bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell‐surface sulfoglycolipids are involved in the attachment of renal‐cancer cells to laminin
Authors: Kobayashi Takahiko , Honke Koichi , Kuramitsu Yasuhiro , Hisokawa Masuo , Miyazaki Tamotsu , Murata Jun , Saiki Ikuo , Ishizuka Ineo , Makita Akira
Published: February 2007

We investigated the role of sulfoglycolipids on human renal‐cell carcinoma cells (SMKT‐R3) in the attachment to a substrate adhesive protein, laminin. SMKT‐R3 cells over‐express sulfoglycolipids, including SM2, SM3 and SM4. When acidic glycolipid fractions were extracted from SMKT‐R3 cells, separated by HPTLC, and then overlaid with laminin, laminin bound specifically to SM3 and SM4. A monoclonal antibody, Sulph‐1, reacting with SM3 and SM4 inhibited attachment of the cells to laminin but not to fibronectin, in a dose‐dependent manner. In addition, when exogenous SM4 was incorporated into the cells, their attachment to laminin, but not to fibronectin, was enhanced. On the other hand, the incorporation of GalCer, which is a precursor of SM4, had no effect on adherence of the cells to laminin or to fibronectin. We also assayed haptotaxis, tumor‐cell migration along a gradient of substratum‐bound laminin. The incorporation of SM4 into the cells caused an approximately 3‐fold increase of the haptotactic response to laminin compared with non‐or GalCer‐incorporation. These results taken together suggest that sulfoglycolipids on renal‐cancer cells are involved in attachment to laminin and that they can modulate the metastatic potential of renal‐cell carcinoma cells.
Risk of multiple primary tumors following oral squamous‐cell carcinoma
Authors: Jovanoic Andreas , van der Tol Ignaz G. H. , Schulten Engelbert A. J. M. , Kostense Pieter J. , de Vries Nico , Snow Gordon B. , van der Waal Isaäc
Published: February 2007

The follow‐up of 727 patients with squamous‐cell carcinoma (SCC) of the lip and oral cavity has been used for the risk analysis of multiple primary tumors (MPTs) following SCC of the lip and oral cavity. Age‐, gender‐and site‐specific cancer‐incidence rates from the general population have been applied to the appropriate persons‐years of follow‐up of patients with SCC of the lip and oral cavity. The study indicates that patients with a primary SCC of the lip and oral cavity have, compared with the general population, a significantly elevated risk of developing an additional cancer of the oral cavity and/or pharynx, the risk being 74.7‐fold for males and 190.4‐fold for females. Furthermore, a 24.6 and 45.3 times higher risk of an additional esophageal tumor was found in males and females respectively. The risk of cancer of the lung and pharynx was less elevated compared with the risk of cancer of the upper digestive tract. No elevated risks were established in organs outside the respiratory and upper digestive tract.
p53 mutations in human bladder cancer: Genotypic versus phenotypic patterns
Authors: Cordon‐Cardo Carlos , Dalbagni Guido , Saez Guillermo T. , Oliva Maria R. , Zhang Zuo‐Feng , Rosai Juan , Reuter Victor E. , Pellicer Angel
Published: February 2007

The objective of this study was to characterize the pattern of p53 mutations in bladder cancer. The sensitivity and specificity to detect these mutations using clinical material was assessed for the following assays: immunohistochemistry, restriction‐fragment‐length polymorphism, single‐strand‐conformation polymorphism, and sequencing.

Discrepancies of reported results aimed at the identification of genetic alterations in the p53 gene may be due to differences in methodology, as well as to deficient morphological evaluation of the source of tissue utilized. In order to address these critical issues, we have implemented a novel experimental design that permits analysis by molecular genetics and immunopathology techniques in any given tissue specimen, allowing morphological correlation with genotypic and phenotypic characteristics of the tissue analyzed.

Forty‐two patients affected with bladder tumors in whom paired normal and tumor tissues were available were used for the present study. Nuclear immunoreactivities were observed in 26 out of 42 bladder tumors analyzed. Abnormal shifts in mobility were noted in 14 of the 42 cases in distinct exons, with one tumor revealing 3 mutations. There was a strong association between p53 nuclear over‐expression and 17p LOH, as well as p53 nuclear over‐expression and detection of mutations by SSCP and sequencing. According to receiver‐operating‐curve statistical analysis, the accuracy of detecting p53 mutations by IHC was estimated to be 90.3%. It is our conclusion that, when properly used, this is a highly sensitive and specific method with simple application using clinical material.
Moderate elevation of body iron level and increased risk of cancer occurrence and death
Authors: Stevens Richard G. , Graubard Barry I. , Micozzi Marc S. , Neriishi Kazuo , Blumberg Baruch S.
Published: February 2007

The purpose of the study was to address the hypothesis that elevated body iron increases the risk of cancer occurrence and death, and to determine the dose response. Subjects were 3, 287 men and 5,269 women participating in the first National Health and Nutrition Examination Survey who had a transferrin saturation determination at enrollment (1971–1975), who remained alive and cancer‐free for at least 4 years, and who were followed to 1988 for cancer outcome. Among 379 men who developed cancer over the study period, the mean transferrin saturation at enrollment was 32.1 % whereas among 2,908 who remained cancer‐free it was 30.7%; the difference for mortality was 32.3% among 233 deaths vs. 30.8% among 3,054 men not dying of cancer. The mean differences among women were hot significant. The mean differences in TIBC and serum iron among men were consistent with the findings for transferrin saturation, and all 3 differences were stable over time when examined by years since blood test. Men and women were divided into 5 groups on the basis of baseline transferrin saturation: 0 to 30%, 30–40%, 40–50%, 50–60%, and 60% and higher. Nineteen percent of men had a baseline transferrin saturation above 40% (the last 3 groups), whereas only 10 percent of women had transferrin saturation above 40%. For men and women combined, risk of cancer occurrence in each group relative to the first was 1.0, 0.95, 1.16, 1.38 and 1.81; for mortality the relative risks were 1.0, 0.96, 1.22, 1.29 and 1.73. There is evidence, in this cohort, of elevated cancer risk in those with moderately elevated iron level. This pattern was seen in women as well as in men.
Growth control of embryonic stem cells injected into mouse uterus on fifth day of pregnancy
Authors: Monzo M. , de Anta J. M. , Peris B. , Ruano D.
Published: February 2007

Previous studies have shown that embryonic stem cells (ES) may participate in normal embryonic development when they are injected into the blastocyst. In contrast, ES cells develop into tumors if injected in ectopic sites in adult mice. In this study we injected ES‐D3 cells, with the LacZ gene incorporated, into 5‐day pregnant mouse uteri, into pregnant unilaterally salpingectomized uteri, into pseudo pregnant uteri and into non‐pregnant uteri. X‐gal staining enabled us to identify injected ES cells on the 7th, 9th, 10th, 12th and 15th days post‐injection. In pregnant decidua, the ES cells were located initially in the mesometrial decidua and later distributed in the basal and capsular decidua and in the endodermic layer of the visceral yolk sac. In pregnant, unilaterally salpingectomized mouse uteri, ES cells were mainly located in the uterine lumen and tumors were not observed in either case. In contrast, ES cells injected into pseudopregnant uteri often developed into tumors and those injected into non‐pregnant uteri always developed into teratocarcinomas. We conclude that the pregnant‐uterine microenvironment may participate in the control of ES cell growth.
Expression of the 100‐kDa glucose‐regulated protein (grp100/endoplasmin) is associated with tumorigenicity in a model of rat colon adenocarcinoma
Authors: Ménoret Antoine , Meflah Khaled , Pendu Jacques Le
Published: February 2007

Resistance to glucose starvation and expression of glucose regulated proteins (grp) were studied in a model of rat colon carcinoma. In this model, various clones originating from the same parental tumor showed distinct tumorigenic potential in syngeneic hosts. Some clones were tumorigenic while others were rejected by an immune‐based mechanism. It appeared that the more tumorigenic clones were more resistant to glucose starvation and able to synthesize larger amounts of grp100 than non‐tumorigenic clones in response to either glucose starvation or tunicamycin treatment. In contrast, there was no difference in the induced levels of synthesis of grp78 between tumorigenic and non‐tumorigenic clones. These results suggest that the ability of cells to synthesize large amounts of the stress protein grp 100 might allow them to resist marginal conditions imposed by fully immunocompetent hosts, thus conferring greater tumorigenicity.
TGF‐β receptor regulation mediates the response to exogenous ligand but is independent of the degree of cellular differentiation in human oral keratinocytes
Authors: Prime S. S. , Matthews J. B. , Patel V. , Game S. M. , Donnelly M. , Stone A. , Paterson I. C. , Sandy J. R. , Yeudall W. A.
Published: February 2007

This study examined the expression of TGF‐β cell‐surface receptors, the response to exogenous TGF‐β1 and the autocrine production of TGF‐β in normal and squamous cell carcinoma‐derived human oral keratinocytes with variable degrees of cellular differentiation. TGF‐β receptor expression, the response to exogenous ligand and the autocrine production of TGF‐β appeared unrelated to cellular differentiation. Cells expressed variable proportions of type‐I,‐II and‐III TGF‐β receptors. The expression of type‐III receptors correlated inversely with the expression of type‐I receptors, but there was no relationship between type‐II and either type‐I or type‐III TGF‐β receptors. Normal cells and the majority (7 of 8) of tumour‐derived keratinocytes were inhibited by exogenous TGF‐β1 and the degree of inhibition correlated with the expression of type‐I, but not type‐II or type‐III, TGF‐β receptors. One tumour‐derived cell line was refractory to exogenous TGF‐β1 although it expressed all 3 receptor types. Endogenous TGF‐β was produced by both normal and tumour‐derived keratinocytes and correlated inversely to the expression of type‐I, but not type‐II, TGF‐β receptors. Further, cells that produced more autocrine TGF‐β had a diminished response to exogenous TGF‐β1. The data indicate a complex interaction between the expression of TGF‐β cell‐surface receptors, endogenous ligand production and the cellular response to exogenous TGF‐β1.
Cyclic AMP increases the release of parathyroid hormone‐related protein from a lung‐cancer cell line
Authors: Rizzoli René , Aubert Michel Lucien , Sappino André Pascal , Bonjour Jean‐Philippe
Published: February 2007

Parathyroid hormone‐related protein (PTHrP) plays an important role in the pathogenesis of malignant hypercalcemia by stimulating bone resorption and/or renal tubular reabsorption of calcium. In cultured cancer cells, its production can be influenced by various factors or ions, but the regulation of its production is still poorly understood. We investigated the effects of stimulators of cAMP synthesis on PTHrP release by a human lung squamous‐carcinoma cell line (BEN). In supervised cells grown on microcarrier beads, PTHrP production was significantly increased after incubation with calcitonin for only 20 min. The release of immunoreactive and bioactive PTHrP was increased by incubating the cells with forskolin, 3‐isobutyl‐I‐methylxanthine or dibutyryl cAMP even in the presence of the protein‐synthesis inhibitor cycloheximide for 6 hr. The calcitonin‐mediated stimulation was not accompanied by. concomitant changes in PTHrP mRNA. The microfilament‐disrupter cytocha‐lasin D was shown to enhance the basal and calcitonin‐induced production of PTHrP. These results indicate that stimulators of cAMP synthesis enhanced PTHrP release by BEN cells.
Activation of the protein kinase a signal transduction pathway by granulocyte‐macrophage colony‐stimulating factor or by genetic manipulation reduces cytoskeletal organization in lewis lung carcinoma variants
Authors: Young M. Rita I. , Charboneau Susan , Lozano Yvonne , Djordjevic Andelka , Young Melvin E.
Published: February 2007

Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) that is produced by metastatic Lewis lung carcinoma (LLC‐LN7) cells functions as an autocrine stimulator of tumor‐cell motility through protein kinase A (PKA) signal transduction. This GM‐CSF‐mediated enhancement of LLC‐LN7 cell motility coincides with a reduction in the level of polymerized F‐actin. In contrast, non‐metastatic LLC‐C8 tumor cells, which have a diminished level of PKA signaling, do not produce GM‐CSF and do not respond to exogenous GM‐CSF, since they remain non‐motile and retain a high content of filamentous actin. The capacity of PKA to regulate the cytoskeletal organization of tumor cells was further studied with the use of LLC variants that had been stably transfected to over‐express the Cα subunit of PKA (CEV cells) or to express a mutant cAMP‐resistant PKA R1α subunit resulting in a defective PKA (REV cells). When compared with wild‐type metastatic LLC‐LN7 cells, in which the F‐actin staining was too diffuse to be clearly visualized microscopically, the PKA‐defective REV‐LN7 transfectants had an increased level of F‐actin. In comparison with the wild‐type non‐metastatic LLC‐C8 cells, which had a high content of F‐actin, the CEV‐C8 transfectants that over‐expressed PKA activity had a reduced level of F‐actin. The reduced polymerization of actin in these CEV‐C8 transfectants was accompanied by reduced levels of the intermediate filament protein vimentin and a shift in the distribution both of F‐actin and of vimentin to the periphery of the cells. These results show reduced cytoskeletal organization in metastatic LLC‐LN7 cells as compared with that of non‐metastatic LLC‐C8 cells, and indicate that elevation of PKA activity, either by autologous GM‐CSF or by genetic manipulation, diminishes cytoskeletal organization.
Qualitative and quantitative intratumoral changes in gene expression following cyclophosphamide injection and the adoptive transfer of t cells: The potential contribution of tumor‐associated macrophages
Authors: Evans Robert , Kamdar Sonya J. , Duffy Theodore M.
Published: February 2007

Adoptive immunotherapy (AIT) of mice bearing the MCA/ 76‐9 rhabdomyosarcoma in combination with cyclophosphamide (CY) injection results in the permanent regression of tumors. This report is concerned with changes in the tumor‐associated macrophage (TAM) population and the influence of both CY injection and CY/AIT on their potential functions. Sequential analyses of FcR, MAC‐1 and Class‐II MHC antigen expressed by tumor‐associated cells (TAC) showed that CY injection or CY/AIT induced marked increases in the proportions of all 3 parameters as compared with the relatively stable levels in progressing tumors. These changes were time‐and treatment‐related. The mean MAC‐1 fluorescence (antigen density per cell) increased nearly 2‐fold by 48 hr after CY injection, regardless of subsequent AIT. In contrast, the density of Class‐II antigen per cell declined by as much as 75% within 48 hr after CY injection and did not recover by 7 days. This initial decline was also seen after CY/AIT and was followed by a rapid recovery to near‐normal values by day 7. Northern analysis of RNA isolated from whole tumor tissue indicated wide fluctuations in expression of the typical macrophage genes encoding the proteins MAC‐1, IL‐1α, IL‐1β, TNFα, IAβ) and c‐fms. However, with the exception of MAC‐1 and IL‐1α/IL‐1β mRNA, the modifications appeared to be qualitative rather than representing changes in the proportions of TAM. The data suggest that the changes in membrane antigen and gene expression by TAM reflect a complex interaction between TAM and their environment, in particular tumor cells and tumor‐infiltrating lymphocytes. In addition, it is evident that CY injection per se is responsible for defined fundamental changes that presumably influence the outcome of AIT.
Internal image anti‐idiotype antibodies related to renal‐cell carcinoma‐associated antigen G250
Authors: Uemura H. , Okajima E. , Debruyne F. M. J. , Oosterwijk E.
Published: February 2007

The potential usefulness of internal‐image anti‐idiotype antibodies (Ab2s) in modulating hosts' immune responses to tumor‐associated antigen (TAA) have stimulated considerable interest in the development and characterization of Ab2s. Six different mouse monoclonal Ab2s (NUH31, 44, 51, 71, 82 and 91) were generated against murine monoclonal antibody G250 (MAbG250) which recognizes a human renal‐cell carcinoma‐associated antigen. All 6 Ab2s showed specificity for the MAbG250 paratope in Western‐blot analysis. In inhibition assays, all Ab2s were able to compete with the nominal antigen, albeit with differing efficiency. Based on cross‐blocking studies for idiotope mapping, the Ab2s could be divided into 2 groups (group 1; NUH31, 51,71, group 2; NUH44, 82, 91). However, cross‐reactivity between these 2 groups was observed, indicating that they recognized partly overlapping epitopes on the paratope of MAbG250. Sera from rabbits immunized with Ab2s showed reactivity with G250 antigen‐positive cell lysates, but not with antigen‐negative cell lysates. Additional studies revealed that all Ab2s were able to induce anti‐anti‐idiotype antibodies resembling MAbG250 (Ab1). These findings suggest that the Ab2s functionally mimic the original G250 antigen and may be of use in the immunotherapy of human renal‐cell carcinoma.
Cancer mortality trends in Uruguay 1953–1991
Authors: De Stefani Eduardo , Fierro Luis , Barrios Enrique , Ronco Alvaro
Published: February 2007

Cancer mortality trends from 1953 to 1991 were assessed by means of data supplied by the Department of Vital Statistics of the Ministry of Public Health. The population at risk was obtained from the Bureau of Statistics and Censuses. Age specific and age‐adjusted mortality rates were calculated, using the world standard population, for a number of sites or groups of sites. In order to obtain relative risks of death for each period, Poisson regression models were fitted to the data using the GLIM program. The main model included age and period as explanatory variables. Among males, the principal increase was observed for lung cancer, followed by prostatic cancer. The rates were mainly stable in colon cancer and leukaemias, whereas gastric cancer showed a marked decline. Also, a recent decline was seen for oesophageal cancer. In females a steady decline in mortality was observed for all sites combined. Major decreases were seen for oesophageal, gastric, cervical and total uterine cancers. The only cancers showing significant increases were breast cancer, and lung cancer for the most recent period. Providing that there were no changes in death registration or in survival rates, changes in prevalence of risk factors might be responsible for the observed trends.
Detection of tumor‐specific cytotoxic drug activity IN VITRO using the fluorometric microculture cytotoxicity assay and primary cultures of tumor cells from patients
Authors: Nygren Peter , Fridborg Helena , Csoka Katalin , Sundström Christer , De La Torre Manuel , Kristensen Jörgen , Bergh Jonas , Hagberg Hans , Glimelius Bengt , Rastad Jonas , Tholander Bengt , Larsson Rolf
Published: February 2007

The semi‐automated fluorometric microculture cytotoxicity assay (FMCA), based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate (FDA) by viable cells, was employed for cytotoxic drug sensitivity testing of tumor cells from patients with hematological or solid tumors. In total, 390 samples from 20 diagnoses were tested‐with up to 12 standard cytotoxic drugs. The technical success rate for different tumor types ranged from 67 to 95%. Fluorescence was linearly related to cell number but variably steep depending on tumor type. Samples from most solid tumors thus showed higher signal‐to‐noise ratios than hematological samples. A wide spectrum of in vitro drug activity was obtained, with acute leukemias and non‐Hodgkin's lymphomas being sensitive to almost all tested drugs, whereas renal and adrenocortical carcinomas were essentially totally resistant. Between these extremes were samples of breast and ovarian carcinomas and sarcomas. When in vitro response was compared with known clinical response patterns, a good correspondence was observed. The results indicate that the FMCA is a rapid and efficient method for in vrtro measurement of tumor‐specific drug activity both in hematological and in solid tumors. The assay may be suitable for new drug development and direction of phase‐2 trials to suitable patients.
Response of normal and oncogene‐transformed human mammary epithelial cells to transforming growth factor β1 (TGF‐β1): Lack of growth‐inhibitory effect on cells expressing the simian virus 40 large‐t antigen
Authors: Basolo Fulvio , Fiore Lisa , Ciardiello Fortunato , Calvo Simonetta , Fontanini Gabriella , Conaldi Pier Giulio , Toniolo Antonio
Published: February 2007

The relationship between the expression of selected oncogenes having different modes of action and the loss of the capacity to respond in vitro to transforming growth factor‐β1 (TGF‐β1) was analyzed in human mammary epithelial cells (MEC). Primary MEC cultures from healthy donors and the spontaneously immortalized MCF‐10A cell line were used as normal controls. Various assays (employing both complete and chemically defined media) were used: short‐term DNA synthesis, long‐term cell proliferation under anchorage‐dependent and ‐independent conditions, expression of surface‐differentiation molecules. Whereas primary MEC and the MCF‐10A cell line were fully responsive to the growth‐inhibitory activity of TGF‐β1 under different test conditions, MEC transformed by c‐Ha‐ras, c‐erbB2, int‐2, or SV40‐large‐T antigen were not inhibited by TGF‐pl in a short‐term DNA‐synthesis assay. However, in anchorage‐dependent conditions TGF‐β1 inhibited the proliferation of all lines investigated, with the exception of SV40‐T‐antigen‐transformed MEC. The colony‐formation assay in soft agar revealed that all lines, but not those expressing the int‐2 or the SV40‐T‐antigen genes, were inhibited by TGF‐β1. Neutralizing antibody to TGF‐β had no significant effects on oncogene‐transformed lines, suggesting that the endogenous production of an active form of this growth factor is not a major determinant in MEC transformation by the oncogenes investigated. The only observed effect of TGF‐β1 on selected surface‐differentiation molecules was that normal MEC produced increased levels of the human milk fat globule antigen‐1. Thus it appears that the response of MEC to TGF‐β1 is consistently attenuated by the insertion of a variety of oncogenes and that it is abolished only by the expression of the SV40‐large‐T antigen. Whereas no single in vitro assay was capable of accurately reflecting the actual responsiveness of different lines, the growth‐curve assay in anchorage‐dependent conditions was the best single predictive test.
Polymorphism of T‐cell receptor genes in nasopharyngeal carcinoma
Authors: Chen Yan , Chan Soh Ha
Published: February 2007

Germ‐line TCR genes from 41 Singaporean Chinese patients with nasopharyngeal carcinoma and 54 Singapore Chinese normal subjects were investigated by restriction fragment length polymorphism (RFLP) analysis. Genomic DNA from BLCLs of patients and normal subjects was digested with the restriction end nucleases BamHI, EcoRI, HindIII, Taql, transferred to nylon membrane by the Southern‐blot technique and hybridized with radioactively labelled TCR cDNA probes. When the combination of BamHI/VβII was used, NPC patients had a lower frequency of the 25/25‐kb allelic pattern and a higher frequency of the 20‐kb fragment compared to controls. With the combination of Taql/Vβ8, the 4.3/3.2‐kb fragment allelic frequency was lower in total NPC but particularly in patients with HLA B46. The result suggested that TCR restriction may be important in the pathogenesis of NPC.
The genotypes and prognostic significance of human papillomaviruses in cervical cancer
Authors: Chen Tzer‐Ming , Chen Chi‐An , Wu Chih‐Cheng , Huang Su‐Cheng , Chang Chin‐Feng , Hsieh Chang‐Yao
Published: February 2007

An integrated study on the role of human papillomaviruses (HPV) in cervical cancer has been conducted. Out of a total of 433 cases of cervical cancer, HPV‐DNA was detected in 342 (79%) using the polymerase chain reaction (PCR). The incidence of HPV infection was not significantly related to histological types, although a lower incidence was noted in adenocarcinonu cases. The incidence of lymph node (LN) metastasis in adenosquamous carcinoma (55.6%) was significantly higher than in squamous cell carcinoma (SCC) and adenocarcinoma. HPV 16 was detected significantly more often in SCC than in adenocarcinoma. In contrast, HPV 18 was detected more often in adenocarcinoma than in SCC. As a whole, pelvic LN metastases were found in 24.3% of HPV+ cases, significantly higher than 11% of HPV− cases. However, the significant association of HPV‐DNA with LN metastasis was only noted in stage I but not stage II. As far as histological types were concerned, the incidence of positive LN was; HPV+ SCC >HPV‐ SCC (p < 0.01), whereas HPV− adenocarcinoma > HPV+ adenocarcinoma (p = 0.12). Genotypes of HPV did not have any effect on nodal status. The presence and types of HPV were not associated with tumor size and distribution of clinical stage. Our results suggest that the prognostic significance of HPV‐DNA on nodal status is dependent on histological types while the genotypes of HPV cannot account for prognostic significance in cervical cancer. © 1994 Wiley‐Liss, Inc.
Autocrine growth stimulation of human renal Wilms' tumour G401 cells by a gastrin‐like peptide
Authors: Blackmore Melanie , Doherty Elaine , Manning Janet E. , Hirst Barry H.
Published: February 2007

The role of gastrin in the control of growth of renal G401 cells isolated from a human nephroblastoma (Wilms' tumour) was investigated. G401 cell growth was enhanced in the presence of exogenous gastrin. Addition of anti‐gastrin antibodies to serum‐free medium significantly inhibited the growth of G401 cells. G401 cells contained the equivalent of 4.3 pg/106 cells of gastrin, and serum‐free medium collected over 48 hr from G401 cells contained the equivalent of 38 ng/106 cells of gastrin, as determined by radioimmunoassay. Growth of G401 cells was inhibited in a concentration‐related way by a variety of gastrin/CCK receptor antagonists. Devazepide and proglumide were, respectively, the most and the least potent inhibitors of G401 cell growth (potency order devazepide > L‐365,260 = lorglumide > loxiglumide > benzotript > proglumide). These gastrin/CCK receptor antagonists had similar growth‐inhibitory activities in human colonic adenocarcinoma HCT‐116 cells. Growth of HCT‐116 cells was stimulated to a lesser extent, as compared with G401 cells, by exogenous gastrin, and endogenous gastrin was not detectable in HCT‐116 cells. The results are consistent with a role for a gastrin‐like peptide in the control of growth of a renal cell line. The data suggest that gastrin/CCK receptor antagonists warrant further investigation as therapeutic agents for the control of gastrin‐responsive tumours derived from outside, as well as inside, the gastrointestinal tract, including tumours derived from the kidney. © 1994 Wiley‐Liss, Inc.
Homozygous deletion, rearrangement and hypermethylation implicate chromosome region 3p14.3‐3p21.3 in sporadic breast‐cancer development
Authors: Buchhagen Dorothy L. , Qiu Luping , Etkind Polly
Published: February 2007

DNAs from 19 malignant human breast tumors and 2 benign fibroadenomas were analyzed for heterozygosity at 5 polymorphic loci on the short arm of chromosome 3. One homozygous deletion and one rearrangement were identified using probe D3S2 which maps to 3p14.3‐3p21.1. This probe also detected novel hybridizing fragments of 2.0 kb and/or 3.4 kb in 6/18 (33%) of the malignant tumor samples that hybridized with the D3S2 probe following digestion with the 5′‐methylcytosine‐insensitive enzyme Mspl. Comparisons of Hpall and Mspl digestion showed that all but one of the tumor DNAs analyzed were hypermethylated. The two fibroadenoma DNAs were not as highly methylated and had hybridizing fragments of 3.4 kb after Hpall digestion. These malignant breast‐tumor DNAs exhibit 3 mechanisms by which a tumor‐suppressor gene hypothesized to reside at 3p 14‐3p21 could be inactivated: homozygous deletion, rearrangement and hypermethylation, and strongly implicate this 3p chromosome region in breast‐tumor development. © 1994 Wiley‐Liss, Inc.
Identification of functional domains of adenovirus tumor‐specific transplantation antigen in types 5 and 12 by viable viruses carrying chimeric E1A genes
Authors: Sawada Yukiharu , Rašková Jana , Fujinaga Kei , Raška Karel
Published: February 2007

The adenovirus (Ad) EIA gene induces in immunized animals a strong tumor transplantation (TSTA) immunity against Ad tumors. Such immunity with group‐A and group‐C viruses is highly group‐specific and no cross‐protection is detected between se retypes 5 and 12. This fact was used to map the domains of the Ad 5 and Ad12 EIA gene products, respectively, which control the TSTA. We constructed a library of 8 recombinant viruses (H5sub1101 through H5sub1108) which carry chimeric Ad5/Ad12 EIA genes in the background of Ad5. The chimeric genes are functional and these viruses are viable. Some of these constructs induce strong and highly specific tumor syngraft immunity in immunized rats. The viruses carrying the 5′ terminus of the first EIA exon derived from Ad12 (viruses H5sub1101, H5sub1102 and H5sub1103) induce strong protection against Ad12 tumors irrespective of the rest of their EIA sequence. The viruses which carry the second exon of the AdS EIA gene (viruses H5sub1101, H5sub1102 and H5sub1106) protect against group‐C tumors, regardless of the origin of the rest of their EIA gene. The 2 viruses that carry the 5′ EIA terminus of the first exon of Ad12 and the second exon of AdS (H5sub1101 and H5sub1102) are thus effective in inducing immunity against Ad12 tumors as well as against Ad2 tumors. The viruses which carry the 5′ terminus of the first exon derived from Ad5 and the second exon of Ad12 (H5sub1107 and H5sub1108) fail to induce immunity against either tumor. Expression of only the truncated 5′ terminus of the Ad12 EIA gene (viruses H5sub1104 and H5sub 1105) is sufficient for induction of Ad12 TSTA. Our results provide direct and unequivocal in vivo evidence that TSTA activities of adenovirus groups A and C are controlled by different domains of their respective EIA genes. The Ad12 TSTA is a function of the 5′ terminus of the first EIA exon, while the Ad5 TSTA is coded for by the 3′ exon of its EIA gene. © 1994 Wiley‐Liss, Inc.
Interaction of IFN α/β with host cells essential to the early inhibition of friend erythroleukemia visceral metastases in mice
Authors: Gresser Ion , Kaido Thomas , Maury Chantal , Woodrow David , Moss Jill , Belardelli Filippo
Published: February 2007

We have previously shown that an intact immune system was essential to the increase in survival time of IFN‐α/β‐treated mice injected i.v. with an IFN‐α/β‐resistant line of Friend erythroleukemia cells (FLC) highly metastatic to the liver and spleen. Here, we have investigated the early interactions of IFN α/β with host cells prior to the development of the immune response. IFN α/β treatment resulted in 50‐ to 100‐fold inhibition of FLC multiplication in the liver and spleen of normal DBA/2 mice shortly after tumor inoculation, as evaluated by colony formation in agarose. IFN treatment was far less effective in inhibiting the multiplication of FLC in the livers of NK‐cell‐deficient DBA/2 beige mice, or in immunocompetent DBA/2 mice treated with antibody to asialo GMI, or silica, or in mice subjected to sub‐lethal irradiation. Injection of antibody to CD4 or CD5 did not affect the early inhibitory action of IFN α/β on FLC multiplication but did decrease survival time. Light‐ and electron‐microscope examination of the livers of IFN‐treated, FLC‐injected mice confirmed the early inhibition of FLC multiplication in the liver and spleen. Our results indicate that IFN α/β inhibits the development of FLC visceral metastases by acting first on host cells, such as NK cells and macrophages, and then continues to act in consort with the developing immune response. © 1994 Wiley‐Liss, Inc.
Identification and potential use of a soluble tumor antigen for the detection of liver‐fluke‐associated cholangiocarcinoma induced in a hamster model
Authors: Prempracha N. , Tengchaisri T. , Chawengkirttikul R. , Boonpucknavig S. , Thamavit W. , Duongchawee G. , Sirisinha S.
Published: February 2007

A liver‐fluke‐associated cholangiocarcinoma (CCA), comparable to that occurring in humans, was induced by exposing Opisthorchis viverrini‐infected hamsters to dimethylnitrosamine (DMN). Tumor masses were removed and histopathologically identified, then one portion was extracted for antigens used in the production of monoclonal antibodies (MAbs). The remaining portions were used to establish CCA cell lines. The antigens produced and secreted by these cell lines, as well as those originally present in the tissue extracts, possessed a 200‐kDa glycoprotein that appeared to be immunologically distinct from other tumor markers. A specific MAb called 6E5 was used to set up a sandwich ELISA for the quantification of this antigen in the serum and bile of tumor‐bearing animals. The assay system was sensitive enough to detect the antigen at concentrations below 10 ng/ml. The serum and biliary levels of this antigen were markedly elevated in animals with progressive tumors when compared with untreated controls. The serum taken serially from each animal that subsequently developed CCA showed a gradual but significant elevation of the antigen as carcinogenesis progressed. A few isolated animals exhibited a slight elevation of the antigen at a time as early as the end of DMN treatment, when the CCA should not yet have developed, judging from microscopic examination. The data from this animal model suggested that the CCA‐associated soluble antigen defined by MAb 6E5 was a useful marker for the detection of tumors at an early stage of development.
Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor
Authors: Rosen Eliot M. , Knesel Jaromir , Goldberg Itzhak D. , Jin Liang , Bhargava Madhu , Joseph Ansamma , Zitnik Ralph , Wines James , Kelley Marianne , Rockwell Sara
Published: February 2007

EMT6 is a transplantede mouse mammary tumor cell line Chat has been utilized widely as a model system to study the effects of various treatments on local tumor growth and pulmonary metastasis. In this study, we examined the cellular mechanisms by which scatter factor (SF), a fibroblast‐derived cytokine that stimulates epithelial cell motility, may contribute to tumor‐cell dissemination, using the EMT6 model system. In vitro, SF stimulated EMT6 cell motility, invasiveness and cell‐surface expression of urokinase (an enzyme required for cell migration through tissue). SF differentially stimulated EHT6 cell adhesion to and migration onto surfaces coated with collagen I and laminin. EMT6 cells treated in vitro with SF and injected i.v. into isogeneic BALB/c‐Rw mice showed a small but significant increase (1.7‐fold) in lung colony formation as compared with control cells. For EMT6 cells in vitro, SF had no effect on DNA synthesis, cell proliferation, cell size distribution, or in vitro colony‐forming ability. Thus, the increase in lung colonization may be due to enhanced ability of SF‐treated cells to adhere to subendothelial basement membrane or to invade through tissue. Studies of the tissue distribution of SF in BALB/c‐Rw mice demonstrated high levels of active factor in the lung. Thus, the presence of endogenous pulmonary SF may have reduced the degree to which SF treatment stimulated EMT6 lung colonization. Significant SF activity was also found in extracts of EMT6 tumors. Cultured EMT6 cells did not produce SF, but did produce high titers of a soluble low‐molecular‐weight protein activity that is capable of stimulating SF production in human fibroblasts 3‐ to 5‐fold. EMT6 tumor extracts contained high titers of a similar SF‐inducing activity. These observations suggest that SF may contribute to the invasive and metastatic phenotype of EMT6 cells via a paracrine mechanism in which tumor cells induce the production of SF in stromal fibroblasts.
Chromosome aberrations in adenomas of the colon. Proof of trisomy 7 in tumor cells by combined interphase cytogenetics and immunocytochemistry
Authors: Herbergs J. , de Bruïne A. P. , Marx P. T. J. , Vallinga M. I. J. , Stockbrügger R. W. , Ramaekers F. C. S. , Arends J. W. , Hopman A. H. N.
Published: February 2007

Thirty‐five colon adenomas from 26 patients were analyzed with centromeric probes for chromosomes 1,7, 17, X and Y in order to study numerical aberrations, chromosome imbalances, aneuploidy and tetraploidization. The fluorescent in situ hybridization (FISH) technique was applied to single‐cell suspensions and a combination of FISH and immunocytochemistry (ICC) was employed to identify the cell type under study. Trisomy of chromosome 7 was detected in 37% of the cases. In 7 out of 13 cases this aberration was combined with abnormalities of one or 2 of the other investigated chromosomes. No correlation could be demonstrated between any of the detected chromosomal aberrations and size, localization or degree of epithelial dysplasia. With the combined FISH/ICC procedure, the abnormal cells were shown to be of epithelial rather than of stromal origin. Our data indicate that trisomy 7 is a common chromosome aberration in the epithelial component of colon adenomas. © 1994 Wiley‐Liss, Inc.
Cytotoxicity of the anticancer agents cisplatin and taxol during cell proliferation and the cell cycle
Authors: Donaldson Karen L. , Goolsby Gay Lynn , Wahl Alan F.
Published: February 2007

The overt effects of the anti‐cancer drugs cisplatin (cis‐DDP) and taxol appear to be DNA modification and microtubule stabilization respectively, yet the mechanisms by which these drugs elicit tumor cell death are not well understood. In this report cell sensitivities to cis‐DDP and taxol were accurately determined as a function of cell proliferation and cell cycle stage. Quiescent fibroblasts restimulated to synchronously enter the cell cycle become maximally sensitive to cis‐DDP immediately preceding DNA synthesis, and resistance increases with onset of DNA synthesis. Mid‐log proliferating cells were separated into progressive stages of the cell cycle by centrifugal elutriation or by double thymidine (dThd) block. Cells staged by either method are maximally sensitive to cis‐DDP in G1, just prior to the onset of DNA synthesis and minimally sensitive in peak DNA synthesis, with entry into S phase resulting in a 2‐fold decrease in sensitivity. Cells that remained blocked at the G1/S phase boundary during cis‐DDP treatment remain maximally sensitive after release. Sensitivity to taxol increases at 2 points: transiently during transition of normal cells from quiescence to proliferation and steadily as proliferating cells progress from early G1 to late G2. This 3‐fold increase in taxol sensitivity through the cell cycle is rapidly reversed upon cell division. Synchronous cells treated with either drug at points of maximum sensitivity initiate apoptotic DNA fragmentation 12‐14 hr post‐exposure to drug. © 1994 Wiley‐Liss, Inc.
Residential radon exposure and lung cancer—an epidemiological study of Norwegian municipalities
Authors: Magnus Knut , Engeland Anders , Green B. Martyn R. , Haldorsen Tor , Muirhead Colin R. , Strand Terje
Published: February 2007

The study is based on a collaboration between the Cancer Registry of Norway, the Norwegian Radiation Protection Authority, and National Radiological Protection Board (NRPB, UK). The association between indoor radon exposure and lung cancer was studied in 427 municipalities. NRPB detectors were sent to 10,000 householders, and 7,500 of the detectors were returned. Data from a nation‐wide survey of smoking habits in 1964‐1965 were available. Data on asbestos exposure were also used in a regression analysis. The reporting to the Cancer Registry of all new cases of cancer is fairly complete, as hospital departments and institutes of pathology are obliged to report all cancer cases. The histologically confirmed lung cancer cases were grouped into squamous‐cell carcinoma, small‐cell carcinoma, adenocarcinoma and other or non‐specified histological types. The age‐adjusted rate of lung cancer by histological type was the dependent variable in the regression analysis. A consistent increase in incidence of lung cancer was seen with increasing tobacco consumption, but no positive trend could be shown with increasing radon exposure in the descriptive presentation of the data. In the regression analysis, however, the incidence of small‐cell anaplastic lung tumors in females increased significantly with increasing radon exposure. When based on the regression coefficients, the fraction of lung cancers attributable to radon is about 2‐4%. However, systematic errors cannot be excluded in an ecological study such as presented here. © 1994 Wiley‐Liss, Inc.
Clinicopathological characteristics of p53 overexpression in endometrial cancers
Authors: Inoue Masaki , Okayama Akira , Fujita Masami , Enomoto Takayuki , Sakata Masahiro , Tanizawa Osamu , Ueshima Hirotsugu
Published: February 2007

Using immunohistochemical methods, we analyzed the association between nuclear p53 overexpression and various clinico‐pathological parameters in patients with endometrial cancers. Formalin‐fined and paraffin‐embedded tissue sections from 139 cases of endometrial cancer (endometrioid type, 126; serous papillary type, 12; and clear‐cell type, 1) were stained with anti‐p53 monoclonal antibody (MAb) DO7. Overexpression of p53 was associated with high malignant potential, including extensive muscular invasion, advanced surgical stage, high histological grade, serous papillary type and a personal history of cancer. Lymph‐node metastasis was also related to p53 overexpression with marginal significance. Survival curves determined by the Kaplan‐Meier method and univariate analysis showed p53 overexpression to be associated with a poor outcome in endometrial cancer patients. However, multivariate analysis using the stepwise Cox proportional‐hazard model showed that whereas lymph‐node metastasis, a personal history of cancer and muscular invasion were related to poor survival rates, p53 overexpression was not. Consequently, p53 overexpression itself does not appear to be an independent prognostic factor in endometrial cancer, although a still larger sample of patient material would be required to assess this issue definitively. © 1994 Wiley‐Liss, Inc.
Intratumoral heterogeneity for amplified genes in human breast carcinoma
Authors: Lönn Ulf , Lönn Sigrid , Nilsson Bo , Stenkvist Björn
Published: February 2007

Intratumoral heterogeneity was studied in human breast cancer by examining separate tumor lesions of individual patients. Tumor samples were obtained from each patient by fine‐needle biopsies from 2 to 4 separate tumor lesions. We used a semi‐quantitative PCR to distinguish between samples with gene amplification and single gene copy samples. Five genes were analyzed in each biopsy: MDR‐1, dihydrofolate reductase, thymidylate synthase, c‐erb‐B2 and int‐2. Three groups of patients were examined: those awaiting initiation of treatment; those receiving first‐line endocrine therapy; and those receiving second‐line endocrine treatment. A pattern of intratumoral heterogeneity for gene amplification was clearly apparent. The frequency of amplification was lowest before initiating therapy and highest in patients receiving second‐line treatment (p = 0.023).
A prospective study of pancreatic cancer in the elderly
Authors: Shibata Atsuko , Mack Thomas M. , Paganini‐Hill Annlia , Ross Ronald K. , Henderson Brian E.
Published: February 2007

Risk factors for pancreatic cancer were examined in a cohort study of 13,979 residents of a retirement community. After 9 years of follow‐up, 65 incident cases of pancreatic cancer were identified. An increased risk of pancreatic cancer was associated with a history of diabetes and cholecystectomy. Higher intake of vegetables, fruits, dietary beta‐carotene, and vitamin C were each associated with a reduced risk of pancreatic cancer, although none of these associations was statistically significant. Risk of pancreatic cancer decreased with increasing tea consumption but was unrelated to coffee consumption. No strong or consistent association was seen between either smoking or alcohol consumption and risk of pancreatic cancer, but a consistent and significant increase in risk followed cholecystectomy. © 1994 Wiley‐Liss, Inc.
Expression and activity of MMPS and their regulators in ovarian cancer
Authors: Naylor M. S. , Stamp G. W. , Davies B. D. , Balkwill F. R.
Published: February 2007

In order to understand the ability of human ovarian cancers to degrade the basement membrane, we have studied the localization and activity of matrix metalloproteases (MMPs) 2 and 9, using in situ hybridization and quantificative zymography on sequential sections of tumor biopsies. We have related these data to expression of some of the controlling elements of the enzymes, namely tissue inhibitors of metastasis (TIMPs) and tumor necrosis factor (TNF). mRNA for MMP‐2 was found in the majority of cases and localized to stromal areas with maximal expression adjacent to neoplastic areas. MMP‐9 expression was associated with cells in epithelial and stromal areas, consistent with distribution of macrophages. Zymography revealed higher levels of MMP‐9 activity in the ovarian cancer biopsy samples than in other cancers studied, but in contrast to our previous observations in breast and bladder cancer, there was no correlation between MMP levels and tumor grade. Nor was there any association between amount of TNF mRNA and levels of MMP enzymes. TIMP‐I expression was localized to stromal areas adjacent to tumor epithelial cells as well as, in some cases, to epithelial cells. The pattern of TIMP‐2 expression wax similar to that of MMP‐2. We conclude that the stromal elements of ovarian tumors express MMP‐2 and 9 and their specific inhibitors, but these do not seem to be controlled by endogenous TNF in the tumor microenvironment. © 1994 Wiley‐Liss, Inc.