastric MALT lymphoma were enrolled in a unicenter study. Helicobacter pylori (H. pylori) infection status and clinical stages were investigated. Antibacterial treatment was performed for every patient. Responsiveness of MALT lymphoma to this treatment was assessed by means of regular follow-up endoscopy combined with biopsy. All cases were examined for API2-MALT1 chimeric transcript by means of RT-PCR and sequencing analyses. H. pylori infection status was assessed as positive in 20 patients and negative in three. With regard to responsiveness to antibacterial treatment, complete remission was observed in two patients, partial remission in 12 and no change in nine. API2-MALT1 chimeric transcript was detected in seven patients, all of whom showed no change in response to antibacterial treatment. API2-MALT1 positivity was found to be significantly correlated with responsiveness to antibacterial treatment (P = 0.0001), absence of H. pylori infection (P = 0.0198), and gross cobblestone mucosa observed endoscopically (P = 0.0198). For the other factors (age, sex, dominant site of lesion, high-grade component, infiltrated layer of gastric wall, nodal involvement or clinical stages), there were no differences between API2-MALT1 chimeric transcript-positive and -negative cases. Gastric API2-MALT1 chimeric transcript-positive MALT lymphoma generally features unresponsiveness to antibacterial treatment, and is thought to be unrelated to H. pylori infection in its pathogenesis. Our findings indicate the presence of different clinical subtypes in gastric MALT lymphomas.
Establishment and characterization of a new lung cancer cell line (MI-4) producing high levels of granulocyte colony stimulating factor.
Harada R, Uemura Y, Kobayashi M … +6 more , Zamecnikova A, Nakata H, Taguchi T, Furihata M, Otsuki Y, Taguchi H
Jpn J Cancer Res · 2002 Jun · PMID 12079515 · Full text
We established a human lung cancer cell line, MI-4 from the pleural effusion of a 69-year-old male with advanced large cell undifferentiated carcinoma of the lung complicated by leukocytosis. The culture supernatant of M...
We established a human lung cancer cell line, MI-4 from the pleural effusion of a 69-year-old male with advanced large cell undifferentiated carcinoma of the lung complicated by leukocytosis. The culture supernatant of MI-4 contained high levels of granulocyte colony stimulating factor (G-CSF). The intracellular localization of the G-CSF was identified by immunocytochemistry. Reverse transcription-polymerase chain reaction (RT-PCR) revealed G-CSF mRNA expression in this cell line. The cell line was successfully transplanted into nude mice. The transplanted nude mice also showed leukocytosis with a high serum G-CSF level. Southern blot analysis did not show amplification or rearrangement of the G-CSF gene in MI-4 cells. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that this cell line has an additional chromosome 17 attached to a segment of chromosome 10 besides two intact chromosomes 17, and that each of these three chromosomes 17 has a G-CSF gene on chromosome 17q. Inflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, significantly enhanced G-CSF expression at both the protein and mRNA levels in MI-4. However, these cytokines did not stimulate the growth of MI-4 cells, regardless of abundant G-CSF production. TNF-alpha rather suppressed it, in a dose-dependent manner. Exogenous recombinant human G-CSF and anti-G-CSF antibody did not promote or inhibit the growth of MI-4 cells at any concentration examined. In addition, RT-PCR analysis did not show G-CSF receptor mRNA expression. These results suggest that this cell line does not have an autocrine growth loop for G-CSF. This cell line should be very useful for understanding the biological activity of G-CSF in G-CSF-overproducing lung cancer.
Expression of PPARgamma and its ligand-dependent growth inhibition in human brain tumor cell lines.
Kato M, Nagaya T, Fujieda M … +3 more , Saito K, Yoshida J, Seo H
Jpn J Cancer Res · 2002 Jun · PMID 12079514 · Full text
Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a superfamily of thyroid / steroid hormone receptors and regulates transcription of their target genes in a ligand-dependent manner. Recently, PPARg...
Peroxisome proliferator-activated receptor gamma (PPARgamma) belongs to a superfamily of thyroid / steroid hormone receptors and regulates transcription of their target genes in a ligand-dependent manner. Recently, PPARgamma was reported to be expressed in several cell lines derived from breast, colon, stomach and lung cancers. Activation of PPARgamma by its ligand inhibits the growth of these tumor cells, suggesting that PPARgamma ligand is a potential anti-cancer agent in PPARgamma-expressing tumors. However, its expression in brain tumors has not been studied. We thus studied the expression in glioma samples with different pathological stages from 20 patients. It was demonstrated that 95% of the glioma tissue expressed PPARgamma mRNA. The results prompted us to study whether PPARgamma ligand affects the growth of cell lines derived from brain tumors. The receptor expression was studied in 9 cell lines either derived from malignant glioma or neuroblastoma. The expression was detected in a glioma cell line SK-MG-1 and in a neuroblastoma cell line NB-1. Addition of one of the PPARgamma ligands, troglitazone, induced growth inhibition in both cell lines. Further analyses revealed that this growth inhibition is caused by a PPARgamma-mediated induction of apoptosis. These results suggest that PPARgamma ligands could be a potential therapeutic agent for the treatment of the brain tumors expressing this receptor.
Expression of laminin-5 enhances tumorigenicity of human fibrosarcoma cells in nude mice.
Mizushima H, Hirosaki T, Miyata S … +3 more , Takamura H, Miyagi Y, Miyazaki K
Jpn J Cancer Res · 2002 Jun · PMID 12079513 · Full text
Laminin-5 (LN5), which consists of laminin alpha3, beta3 and gamma2 chains, is a laminin isoform produced by various kinds of normal epithelial cells and tumor cells. Strong activity of LN5 in adhesion, migration and sca...
Laminin-5 (LN5), which consists of laminin alpha3, beta3 and gamma2 chains, is a laminin isoform produced by various kinds of normal epithelial cells and tumor cells. Strong activity of LN5 in adhesion, migration and scattering of cells in vitro and its frequent detection in human tumor tissues have suggested a possible role of LN5 in the malignant growth of tumor cells. To examine whether LN5 affects the malignant potential of tumor cells, we prepared human fibrosarcoma HT1080 cell lines producing LN5 by transfecting a cDNA of laminin alpha3 chain into the parent cell line, which constitutively expressed the laminin beta3 and gamma2 chains. The exogenous alpha3 chain associated with the endogenous beta3 and gamma2 chains to secrete the LN5 heterotrimer that has strong cell-scattering and cell adhesion activities. The HT1080 transfectants expressing LN5 efficiently adhered to culture dishes in a serum-free condition as compared with control HT1080 cells, which secreted the monomers and heterodimer of the beta3 and gamma2 chains. When injected into nude mice subcutaneously, the HT1080 transfectants expressing LN5 grew faster and formed much larger tumors than the control cells. This suggests that LN5 promotes tumor growth in vivo.
Expression of vascular endothelial growth factor and E-cadherin in human ovarian cancer: association with ascites fluid accumulation and peritoneal dissemination in mouse ascites model.
Akutagawa N, Nishikawa A, Iwasaki M … +6 more , Fujimoto T, Teramoto M, Kitajima Y, Endo T, Shibuya M, Kudo R
Jpn J Cancer Res · 2002 Jun · PMID 12079512 · Full text
Ascites formation and peritoneal dissemination are critical problems in patients with advanced ovarian cancer. Vascular endothelial growth factor (VEGF), also known as angiogenic growth factor, is a potent mediator of pe...
Ascites formation and peritoneal dissemination are critical problems in patients with advanced ovarian cancer. Vascular endothelial growth factor (VEGF), also known as angiogenic growth factor, is a potent mediator of peritoneal fluid accumulation and angiogenesis of tumors. E-Cadherin is an adhesion molecule that is important for cell-to-cell interaction. To elucidate the molecular mechanism of ascites formation and peritoneal dissemination of ovarian cancer, we examined the expression of VEGF and E-cadherin in different ovarian cancer cell lines and utilized nude mice to compare the biological characteristics of ovarian cancer cells. Three human ovarian cancer cell lines (AMOC-2, HNOA and HTBOA) were used in this study. Expression of genes was analyzed by northern blotting and RT-PCR methods. AMOC-2 expressed E-cadherin, but not VEGF. HNOA expressed VEGF without E-cadherin expression. HTBOA expressed both VEGF and E-cadherin. Each human ovarian cancer model revealed a specific feature. The AMOC-2 mouse had a single large peritoneal tumor without ascites or remarkable peritoneal dissemination. HTBOA and HNOA mice had bloody ascites and marked peritoneal dissemination. Introduction of VEGF antisense into HTBOA cells could inhibit the ascites formation. It is suggested that VEGF is important for the ascites formation via the increased vascular permeability effect. The deregulation of E-cadherin expression might be involved in the peritoneal dissemination. These molecules are important for the formation of specific features of advanced ovarian cancer. Ovarian cancer cell lines that had different gene expression patterns produced nude mouse human ovarian cancer models with different characteristics.
Identification of genes associated with dedifferentiation of hepatocellular carcinoma with expression profiling analysis.
Midorikawa Y, Tsutsumi S, Taniguchi H … +5 more , Ishii M, Kobune Y, Kodama T, Makuuchi M, Aburatani H
Jpn J Cancer Res · 2002 Jun · PMID 12079511 · Full text
To identify the genes associated with dedifferentiation of hepatocellular carcinoma (HCC), gene expression profiles of HCCs of well-and moderately differentiated grades were compared by means of oligonucleotide arrays. O...
To identify the genes associated with dedifferentiation of hepatocellular carcinoma (HCC), gene expression profiles of HCCs of well-and moderately differentiated grades were compared by means of oligonucleotide arrays. One tumor showed a nodule-in-nodule appearance (NIN), which is occasionally observed in the course of progression of HCC from well to less differentiated grade, when an inner, moderately differentiated tumor (MD) develops sequentially from the outer, well-differentiated tumor (WD). Seventy-six genes were identified to be up-regulated more than 3-fold and 33 genes were down-regulated in the inner nodule in NIN. By statistical analysis of the profiles from 10 individual additional liver tumors, 5 WDs and 5 MDs, we were able to identify 12 genes, LAMA3, PPIB, ADAR, PSMD4, NDUFS8, D9SVA, CCT3, GBAP, ARD1, RDBP, CSRP2, and TLE1, with significantly elevated expression, and 4 genes, CP, IL7R, CD48, and PLGL, with decreased expression in MD. These selected genes were further validated using another 12 tumors, 5 WDs and 7 MDs, with semi-quantitative RT-PCR. We also applied neighborhood analysis to list the genes with high predictability values as most closely correlated with WD-MD distinction. Seven genes, ADAR, PSMD4, D9SVA, CCT3, GBAP, RDBP, and CSRP2, whose expression was elevated and one gene, IL7R, whose expression was decreased, were included among the top 50 predictor genes. These genes are likely to be associated with dedifferentiation of HCC and their identification may help to elucidate the mechanism of liver cancer progression.
Inhibitory effects of toremifene on N-methyl-N-nitrosourea and estradiol-17beta-induced endometrial carcinogenesis in mice.
Niwa K, Hashimoto M, Lian Z … +5 more , Gao J, Tagami K, Yokoyama Y, Mori H, Tamaya T
Jpn J Cancer Res · 2002 Jun · PMID 12079510 · Full text
Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g bo...
Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg / 30 g body weight) decreased expression of c-fos, interleukin (IL)-1alpha, estrogen receptor (ER)-alpha mRNAs and corresponding proteins induced by estradiol-17beta (E(2)), in the uteri of the ovariectomized mice. Expression of ER-beta mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E(2) diet (5 ppm) plus TOR (0.2 mg / 30 g body weight, subcutaneously, every four weeks); group 2, E(2) diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c-fos as well as IL-1alpha expression induced by E(2). Such suppressive effects of TOR may be related to the decreased ER-alpha and increased ER-beta expressions.
Down-regulation of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in rats.
Fujita K, Ohnishi T, Sekine K … +2 more , Iigo M, Tsuda H
Jpn J Cancer Res · 2002 Jun · PMID 12079509 · Full text
The inhibitory influence of bovine lactoferrin (bLF) on induction of preneoplastic hepatic glutathione S-transferase placental form-positive (GST-P( +)) cell foci and colon aberrant crypt foci (ACF) by diethylnitrosamine...
The inhibitory influence of bovine lactoferrin (bLF) on induction of preneoplastic hepatic glutathione S-transferase placental form-positive (GST-P( +)) cell foci and colon aberrant crypt foci (ACF) by diethylnitrosamine (DEN) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in F344 rats. Rats were initially treated with DEN, then placed on basal diet containing MeIQx (200 ppm) alone, MeIQx plus 2% bLF, or MeIQx plus 0.2% bLF from week 2 to week 8, with partial hepatectomy performed at week 3. Concomitant administration of 2% or 0.2% bLF with MeIQx caused significant dose-dependent decreases in both number and unit area of GST-P(+) cell foci (2% bLF, P < 0.001; 0.2% bLF, P < 0.01). Similar results were observed for MeIQx-induced colon ACF in the groups without DEN treatment (2% and 0.2% bLF, P < 0.05). To investigate the underlying mechanisms, we analyzed the influence of bLF on levels of cytochrome P4501A2 (CYP1A2), a metabolically activating enzyme of MeIQx in the liver. The results demonstrated that combined administration of 2% bLF significantly reduced levels of MeIQx-induced CYP1A2 mRNA (P < 0.05) and protein (P < 0.05) to the normal levels, in association with reduced values for MeIQx-DNA adducts (P < 0.05), liver GST-P(+) cell foci and colon ACF. These results suggest that bLF is a chemopreventive agent for DEN alone or DEN plus MeIQx-induced liver, and MeIQx-induced colon carcinogenesis in rats. One possible mechanism is a normalizing down-regulation of CYP1A2 expression by bLF, with consequent reduction of carcinogen activation and adduct formation.
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