bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular endothelial growth factor expression correlates with matrix metalloproteinases MT1‐MMP, MMP‐2 and MMP‐9 in human glioblastomas
Authors: Munaut Carine , Noël Agnès , Hougrand Olivier , Foidart Jean‐Michel , Boniver Jacques , Deprez Manuel 
Published: August 2003

AbstractVascular endothelial growth factor (VEGF) is the major endothelial mitogen in central nervous system neoplasms and it is expressed in 64–95% of glioblastomas (GBMs). Tumour cells are the main source of VEGF in GBMs whereas VEGF receptors (VEGFR‐1, its soluble form sVEGFR‐1, VEGFR‐2 and neuropilin‐1) are expressed predominantly by endothelial cells. Infiltrating tumour cells and newly‐formed capillaries progress through the extracellular matrix by local proteolysis involving matrix metalloproteinases (MMPs). Recent studies have shown that VEGF expression and bioavailability can be modulated by MMPs. We reported previously that the expression of MT1‐MMP in human breast cancer cells was associated with an enhanced VEGF expression. We used quantitative RT‐PCR, Western blot, gelatin zymography and immunohistochemistry to study the expression of VEGF, VEGFR‐1, VEGFR‐2, sVEGFR‐1, neuropilin‐1, MT1‐MMP, MMP‐2, MMP‐9 and TIMP‐2 in 20 human GBMs and 5 normal brains. The expression of these MMPs was markedly increased in most GBMs with excellent correlation between mRNA and protein levels; activated forms of MMP‐2 and MMP‐9 were present in 8/18 and 7/18 of GBMs. A majority of GBMs (17/20) also expressed high levels of VEGF, as previously reported, with strong correlation between VEGF and MT1‐MMP gene expression levels, and double immunostaining showed that VEGF and MT1‐MMP peptides co‐localize in tumour and endothelial cells. Our results suggest that the interplay between metalloproteinases and VEGF previously described in experimental tumours may also be operative in human GBMs. Because of its dual ability to activate MMP‐2 and to up‐regulate VEGF, MT1‐MMP might be of central importance in the growth of GBMs and represent an interesting target for anti‐cancer treatments. © 2003 Wiley‐Liss, Inc.
Role of thymidine phosphorylase on invasiveness and metastasis in lung adenocarcinoma
Authors: Sato Jun , Sata Makoto , Nakamura Hidenori , Inoue Sumito , Wada Toshihiro , Takabatake Noriaki , Otake Kazuhisa , Tomoike Hitonobu , Kubota Isao 
Published: August 2003

AbstractThymidine phosphorylase (TP) is expressed at higher levels in a variety of human cancers than in adjacent normal tissue. It is reported that the higher expression is associated with an increase of intratumoral microvessel density and a poor prognosis. We investigated the role of TP in human non small cell lung cancers (NSCLCs). The concentrations of TP in the tumors and the adjacent normal tissue from surgically resected specimens of 54 cases of NSCLCs were measured by using an enzyme‐linked immunosorbent assay. Tumor specimens were also examined immunohistochemically. TP concentrations in the tumors were 169 ± 18 units/mg protein (mean ± SD), whereas those in normal tissue were 43 ± 4 units/mg protein (mean ± SD), consistent with TP staining patterns. There was no correlation between TP expression and microvessel density. Among clinicopathologic factors examined, the concentrations of TP but not TP immunoreactivity correlated with tumor differentiation in lung adenocarcinoma. Although a specific TP inhibitor (TPI) and overexpression of TP did not affect the growth of A549 lung adenocarcinoma cells, Matrigel invasion assay showed that A549 transfected with TP had higher invasive potential than mock transfectant, and such enhanced invasive activity was markedly diminished by treatment with TPI. Furthermore, administration of TPI suppressed lung metastasis of TP‐overexpressing A549 cells in nude mice. These results demonstrate that TP may play an important role in tumor differentiation, invasiveness and metastasis in lung adenocarcinoma, and suggest that TP could be a novel target for treatment of TP‐overexpressing lung adenocarcinoma. © 2003 Wiley‐Liss, Inc.
Epigallocatechin‐3‐gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells
Authors: Brusselmans Koen , De Schrijver Ellen , Heyns Walter , Verhoeven Guido , Swinnen Johannes V. 
Published: August 2003

AbstractChemical inhibitors of fatty acid synthase (FAS) inhibit growth and induce apoptosis in several cancer cell lines in vitro and in tumor xenografts in vivo. Recently the green tea component epigallocatechin‐3‐gallate (EGCG) was shown to act as a natural inhibitor of FAS in chicken liver extracts. Here we investigated whether EGCG inhibits FAS activity in cultured prostate cancer cells and how this inhibition affects endogenous lipid synthesis, cell proliferation and cell viability. The high levels of FAS activity in LNCaP cells were dose‐dependently inhibited by EGCG and this inhibition was paralleled by decreased endogenous lipid synthesis, inhibition of cell growth and induction of apoptosis. In contrast, epicatechin (EC), another closely related green tea polyphenolic compound, which does not inhibit FAS, had no effect on LNCaP cell growth or viability. Treatment of nonmalignant cells with low levels of FAS activity (fibroblasts) with EGCG led to a decrease in growth rate but not to induction of apoptosis. These data indicate that EGCG inhibits FAS activity as efficiently as presently known synthetic inhibitors and selectively causes apoptosis in LNCaP cells but not in nontumoral fibroblasts. These findings establish EGCG as a potent natural inhibitor of FAS in intact cells and strengthen the molecular basis for the use of EGCG as a chemopreventive and therapeutic antineoplastic agent. © 2003 Wiley‐Liss, Inc.
Malignant transformation of human bronchial epithelial cells with the tobacco‐specific nitrosamine, 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone
Authors: Zhou Hongning , Calaf Gloria M. , Hei Tom K. 
Published: August 2003

AbstractSufficient evidence has demonstrated that cigarette smoking is causally associated with various types of human cancers. In the United States, about 90% of deaths from lung cancer among men and 79% of those among women are associated with smoking. Tobacco‐specific nitrosamines are formed from nicotine and related tobacco alkaloids and are the most carcinogenic compounds of tobacco smoke. The most potent N‐nitrosamine contained in tobacco smoke is 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone, NNK. In the our study, the oncogenic transforming effects of graded doses of NNK were examined using papillomavirus‐immortalized human bronchial epithelial cells. Growth kinetics, saturation density, resistance to serum‐induced terminal differentiation, anchorage independent growth and tumorigenicity in nude mice were used to investigate the various stages of transformation in bronchial epithelial cells. We show here that immortalized human bronchial epithelial cells in culture can be malignantly transformed by treatment with NNK (100 μg/ml or 400 μg/ml) for 7 days. Transformed cells produced progressively growing subcutaneous tumors upon inoculation into nude mice. Immunofluorescence staining for keratin expression confirmed the epithelial nature of the tumor cells. Increased expression of p16, β‐catenin and PCNA in the established cell lines were detected by immunofluorescence staining and quantified by confocal microscopy. These data suggested that NNK can induce malignant transformation of human bronchial epithelial cells, and the tumor cell lines established are useful models in investigating the carcinogenic mechanism(s) of NNK. © 2003 Wiley‐Liss, Inc.
Renal cell carcinoma‐infiltrating natural killer cells express differential repertoires of activating and inhibitory receptors and are inhibited by specific HLA class I allotypes
Authors: Schleypen Julia S. , von Geldern Marion , Weiß Elisabeth H. , Kotzias Nicole , Rohrmann Karl , Schendel Dolores J. , Falk Christine S. , Pohla Heike 
Published: August 2003

AbstractAmong tumor‐infiltrating lymphocytes (TILs) directly isolated from renal cell carcinomas (RCCs), we found substantial numbers of natural killer (NK) cells in most tumor tissues. They could be identified reliably in situ with an antibody directed against the activating receptor (AR) NKp46 that is exclusively expressed by all NK cells. NK‐enriched TILs (NK‐TILs) showed cytotoxicity against major histocompatibility complex (MHC) class I‐negative cell lines. The ability to detect lysis of target cells was dependent on the percentage of NK cells within the TILs, and cytotoxicity was only observed after overnight activation with low‐dose interleukin‐2 (IL‐2). Infiltrating NK cells were found to express various inhibitory receptors (IRs); among these the CD94/NKG2A receptor complex was overrepresented compared to the autologous peripheral blood mononuclear cell (PBMC) population. Other IRs were underrepresented, indicating that NK subpopulations vary in their tumor‐infiltrating capacity. IRs expressed by NK‐TILs are functional since receptor engagement with MHC class I ligands presented by human leukocyte antigen (HLA)‐transfected target cell lines was able to inhibit NK‐mediated cytotoxicity. NK‐TILs were also able to lyse autologous or allogeneic tumor cell lines in vitro. This activity correlated with low HLA class I surface expression since lysis could be inhibited by interferon (IFN)‐γ‐expressing RCC transductants that displayed a higher surface density of HLA class I molecules. Therefore, NK cells infiltrating tumor tissues have an inherent ability to recognize transformed cells, but they require cytokine activation and are sensitive to inhibition by IR ligands. © 2003 Wiley‐Liss, Inc.
Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer
Authors: Jarmalaite Sonata , Kannio Annamaria , Anttila Sisko , Lazutka Juozas R. , Husgafvel‐Pursiainen Kirsti 
Published: August 2003

AbstractHypermethylation of cytosines in CpG‐rich islands of the promoter regions of regulatory genes has been discovered as a common mechanism of gene silencing during carcinogenesis. We analysed 64 primary lung carcinomas for promoter methylation of the tumour suppressor genes (TSGs) p16 (p16INK4a/CDKN2A) and p14 (p14ARF) by methylation‐specific PCR, in order to evaluate aberrant methylation as a potential biomarker for epigenetic alterations in tobacco‐related lung cancer. Methylation of p16 was observed in 34% (22/64) of the lung tumours examined. In particular, p16 methylation occurred in nonsmall cell lung cancer (NSCLC) only, with 41 % (22/54) of the tumours being positive. The highest frequency was found in large cell carcinoma (5/7, 71%), followed by adenocarcinoma (9/25, 36%) and squamous cell carcinoma (7/21, 33%). Methylation of the p14 gene was less frequent in lung cancer (4/52, 8%). When association with tobacco smoking was analysed, 42% (21/50) of NSCLC from ever smokers exhibited p16 methylation. Interestingly, the analysis revealed a significantly higher risk of p16 methylation in former smokers as compared to current smokers [odds ratio (OR) 5.1; 95% confidence interval (CI) 1.3–22]. The difference was retained after adjustment for age (OR 3.7; 95% CI 0.9–17). The promoter methylation results were then combined with data on genetic alterations determined previously in the same set of tumours. This data similarly showed that p16 methylation in parallel with p53 gene mutation or p14 methylation occurred more frequently in former smokers than in current smokers (44% vs. 14%; P = 0.035). Taken together, our data suggest that analysis of promoter methylation in TSGs may provide a valuable biomarker for identification of groups with an elevated risk of cancer, such as smokers and ex‐smokers. © 2003 Wiley‐Liss, Inc.
Deletion of Trp‐557 and Lys‐558 in the juxtamembrane domain of the c‐kit protooncogene is associated with metastatic behavior of gastrointestinal stromal tumors
Authors: Wardelmann Eva , Losen Inge , Hans Volkmar , Neidt Iris , Speidel Nicola , Bierhoff Erhard , Heinicke Thomas , Pietsch Torsten , Büttner Reinhard , Merkelbach‐Bruse Sabine 
Published: August 2003

AbstractGastrointestinal stromal tumors (GISTs) typically express high levels of the Kit‐receptor. The majority of GISTs carry mutations in the c‐kit protooncogene clustering in exon 11. The significance of c‐kit mutations for the biological behavior of GISTs is still under discussion. We evaluated 55 sporadic GISTs with available follow‐up data for c‐kit mutations in the juxtamembrane domain and detected mutations in 35 cases (63.6%). We found a mutational hotspot in codons 557 (tryptophan) and 558 (lysine) preferentially in histomorphologically malignant tumors. In the group of GISTs carrying c‐kit mutations, 16 of 21 malignant, but only 3 of 8 benign GISTs and 3 of 6 lesions with uncertain malignant potential, carried mutations of Trp‐557 and/or Lys‐558. We investigated whether mutations in these 2 amino acids had an impact on biological behavior. Trp‐557 and/or Lys‐558 were mutated in all 15 metastatic GISTs carrying c‐kit mutations but only in a minority of nonmetastatic tumors. A combined deletion of Trp‐557 and Lys‐558 occurred exclusively in 8 metastatic GISTs. We conclude that in addition to histomorphological evaluation determination of mutations in exon 11 may be an additional parameter for predicting the metastatic risk of GISTs and may be important for the decision that patients will need close clinical follow‐up or further adjuvant treatment with kit antagonists. © 2003 Wiley‐Liss, Inc.
Green tea catechins inhibit VEGF‐induced angiogenesis in vitro through suppression of VE‐cadherin phosphorylation and inactivation of Akt molecule
Authors: Tang Feng‐Yao , Nguyen Nhan , Meydani Mohsen 
Published: August 2003

AbstractStudies have indicated that the consumption of green tea is associated with a reduced risk of developing certain forms of cancer and angiogenesis. The mechanism of inhibition of angiogenesis by green tea or its catechins, however, has not been well‐established. Vascular endothelial (VE)‐cadherin, an adhesive molecule located at the site of intercellular contact, is involved in cell–cell recognition during vascular morphogenesis. The extracellular domain of VE‐cadherin mediates initial cell adhesion, whereas the cytosolic tail binding with β‐catenin is required for interaction with the cytoskeleton and junctional strength. Therefore, the cadherin–catenin adhesion system is implicated in cell recognition, differentiation, growth and migration of capillary endothelium. Using tube formation of human microvascular endothelial cells (HMVEC) in culture as an in vitro model of angiogenesis, we reported that vascular endothelial growth factor (VEGF)‐induced tube formation is inhibited by anti‐VE‐cadherin antibody and dose‐dependently by green tea catechins. We also demonstrated here that inhibition of tube formation by epigallocatechin gallate (EGCG), one of the green tea catechins, is in part mediated through suppression of VE‐cadherin tyrosine phosphorylation and inhibition of Akt activation during VEGF‐induced tube formation. These findings indicate that VE‐cadherin and Akt, known downstream proteins in VEGFR‐2‐mediated cascade, are the new‐targeted proteins by which green tea catechins inhibit angiogenesis. © 2003 Wiley‐Liss, Inc.
Mortality from cancer and other causes among male airline cockpit crew in Europe
Authors: Blettner Maria , Zeeb Hajo , Auvinen Anssi , Ballard Terri J. , Caldora Massimiliano , Eliasch Harald , Gundestrup Maryanne , Haldorsen Tor , Hammar Niklas , Hammer Gaël P. , Irvine David , Langner Ingo , Paridou Alexandra , Pukkala Eero , Rafnsson Vilhjálmur , Storm Hans , Tulinius Hrafn , Tveten Ulf , Tzonou Anastasia 
Published: August 2003

AbstractAirline pilots and flight engineers are exposed to ionizing radiation of cosmic origin and other occupational and life‐style factors that may influence their health status and mortality. In a cohort study in 9 European countries we studied the mortality of this occupational group. Cockpit crew cohorts were identified and followed‐up in Denmark, Finland, Germany, Great Britain, Greece, Iceland, Italy, Norway and Sweden, including a total of 28,000 persons. Observed and expected deaths for the period 1960–97 were compared based on national mortality rates. The influence of period and duration of employment was analyzed in stratified and Poisson regression analyses. The study comprised 547,564 person‐years at risk, and 2,244 deaths were recorded in male cockpit crew (standardized mortality ratio [SMR] = 0.64, 95% confidence interval [CI] = 0.61–0.67). Overall cancer mortality was decreased (SMR = 0.68; 95% CI = 0.63–0.74). We found an increased mortality from malignant melanoma (SMR = 1.78, 95% CI = 1.15–2.67) and a reduced mortality from lung cancer (SMR = 0.53, 95% CI = 0.44–0.62). No consistent association between employment period or duration and cancer mortality was observed. A low cardiovascular mortality and an increased mortality caused by aviation accidents were noted. Our study shows that cockpit crew have a low overall mortality. The results are consistent with previous reports of an increased risk of malignant melanoma in airline pilots. Occupational risk factors apart from aircraft accidents seem to be of limited influence with regard to the mortality of cockpit crew in Europe. © 2003 Wiley‐Liss, Inc.
Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer
Authors: Hiraga Toru , Ueda Akimi , Tamura Daisuke , Hata Kenji , Ikeda Fumiyo , Williams Paul J. , Yoneda Toshiyuki 
Published: August 2003

AbstractBone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Therefore, intervention of bone metastases is one of the important targets in the management of breast cancer. In the present study, we examined the effects of the orally administrable chemotherapeutic agent UFT (a combination of tegafur and uracil at a molar ratio of 1:4) on bone metastases using an animal model of the 4T1/luc mouse breast cancer. The 4T1/luc cells developed spontaneous metastases to bone following orthotopic cell inoculation. Oral daily administration of UFT (20 mg/kg/day) significantly reduced the orthotopic tumor burden; however, the lower dose (15 mg/kg/day) did not. In contrast, histologic examination showed that both doses of UFT significantly suppressed bone metastases in a dose‐dependent manner. Since clinical studies have demonstrated that bisphosphonates (BPs), specific inhibitors of osteoclastic bone resorption, are beneficial for breast cancer patients with bone metastases, we next examined the effects of UFT combined with the BP zoledronic acid (ZOL) on established bone metastases. The combination of UFT (20 mg/kg/day) with ZOL (250 μg/kg) caused an enhanced reduction of bone metastases compared with UFT alone. In vitro studies showed that 5‐fluorouracil (5‐FU), an active metabolite of UFT, and ZOL increased apoptosis in 4T1/luc cells and inhibited osteoclast‐like cell formation in an additive fashion. Our results suggest that oral UFT is an effective chemotherapeutic agent for advanced breast cancer accompanying bone metastases and that the combination with BP increases its benefits for bone metastases. © 2003 Wiley‐Liss, Inc.
Human papillomavirus type 16 E6 variants and HLA class II alleles among Japanese women with cervical cancer
Authors: Matsumoto Koji , Yasugi Toshiharu , Nakagawa Shunsuke , Okubo Mitsuo , Hirata Ranko , Maeda Hiroo , Yoshikawa Hiroyuki , Taketani Yuji 
Published: August 2003

AbstractThe enhanced oncogenicity of particular human papillomavirus type 16 (HPV16) E6 variants is population‐dependent, implying the involvement of additional genetic cofactors. This study was designed to investigate the association between E6 variants and human leukocyte antigen (HLA) polymorphism within a Japanese population. Fifty‐seven women with HPV16‐positive cervical cancer were analyzed for E6 sequence variation and its relationship to HLA class II alleles. Compared with local controls (n = 138) and published controls (n = 916), DRB1*1501 and DQB1*0602 frequencies were significantly increased among patients with HPV16 E6 prototype (n = 11). Additionally, DRB1*1502 was positively associated with a particular E6 variant designated D25E (n = 25), although we could not find a significant association between HLA class II alleles and L83V variants (n = 16). Our observations suggest that a specific match between E6 variant proteins and HLA types may contribute to HPV16‐related cervical carcinogenesis. © 2003 Wiley‐Liss, Inc.
A comprehensive natural history model of HPV infection and cervical cancer to estimate the clinical impact of a prophylactic HPV‐16/18 vaccine
Authors: Goldie Sue J. , Grima Daniel , Kohli Michele , Wright Thomas C. , Weinstein Milton , Franco Eduardo 
Published: August 2003

AbstractThe object of our study is to project the impact of a prophylactic vaccine against persistent human papillomavirus (HPV)‐16/18 infection on age‐specific incidence of invasive cervical cancer. We developed a computer‐based mathematical model of the natural history of cervical carcinogenesis to incorporate the underlying type‐specific HPV distribution within precancerous lesions and invasive cancer. After defining plausible ranges for each parameter based on a comprehensive literature review, the model was calibrated to the best available population‐based data. We projected the age‐specific reduction in cervical cancer that would occur with a vaccine that reduced the probability of acquiring persistent infection with HPV 16/18, and explored the impact of alternative assumptions about vaccine efficacy and coverage, waning immunity and competing risks associated with non‐16/18 HPV types in vaccinated women. The model predicted a peak age‐specific cancer incidence of 90 per 100,000 in the 6th decade, a lifetime cancer risk of 3.7% and a reproducible representation of type‐specific HPV within low and high‐grade cervical precancerous lesions and cervical cancer. A vaccine that prevented 98% of persistent HPV 16/18 was associated with an approximate equivalent reduction in 16/18‐associated cancer and a 51% reduction in total cervical cancer; the effect on total cancer was attenuated due to the competing risks associated with other oncogenic non‐16/18 types. A vaccine that prevented 75% of persistent HPV 16/18 was associated with a 70% to 83% reduction in HPV‐16/18 cancer cases. Similar effects were observed with high‐grade squamous intraepithelial lesions (HSIL) although the impact of vaccination on the overall prevalence of HPV and low‐grade squamous intraepithelial lesions (LSIL) was minimal. In conclusion, a prophylactic vaccine that prevents persistent HPV‐16/18 infection can be expected to significantly reduce HPV‐16/18‐associated LSIL, HSIL and cervical cancer. The impact on overall prevalence of HPV or LSIL, however, may be minimal. Based on the relative importance of different parameters in the model, several priorities for future research were identified. These include a better understanding of the heterogeneity of vaccine response, the effect of type‐specific vaccination on other HPV types and the degree to which vaccination effect persists over time. © 2003 Wiley‐Liss, Inc.