Cancer Lett

Frequent allelic loss on chromosomes 4q and 16q associated with human hepatocellular carcinoma in Taiwan.

Chou YH. Chung KC. Jeng LB. Chen TC. Liaw YF.
Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
To define the critical region of liver-specific tumor suppressor genes in human hepatocellular carcinoma (HCC), we analyzed 30 cases of hepatocellular carcinoma using nine 4q and six 16q microsatellite polymorphic DNA markers. We observed one major common deleted region which was flanked by D4S175-D4S1625 and there may be two tumor suppressor genes on chromosome 16q associated with HCC. An extensive study of allelotyping of human HCC was therefore carried out in the candidate region on arms of chromosome 4q with additional tumor tissues and more informative microsatellite DNA markers. These data imply that at least one putative tumor suppressor gene is located in the human chromosome 4q26-q27 region and provides very useful information for further construction of a long-range physical restriction map and thereafter cloning of the putative tumor suppressor gene.

Reduced tumorigenicity of human gastric carcinoma cells engineered to produce IL-2 in SCID mice reconstituted with peripheral blood cells from cancer patients.

Tagawa M. Goto S. Takenaga K. Takeshita A. Saotome T. Takenouchi T. Tsurumachi T. Gunji Y. Matsubara H. Sakiyama S.
Division of Pathology, Chiba Cancer Center, Japan. mtagawa@biolab.kazusa.or.jp
We have examined the validity of a humanized immune system with an animal model to assess cytokine gene therapy for cancer patients. For that purpose, we prepared hematologically-reconstituted severe combined immunodeficiency mice by transferring patient's peripheral blood cells containing CD34+ cells. These animals were inoculated subcutaneously with human gastric cancer lines transduced with cytokine genes. Tumorigenicity of interleukin-2-producing cells was significantly reduced in reconstituted but not in non-reconstituted mice, whereas that of wild-type and interleukin-6 producer cells was not affected irrespective of the reconstitution status. An inability to induce protective immunity in the reconstituted mice, which had rejected interleukin-2-producers, suggested that the effector cells mediating the antitumor response were non-T cells of donor origin. The experimental system presented in this study seems to be a feasible model to investigate applicable cytokines for patients.

Do HPA and PHA-L have the same binding pattern in metastasizing human breast and colon cancers?

Mitchell BS. Brooks SA. Leathem AJ. Schumacher U.
Anglo-European College of Chiropractic, Bournemouth, UK.
Glycoconjugates on the tumour cell surface are functionally important for the interaction of the tumour cell with its environment. Several studies have demonstrated that particular carbohydrate residues on primary cancers are associated with metastasis. Identification of such residues is possible using lectins, including Helix pomatia agglutinin (HPA) which has a nominal monosaccharide specificity for N-acetyl galactosamine (GalNAc) and Phaseolus vulgaris leucoagglutinin (PHA-L) which recognizes beta1-6 branched oligosaccharides. Both lectins have been reported to be valuable prognostic markers in breast and colon cancers. In the present study, the binding patterns of both lectins were investigated on serial sections of human breast cancers and on metastatic and non-metastatic human breast and colon cancer cell lines grown in severe combined immunodeficient (SCID) mice. The two lectins gave very different staining patterns and HPA was more often associated with metastases than PHA-L. Our results indicate that both lectins are not simply recognizing different oligosaccharides associated with the same common metastasis-related glycoconjugate.

Cyclooxygenase-2-selective antagonists do not inhibit growth of colorectal carcinoma cell lines.

Murphy VJ. Yang Z. Rorison KA. Baldwin GS.
Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of colorectal carcinoma. We now report that the potent cyclooxygenase-1 inhibitor indomethacin had no effect on the growth of human colorectal carcinoma cell lines in vitro at concentrations up to 30 microM. The selective cyclooxygenase-2 inhibitors L-745337 and NS-398 reduced cyclooxygenase activity, but had no effect on cell growth at concentrations as high as 100 microM. Our results provide direct evidence that inhibition of cyclooxygenase activity does not necessarily inhibit the growth of colorectal carcinoma cell lines and imply that the growth-inhibitory effects of NSAIDs in vitro are not mediated by inhibition of cyclooxygenases.

PyNPase expression in human colon cancer.

Haba A. Monden T. Sekimoto M. Ikeda K. Izawa H. Kanou T. Amano M. Kan'yama H. Monden M.
Department of Surgery II, Osaka University Medical School, Suita, Japan.
Although colorectal cancer tissue is rich in pyrimidine nucleoside phosphorylase (PyNPase), there is no consensus as to whether cancer cells or stromal cells predominately express PyNPase. We micro-dissected OCT compound embedded frozen tissue sections into epithelial and stromal components and then analyzed the extracted samples separately. The PyNPase expression level was higher in stromal cells than in cancer cells and the difference increased with inflammation induced by the immunostimulator OK432. These results suggest that stromal cells are the major PyNPase source in colorectal cancer.

DNA hypermethylation at the D17S5 locus is associated with gastric carcinogenesis.

Kanai Y. Ushijima S. Ochiai A. Eguchi K. Hui A. Hirohashi S.
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
The aim of this study was to elucidate the significance of aberrant DNA methylation in gastric carcinogenesis. The DNA methylation status at the D17S5 locus, at which a candidate tumor suppressor gene, HIC-1, was identified, of gastric cancers and non-cancerous gastric mucosae from 42 gastric cancer patients was examined by Southern blotting using a methylation-sensitive restriction enzyme. DNA hypermethylation was observed in 15, 13, 25 and 45% of the tissues showing no remarkable histological findings, chronic gastritis without intestinal metaplasia, intestinal metaplasia and gastric cancer, respectively. The incidence of DNA hypermethylation was significantly higher in gastric cancers than in non-cancerous gastric mucosae (P < 0.05). DNA hypermethylation was often accompanied by allelic loss at the same locus in gastric cancers. DNA hypermethylation at the D17S5 locus, which was even detected in precancerous conditions, including intestinal metaplasia, may play a role in gastric carcinogenesis.

Genomic structure of the human Smad3 gene and its infrequent alterations in colorectal cancers.

Arai T. Akiyama Y. Okabe S. Ando M. Endo M. Yuasa Y.
Department of First Surgery, Tokyo Medical and Dental University School of Medicine, Japan.
The Smad3 gene is a member of the Smad family, vertebrate homologues of Drosophila Mad, and its gene product is a cytoplasmic element in the TGF-beta signaling pathway. Smad2 and Smad4/DPC4, other members of the Smad family, are possibly tumor suppressor genes because alterations of these genes occurred in various carcinomas. We determined the genomic structure of human Smad3 which consists of nine exons. Then we examined whether or not Smad3 gene mutations exist in sporadic and hereditary non-polyposis colorectal cancers and found no mutations in the entire coding region in 50 cancers. Loss of heterozygosity of Smad3 was observed in two of the 17 (11.8%) informative cases using a polymorphism found in intron 2. These findings suggest that the Smad3 gene may not play an important role in the tumorigenesis of colorectal cancers.

Effects of accelerated carbon-ions on growth inhibition of transplantable human esophageal cancer in nude mice.

Takahashi A. Yano T. Matsumoto H. Wang X. Ohnishi K. Tamamoto T. Tsuji K. Yukawa O. Ohnishi T.
Department of Biology, Nara Medical University, Kashihara, Japan.
We have studied the effectiveness of 290 MeV/u carbon-ion (C-) beams (linear energy transfer (LET) of 70 keV/mm) and 200 kVp X-rays on tumor growth inhibition as an in vivo model for radiotherapy of cancer. We measured the size of tumor growth of transplantable human esophageal cancer in nude mice after radiation with C-beams and compared this with X-rays as the control. A significant inhibition of tumor growth was observed by C-beams as compared with X-rays. The relative biological effectiveness (RBE) of C-beams against X-rays was 2.02. Histopathological studies showed that C-beams at 20 Gy induced prominent necrosis in the central region and multinucleate giant cells and inflammatory cells in peripheral regions of the tumor, whereas X-rays at 20 Gy induced only mild necrosis. The high RBE of C-beams obtained in this study provides in vivo evidence that C-beams are more effective than conventional X-rays for radiotherapy of cancer.

Homozygous deletions of the CDKN2 gene and loss of heterozygosity of 9p in primary hepatocellular carcinoma.

Piao Z. Park C. Lee JS. Yang CH. Choi KY. Kim H.
Department of Pathology, Yonsei University, College of Medicine, Seoul, South Korea.
To elucidate the alterations of CDKN2 in hepatocarcinogenesis, we performed a loss of heterozygosity (LOH) study using eight polymorphic markers surrounding the CDKN2 gene and analyzed the homozygous deletions and mutations of the CDKN2 gene in 41 primary hepatocellular carcinomas (HCCs). Frequent LOH (27.8-44%) was found in the eight loci on chromosome 9p, however, no intragenic mutations of CDKN2 were observed by PCR-SSCP analysis. Homozygous deletions were detected in 25 of 41 HCCs (61%) by a comparative multiplex PCR. No expression of the CDKN2 protein was noted in five out of nine available HCCs by Western blot analysis. These results suggest that inactivation of the CDKN2 gene in HCC is a frequent event in which homozygous deletions are the most common mechanism of CDKN2 inactivation.

Identification of a neutrophil gelatinase-associated lipocalin mRNA in human pancreatic cancers using a modified signal sequence trap method.

Furutani M. Arii S. Mizumoto M. Kato M. Imamura M.
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan.
To identify the intercellular signal-transducing proteins and receptors produced by cancer cells, we attempted to clone cDNAs encoding secreted and type I membrane proteins using a signal sequence trap (SST) method with some modifications. By screening an SST library derived from pancreatic cancer cells, we identified two secretory proteins (neutrophil gelatinase-associated lipocalin (NGAL) and lung surfactant protein D) and three membrane proteins (carcinoembryonic antigen, BiP/GRP78 and Hsa4 mitochondrion cytochrome oxidase subunit II). NGAL mRNA was expressed in eight of the pancreatic cancer cell lines and eight pancreatic cancer tissues. The expression of NGAL mRNA was also observed in colorectal and hepatic tumors.

A study on pancreatic cancer in Chennai (Madras), India.

Gajalakshmi CK. Swaminathan R. Shanta V.
Division of Epidemiology and Cancer Registry, Cancer Institute (WIA), Tamilnadu, India. caninst@md2.vsnl.net.in
A total of 299 pancreatic cancer (PC) cases were registered in Chennai during 1982-1993 with an age-adjusted incidence rate (AAR) of 1.0 per 100,000. The present study shows an increasing trend in the risk of PC with an increase in the literacy level among males (P < 0.001). The relative survival rates at 1, 3 and 5 years were 35.7, 14.4 and 6.1%, respectively. Age at diagnosis, sex, religious group and literacy level did not emerge as significant prognostic factors for survival from PC. It is reiterated that emphasis should be placed on primary prevention of pancreatic cancer as opposed to early detection, by controlling the use of tobacco.

Targeted chemotherapy in mice with peritoneally disseminated gastric cancer using monoclonal antibody-drug conjugate.

Okamoto K. Yamaguchi T. Otsuji E. Yamaoka N. Yata Y. Tsuruta H. Kitamura K. Takahashi T.
First Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
The murine monoclonal antibody A7 (MAb A7) is reactive against most human gastric cancer cell lines. Using a nude mouse peritoneal dissemination model of human gastric cancer, we investigated targeted chemotherapy using a conjugate of neocarzinostatin (NCS) with MAb A7 (A7-NCS). After demonstrating cytotoxicity of the complex against the human gastric cancer cell line MKN45 in vitro, we intraperitoneally injected A7-NCS, NCS or saline into nude mice bearing peritoneally disseminated human gastric cancer. A7-NCS inhibited peritoneal dissemination significantly more effectively than NCS. MAb A7 may prove to be an effective carrier for antineoplastic drugs in patients with peritoneal dissemination of gastric cancer.

MHC class I bound peptides of a colon carcinoma cell line, a Ki-ras gene-targeted progeny cell line and a B cell line.

Savoie CJ. Kamikawaji N. Sudo T. Furuse M. Shirasawa S. Tana T. Sasazuki T.
Department of Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
MHC class I associated peptides on cancer cells represent potential targets for CD8+ cytotoxic T cell activity against tumor cells. We eluted the naturally bound MHC class I peptides of a colon carcinoma cell line and compared them to peptides isolated from a B cell line and a slow-growing activated Ki-ras-disrupted colon cancer cell line. While we failed to detect any significant differences in class I associated peptides due to the presence or absence of activated Ki-ras in colon cancer cell lines, the colon cancer cell lines and B cell line presented vastly different peptide repertoires in the context of HLA-A*0201 molecules.

Volatile N-nitrosamines in gastric juice of patients with various conditions of the gastrointestinal tract determined by gas chromatography-mass spectrometry and related to intragastric pH and nitrate and nitrite levels.

Year 1998
Dallinga JW. Pachen DM. Lousberg AH. van Geel JA. Houben GM. Stockbrugger RW. van Maanen JM. Kleinjans JC.
Department of Health Risk Analysis and Toxicology, Faculty of Health Sciences, Maastricht University, The Netherlands.
Gastric juice samples of 71 patients undergoing upper gastrointestinal endoscopy were collected as well as saliva samples from 40 of these patients. Age, sex, endoscopic diagnosis and medication were recorded. The gastric juice samples were analyzed for the presence and quantity of individual volatile N-nitrosamines, which were detected by gas chromatography-mass spectrometry, without prior derivatization. The samples were screened for eight nitrosamines, i.e. N-nitrosodimethylamine, N-nitrosoethylmethylamine, N-nitrosodiethylamine, N-nitrosodi-n-propylamine, N-nitrosodi-n-butylamine, N-nitrosopyrrolidine, N-nitrosopiperidine and N-nitrosomorpholine. The pH of the fresh gastric juice as well as nitrate and nitrite levels of gastric juice and saliva were determined. The mean total level of volatile N-nitrosamines in gastric juice was found to be 4.84 nmol/l (range 0-17.7 nmol/l). The main N-nitrosamines found were N-nitrosodiethylamine (mean concentration 3.1 nmol/l), N-nitrosodimethylamine (mean concentration 0.90 nmol/l) and N-nitrosopyrrolidine (mean concentration 0.38 nmol/l). Significant correlations between mean intragastric pH values and mean N-nitrosodi-n-butylamine level (P = 0.005) and total volatile N-nitrosamine contents (P = 0.009) were observed.

Blockade of long chain fatty acid oxidation by non-steroidal anti-inflammatory drugs may contribute to inhibition of proliferation of human colorectal carcinoma cell lines.

Year 1998
Yang Z. Hollande F. Baldwin GS.
University Department of Surgery, Melbourne, Victoria, Australia.
Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the growth of colorectal carcinoma (CRC) cell lines. Although the mechanism appears to be independent of cyclooxygenases, the inhibitory target has not previously been defined. We now report for the first time that NSAIDs inhibit oxidation of the long chain fatty acid palmitate in human CRC cell lines with potencies which are in good agreement with the potencies of NSAIDs as inhibitors of cell proliferation. The absence of inhibition of acetate oxidation rules out an effect on mitochondrial functions. We conclude that the long chain fatty acid oxidation pathway may be a novel target for some of the inhibitory effects of NSAIDs on the growth of CRC cell lines.

Microsatellite instability in Japanese hereditary non-polyposis colorectal cancer does not induce mutation of a simple repeat sequence of the bax gene.

Year 1998
Sakakibara T. Nakamura T. Yamamoto M. Matsuo M.
Division of Genetics, International Center for Medical Research, Kobe University School of Medicine, Chuo, Japan.
The identification of frameshift mutations in the coding region of the bax gene in Western cases of hereditary non-polyposis colorectal cancer provided evidence that the disease could be caused by the disruption of a tumor suppressor gene associated with microsatellite instability. In order to determine whether this observation could be extended to Japanese colorectal cancers, we analyzed the simple repeat sequence of (G)8 in the bax gene of tumor genomes from 15 cases of Japanese hereditary non-polyposis colorectal cancer that showed microsatellite instability in at least one of four examined microsatellite loci. None of 15 tumor DNA samples had a frameshift mutation in this region of the bax gene. Our results suggest that direct disruption of the bax gene is not a major factor responsible for carcinogenesis in Japanese hereditary non-polyposis colorectal cancers even though microsatellite instability is present.

Hypoxia-induced apoptosis in human hepatocellular carcinoma cells: a possible involvement of the 6-TG-sensitive protein kinase(s)-dependent signaling pathway.

Year 1998
Bae SK. Baek JH. Lee YM. Lee OH. Kim KW.
Department of Molecular Biology, Pusan National University, South Korea.
Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents both during normal developments and in adult pathological states. However, the molecular mechanism of apoptotic cell death due to hypoxia has not been clearly elucidated. In this study, we investigated critical factors involved in hypoxia-induced apoptosis using HepG2, a human hepatocellular carcinoma cell line, as an experimental model. We found that 24 h of exposure of HepG2 cells to hypoxia induced apoptosis, for which de novo protein synthesis was required. Apoptosis was demonstrated by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Hypoxia-induced apoptosis was associated with a marked induction of c-jun and c-fos messenger RNAs. Electromobility shift assay showed the increased DNA binding activity of AP-1 during hypoxia, suggesting that AP-1 may be involved in the induction of cell death by acting as a transcriptional regulator. A purine analogue, 6-thioguanine (6-TG), significantly blocked the induction of apoptosis by hypoxia. Moreover, the inductive effect of hypoxia on c-jun expression was also inhibited by 6-TG, whereas the levels of c-fos mRNA and its protein were rather strongly increased. Iodoacetamide (IAA), a non-specific inhibitor of ICE family proteases, also has an inhibitory effect on hypoxia-induced apoptosis. These results suggest that the 6-TG-sensitive protein kinase(s)-dependent signaling pathway may be involved in the apoptotic response of HepG2 cells exposed to hypoxia by increasing the level of c-jun and c-fos and the activity of AP-1 and/or by activating ICE family protease(s).

Helicobacter pylori and gastric cancer in Croatia.

Year 1998
Babus V. Strnad M. Presecki V. Katicic M. Kalinic S. Balija M.
Faculty of Medicine, A. Stampar School of Public Health, Zagreb, Croatia.
The seroprevalence of Helicobacter pylori infection was studied in a population from two areas of Croatia with significantly different average gastric cancer (GC) cumulative incidence and mortality rates. In a random sample of 456 blood sera from both areas, which was tested with the ELISA Helicobacter pylori-antibody test, 48.8% of people in the north and 53.3% in the south of the country were found to be infected. The difference between the two areas in the seroprevalence of the infection was not statistically significant, nor did their populations differ in age, sex, educational background, smoking habit or wine consumption. Our results do not point to any association between the prevalence of Helicobacter pylori infection and the level of cumulative incidence and GC mortality levels.

Increased susceptibility of the c-Myc overexpressing cell line, SNU-16, to TNF-alpha.

Year 1998
Park IC. Park MJ. Lee SH. Choe TB. Jang JJ. Hong SI.
Laboratory of Cell Biology, Korea Cancer Center Hospital, Seoul, South Korea.
Tumor necrosis factor-alpha (TNF-alpha) is a macrophage-derived multifunctional cytokine that acts as a cytostatic or cytotoxic agent in many tumor cells. However, the molecular mechanisms by which tumor cells become sensitive to the cytotoxic action of TNF-alpha are not clear. In this study we demonstrated that the cytotoxicity of TNF-alpha markedly increased in c-Myc overexpressing tumor cells. The stomach cancer cell line, SNU-16, in which c-Myc expression is high due to gene amplification, showed programmed cell death detected by DNA fragmentation and morphological changes. An antisense c-myc S-oligonucleotide specifically inhibited the TNF-alpha-induced apoptosis of SNU-16 cells, provided that the oligonucleotide was added 4 h prior to TNF-alpha treatment. Western immunoblot analysis of p53 and Bax showed that in this cell line, TNF-alpha increased the level of these proteins in a time-dependent manner and that this effect lasted for 12 h. Taken together these data indicate that the deregulation of c-Myc plays an important role in sensitizing tumor cells to TNF-alpha. Furthermore, TNF-alpha-induced apoptosis in the SNU-16 cell line showed increased expression of p53 and Bax protein levels following TNF-alpha treatment. Therefore, we suggest that TNF-alpha-induced apoptosis, which is cytotoxic to tumor cells, is coupled with a p53 and Bax apoptotic pathway.

Benzo[a]pyrene diol-epoxide-I-DNA and oxidative DNA adducts associated with gastric adenocarcinoma.

Year 1998
Lee BM. Jang JJ. Kim HS.
Division of Toxicology, College of Pharmacy, Sung Kyun Kwan University, Suwon, South Korea. bmlee@yurim.skku.ac.kr
BPDE-I-DNA and oxidative DNA adducts (8-OHdG) were investigated in stomach tissues (tumor and tumor-adjacent) of patients (N = 211) with gastric adenocarcinoma and in normal stomach tissues (N = 113). In each stomach specimen, the levels of BPDE-I-DNA adducts were quantitatively measured by enzyme linked immunosorbent assay (ELISA) and oxidative DNA damage was measured by HPLC-ECD. Higher levels of total BPDE-I-DNA adduct were observed in tumor (4.20 +/- 0.59 fmol/microg DNA) and tumor-adjacent (3.68 +/- 0.62 fmol/microg DNA) tissues than in normal stomach tissues (2.80 +/- 0.53 fmol/microg DNA) but were not significant. In males, BPDE-I-DNA adduct was significantly higher in tumor tissues (4.25 +/- 0.42 fmol/microg DNA) than in normal tissues (2.83 +/- 0.59 fmol/microg DNA) (P < 0.05). In smokers, BPDE-I-DNA adduct was slightly higher in tumor tissues (4.92 +/- 0.82 fmol/microg DNA) than in tumor-adjacent tissues (3.99 +/- 0.92 fmol/microg DNA). Gastric cancer patients had significantly higher levels of 8-OHdG in their tumor-adjacent (7.54 +/- 0.43 residues/10(5) dG) and tumor tissues (6.29 +/- 0.39 residues/10(5) dG) than in normal tissues (2.86 +/- 0.11 residues/10(5) dG) (P < 0.001). Smokers showed higher levels of 8-OHdG in both tumor (6.44 +/- 0.62 residues/10(5) dG) and tumor-adjacent (8.12 +/- 0.68 residues/10(5) dG) tissues than in non-smokers (5.80 +/- 0.47 and 7.11 +/- 0.57 residues/10(5) dG, respectively). 8-OHdG levels were significantly increased in positive tissues with Helicobacter pylori (H. pylori) infection compared with negative tissues (P < 0.01). Also, the frequency of H. pylori infection was higher in tumor-adjacent tissues (73%) than in tumor (42%) or normal tissues (44%). These results demonstrate that there are higher levels of 8-OHdG and BPDE-I-DNA adducts in tumor and tumor-adjacent tissues than in normal tissues and that these higher levels might be related to gastric tumorigenesis, although benzo[a]pyrene could be a minor contributing component in the environment.

Genetic alterations are frequent in APC but rare in the TGF-beta type II receptor gene in cancer in adenomas of the colon.

Year 1998
Akiyama Y. Yagi OK. Ishikawa T. Nagasaki H. Saitoh K. Yuasa Y.
Department of Hygiene and Oncology, Tokyo Medical and Dental University School of Medicine, Japan.
Cancer in adenomas are thought to be an excellent model of colorectal carcinogenesis based on the adenoma-carcinoma sequence. We searched for alterations in the APC mutation cluster region, the whole coding regions of TGF-beta type II receptor (RII) and beta-catenin exon 3 in 16 cases of cancer in adenomas of the colon. Overexpression of the p53 protein was also analyzed. Nine of the 16 cases showed APC mutations in both the adenoma and cancer regions. Loss of heterozygosity in APC was found in one cancer in adenoma that had no mutation. p53 overexpression was detected in one adenoma and 10 cancerous regions, most of which also exhibited APC alterations. Two cases showed a missense mutation at codon 191 or loss of heterozygosity in TGF-beta RII in both the adenoma and cancer. Our data support the hypothesis that alterations of APC and p53 are responsible for most of the adenoma-carcinoma pathway, rather than TGF-beta RII alterations.

Prevention of severe hepatic injury by interferon-alpha in chronic active hepatitis lacking HBeAg (mutant strain) in a patient with malignant lymphoma.

Year 1998
Kondo H. Kasahara Y.
Department of Medicine, Shimizu Kosei Hospital, Shizuoka, Japan. Haruki_Kondo@msn.com
Multidrug chemotherapy with concomitant interferon (IFN)-alpha was performed in a patient with chronic hepatitis lacking the hepatitis Be antigen and malignant lymphoma (ML). Levels of trans-aminases and DNA polymerase (DNA-P) values increased after the fifth course of chemotherapy. Therapy with IFN-alpha for 9 weeks induced a remission in liver disease and complete remission of ML was obtained with subsequent chemotherapy. It was possible to prevent severe liver damage by administering IFN immediately after the elevation of DNA-P. Early introduction of IFN may be effective in the prevention of fulminant hepatic failure from hepatitis from a precore mutant after chemotherapy.

Glycogen content in the gastric mucosa of partially resected stomach; a possible relationship with the development of cancer.

Year 1998
Skwarski L. Namiot Z. Stasiewicz J. Kemona A. Kralisz M. Gorski J.
Department of Gastroenterology, J. Sniadecki's Regional Hospital, Bialystok, Poland.
Since gastric carcinoma, unlike uninvaded mucosa, has a relatively high glycogen content and the risk of gastric carcinoma is especially high in patients with a partially resected stomach, the aim of this study was to follow glycogen storage in both uninvaded gastric stump mucosa and carcinoma developing in the stump postsurgery performed for benign and malignant conditions. One hundred patients were recruited, including controls with non-operated stomachs (duodenal ulcer or gastric cancer patients). In endoscopically taken biopsies glycogen was determined by the anthrone method. It was found that the glycogen content in the gastric remnants was higher than in non-operated stomachs and increased with the time after surgery. It is possible that the risk of gastric cancer, which increases with the time from surgery, may be related to glycogen storage.

A novel method of assessing carcinoma cell proliferation by biophoton emission.

Year 1998
Takeda M. Tanno Y. Kobayashi M. Usa M. Ohuchi N. Satomi S. Inaba H.
Biophotonics Information Laboratories, Yamagata Advanced Technology, Research & Development Center, Matsuei, Japan.
Changes in the emission intensities of ultraweak biophoton emission during the cell proliferation of human carcinoma cell culture (TE9 cell line) were detected using a highly sensitive and low noise measurement apparatus coupled with a flow culture system. In the sampling period of 93 h, the biophoton emission intensity from the culture followed a similar course as that of the growth curve. Spectral analysis of the biophoton emission from the cell culture demonstrated a significant peak at around 530 nm. Our results suggest that the emission intensity mainly depends on the cell population and that this noninvasive technique has a potential role in cancer diagnosis.

A subcloned human esophageal squamous cell carcinoma cell line with low thrombomodulin expression showed increased invasiveness compared with a high thrombomodulin-expressing clone--thrombomodulin as a possible candidate for an adhesion molecule of squ

Year 1998
Matsushita Y. Yoshiie K. Imamura Y. Ogawa H. Imamura H. Takao S. Yonezawa S. Aikou T. Maruyama I. Sato E.
Department of Pathology II, Faculty of Medicine, Kagoshima University, Japan.
Thrombomodulin (TM) is an endothelial cell surface glycoprotein which converts thrombin from a procoagulant protease to an anticoagulant. We have previously reported that TM is a useful marker for immunohistochemical diagnosis of angiogenic tumors and also have reported that TM is expressed on squamous cell carcinoma (SCC) of the human esophagus. In addition, the expression of TM is significantly decreased in metastatic foci in lymph nodes compared with that in primary lesions. In order to reveal the biological significance of TM in SCC, we subcloned and established two different cell lines, i.e. TM-high-expressing (TE3HTM) cells and TM-low-expressing (TE3LTM) cells, from a human SCC cell line, TE3, using fluorescence-activated cell sorter (FACS) and examined the biological characteristics of these variant cell lines. These tumor cells revealed very similar morphological figures in ordinary cultured conditions and showed almost equal growth rates under various cultured conditions. By the invasion assay of these tumor cells using matrigel, we found that TE3LTM cells showed significantly increased invasive ability compared with that of TE3HTM cells. Characteristic intercellular localization of TM and a different manner of invasiveness between TE3LTM cells and TE3HTM cells suggest that TM may act as a cell-to-cell interaction molecule.

Changes in expression of the antigen recognized by monoclonal antibody A7 in human pancreatic carcinoma cells following exposure to anticancer agents.

Year 1998
Yamaguchi T. Yamaoka N. Kitamura K. Otsuji E. Okamoto K. Tsuruta H. Yata Y. Takahashi T.
First Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
Techniques which can increase the expression level of tumor-associated antigens may improve immunotargeting therapy. We studied the reactivity of MAb A7 toward an antigen expressed on the surface of the human pancreatic cancer cell line HPC-YS after treatment with various antitumoral agents. When we applied 1 microg/ml mitomycin C (MMC) or 0.1 microg/ml neocarzinostatin (NCS) for 1 h, A7 recognizing antigen expression was enhanced until 24 h after the treatments. At a dose that completely suppressed cell growth, increased antigen expression was maintained for 96 h. Therefore, this study suggests that the combined application of an anticancer drug and MAb A7 may be useful for immunotargeting chemotherapy.

Role of K-ras mutations in colorectal carcinoma.

Year 1998
Chiang JM.
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan.
In order to investigate whether two common types of colorectal cancer with different gross appearances share the same incidence of K-ras mutation, the occurrence of a point mutation in codon 12 or codon 13 of the K-ras oncogene was determined in 50 cases of colorectal carcinoma. The PCR technique was employed, followed by RFLP analysis and sequencing to identify specific point mutations. No correlation was found between the presence of a K-ras gene mutation and histological parameters. A strong association was found between K-ras mutations and the gross polypoid appearance of colorectal carcinoma (polypoid 73% versus ulcerative 8%). The results indicate a preferential association with the K-ras oncogene involved in polypoid type colorectal carcinoma.

Serum concentration of hepatocyte growth factor in patients with metastatic breast cancer.

Year 1998
Maemura M. Iino Y. Yokoe T. Horiguchi J. Takei H. Koibuchi Y. Horii Y. Takeyoshi I. Ohwada S. Morishita Y.
Second Department of Surgery, Gunma University School of Medicine, Maebashi, Japan.
The serum concentration of hepatocyte growth factor (HGF) was examined in 34 patients with metastatic breast cancer. Although no significant difference was observed between HGF concentration and the site of metastasis, serum HGF levels were slightly higher in patients with liver metastasis and in patients with multiple metastatic sites than in patients with other lesions. Significantly higher levels of serum HGF were observed in patients with progressive metastasis of breast cancer compared with those with stable metastasis. The patients with high HGF levels exhibited a significantly shorter survival rate than those with low HGF levels. Circulating HGF levels may be a useful indicator for the progression of metastatic lesions and the prognosis of patients with metastatic breast cancer.