bluuebunny/crossref_metadata_2025_split huggingface dataset:
MSH6 germline mutations are rare in colorectal cancer families
Authors: Peterlongo Paolo , Nafa Khedoudja , Lerman Gabriel S. , Glogowski Emily , Shia Jinru , Ye Tian Z. , Markowitz Arnold J. , Guillem José G. , Kolachana Prema , Boyd Jeffrey A. , Offit Kenneth , Ellis Nathan A. 
Published: September 2003

AbstractGermline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease‐causing mutations of MSH6 may or may not exhibit MSI. We used D‐HPLC to screen for germline mutations in the promoter region, the coding region and the 3′‐UTR of MSH6. Eighty‐four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC‐like families), were tested for MMR gene mutations; 27 families had a disease‐causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein‐truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early‐onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease‐causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. Altogether, our results indicate that disease‐causing germline mutations of MSH6 are rare in HNPCC and HNPCC‐like families. © 2003 Wiley‐Liss, Inc.
High tumor tissue concentration of urokinase plasminogen activator receptor is associated with good prognosis in patients with ovarian cancer
Authors: Borgfeldt Christer , Bendahl Pär‐Ola , Gustavsson Barbro , Långström Eva , Fernö Mårten , Willén Roger , Grenman Seija , Casslén Bertil 
Published: September 2003

AbstractThe urokinase plasminogen activator (uPA) system is involved in tumor growth and metastasis. We assayed the components of the uPA system in homogenates of 64 primary epithelial ovarian tumors and 5 metastases and evaluated the association of these parameters to prognosis in the 51 malignant cases. The levels of uPA, PAI‐2 and the uPA:PAI‐1 complex increased with progressive loss of histological differentiation (ptrend <0.001, <0.05 and <0.001). The level of PAI‐1 was higher in poorly than in well/moderately differentiated tumors (p = 0.03). The content of uPAR was lower in benign tumors as compared to borderline malignancies (p = 0.002), invasive primary tumors (p < 0.001), and metastases (p = 0.002). Surprisingly, the level of uPAR was lower in poorly differentiated as compared to both borderline (p = 0.01) and well differentiated malignant tumors (p = 0.005). Also, the level of uPAR was lower in advanced as compared to early stages of the disease (ptrend = 0.002). The median follow‐up time for patients was 5.8 years. High tumor tissue levels of uPAR were associated with longer postoperative survival (HR = 0.4, 95% CI = 0.2–0.8, p = 0.01). In contrast, shorter survival was evident in patients with high tumor levels of uPA from 2 years on after operation (HR = 4.6, 95% CI = 1.2–17, p = 0.02). High tPA levels tended to be associated with shorter overall survival after 2 years (HR = 2.9, 95% 95% CI = 0.9–9.8, p = 0.08). Although high tumor tissue content of uPAR was associated with a less aggressive phenotype characterized by well differentiated histology and longer survival, low content of uPAR in the poorly differentiated tumors and metastases presumably results from increased elimination of uPAR. © 2003 Wiley‐Liss, Inc.
Expression of microsomal prostaglandin E synthase‐1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines
Authors: van Rees Bastiaan P. , Sivula Anna , Thorén Staffan , Yokozaki Hiroshi , Jakobsson Per‐Johan , Offerhaus G. Johan A. , Ristimäki Ari 
Published: September 2003

AbstractGastrointestinal carcinomas synthesize elevated levels of prostaglandin E2 (PGE2), which has been mechanistically linked to carcinogenesis. Recently, microsomal prostaglandin E synthase‐1 (mPGES‐1) was cloned, which seems to be inducible and linked to cyclooxygenase‐2 (Cox‐2) in the biosynthesis of PGE2. We examined expression of mPGES‐1 in intestinal type gastric adenocarcinomas and in gastric cancer cell lines. The transcript for mPGES‐1 was elevated in 57% (4/7) of gastric carcinomas as detected by Northern blot analysis. Moderate to strong mPGES‐1 immunoreactivity was observed in 56% (5/9) of the carcinomas as detected by immunohistochemistry. Furthermore, mPGES‐1 mRNA, protein and microsomal PGES activity were detected in gastric adenocarcinoma cell lines that originated from intestinal type tumors (MKN‐7 and MKN‐28). In contrast to Cox‐2, however, expression of mPGES‐1 mRNA or protein were not induced by phorbol 12‐myristate 13‐acetate (PMA) or interleukin‐1β (IL‐1β) in any of the gastric cancer cell lines tested (MKN‐1, ‐7, ‐28, ‐45 and ‐74). Two gastric cancer cell lines (MKN‐45 and MKN‐74) did not express mPGES‐1 and lacked microsomal PGES activity, but were still able to synthesize PGE2. Because all gastric cell lines expressed cPGES as detected by immunoblotting, it is possible that Cox‐2 can interact with cPGES or with some other yet unidentified PGES in gastric cancer cells. Furthermore, our data show that regulatory mechanisms that drive expression of mPGES‐1 and Cox‐2 dissociate in gastric cancer cell lines. © 2003 Wiley‐Liss, Inc.
Relaxin‐like peptides in cancer
Authors: Silvertown Josh D. , Summerlee Alastair J.S. , Klonisch Thomas 
Published: September 2003

AbstractThe members of the relaxin‐like hormone family, relaxin and INSL3, also known as relaxin‐like factor (RLF) or Leydig cell‐derived insulin‐like factor (LEY‐I‐L), are implicated in various mechanisms associated with tumor cell growth, differentiation, invasion and neovascularization. The recent discovery of the relaxin receptor LGR7 and the INSL3/relaxin receptor LGR8 has provided evidence of an auto/paracrine relaxin‐like action in tumor tissues and enables the elucidation of the cellular pathways involved in the proposed functions of relaxin in tumor biology. Our review summarizes our current knowledge of the expression of relaxin and INSL3 in human neoplastic tissues and discusses the etiological roles of these heterodimeric peptide hormones in cancer. Discussion of possible cellular cascades involved in actions linking relaxin‐like peptides and neoplasia include the role of relaxin‐like peptides in tumor cell growth and differentiation; the effect of relaxin in stimulating the synthesis of the vasodilatory and tumor cell cytostatic and antiapoptotic molecule, nitric oxide; the potential ability of relaxin to upregulate vascular endothelial growth factor to promote angiogenesis and neovascularization and the concerted fine‐tuned action of relaxin on the matrix metalloproteinases on the extracellular matrix to facilitate tumor cell attachment, migration and invasion. © 2003 Wiley‐Liss, Inc.
Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC)
Authors: González Carlos A. , Pera Guillem , Agudo Antonio , Palli Domenico , Krogh Vittorio , Vineis Paolo , Tumino Rosario , Panico Salvatore , Berglund Göran , Simán Henrik , Nyrén Olof , Agren Asa , Martinez Carmen , Dorronsoro Miren , Barricarte Aurelio , Tormo María J. , Quiros Jose R. , Allen Naomi , Bingham Sheila , Day Nicholas , Miller Antony , Nagel Gabriele , Boeing Heiner , Overvad Kim , Tjonneland Anne , Bueno‐de‐Mesquita H. Bas , Boshuizen Hendriek C. , Peeters Petra , Numans Mattijs , Clavel‐Chapelon François , Helen Ishaki , Agapitos Emmanuel , Lund Eiliv , Fahey Michael , Saracci Rodolfo , Kaaks Rudolf , Riboli Elio 
Published: September 2003

AbstractSmoking has recently been recognised as causally associated with the development of gastric cancer (GC). However, evidence on the effect by sex, duration and intensity of smoking, anatomic subsite and cessation of smoking is limited. Our objective was to assess the relation between tobacco use and GC incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC). We studied data from 521,468 individuals recruited from 10 European countries taking part in the EPIC study. Participants completed lifestyle questionnaires that included questions on lifetime consumption of tobacco and diet in 1991–1998. Participants were followed until September 2002, and during that period 305 cases of stomach cancer were identified. After exclusions, 274 were eligible for the analysis, using the Cox proportional hazard model. After adjustment for educational level, consumption of fresh fruit, vegetables and preserved meat, alcohol intake and body mass index (BMI), there was a significant association between cigarette smoking and gastric cancer risk: the hazard ratio (HR) for ever smokers was 1.45 (95% confidence interval [CI] = 1.08–1.94). The HR of current cigarette smoking was 1.73 (95% CI = 1.06–2.83) in males and 1.87 (95% CI = 1.12–3.12) in females. Hazard ratios increased with intensity and duration of cigarette smoked. A significant decrease of risk was observed after 10 years of quitting smoking. A preliminary analysis of 121 cases with identified anatomic site showed that current cigarette smokers had a higher HR of GC in the cardia (HR = 4.10) than in the distal part of the stomach (HR = 1.94). In this cohort, 17.6 % (95% CI = 10.5–29.5 %) of GC cases may be attributable to smoking. Findings from this large study support the causal relation between smoking and gastric cancer in this European population. Stomach cancer should be added to the burden of diseases caused by smoking. © 2003 Wiley‐Liss, Inc.
Physical activity and risk of renal cell carcinoma
Authors: Menezes Ravi J. , Tomlinson George , Kreiger Nancy 
Published: September 2003

AbstractThe role of physical activity in the development of renal cell carcinoma was examined using a population‐based case‐control study conducted in the province of Ontario. Physical activity was examined in several ways, including by intensity and during various life periods. Frequency‐matching by 5‐year age groups and sex produced sets of 486 females (133 cases and 353 controls) and 447 males (172 cases, 275 controls). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). After adjusting for age, body mass index and smoking, women who performed relatively high amounts of recent recreational activity (OR = 0.41, 95% CI 0.21–0.82 for the highest vs. lowest quartile of activity, 2 years ago), as well as strenuous recreational activity (OR = 0.40, 95% CI 0.22–0.75), had a reduced risk of developing the disease. In general, moderate recreational activity did not appear to be associated with risk in females. In males, a relatively high frequency of total and moderate recreational activity was associated with reduced risk (total, OR = 0.49, 95% CI 0.27–0.87; moderate, OR = 0.49, 95% CI 0.27–0.89), especially during the teen years. Recreational activity during one's 30s was not associated with cancer risk. There was also no association between occupational activity and cancer risk in females or males. The results of our study, in general, suggest that physical activity may be associated with a decreased risk of developing renal cell carcinoma. © 2003 Wiley‐Liss, Inc.
Gene expression profiling of tumor xenografts: In vivo analysis of organ‐specific metastasis
Authors: Lee Hyerim , Lin Emme C. K. , Liu Limin , Smith Jeffrey W. 
Published: September 2003

AbstractMammary carcinoma frequently metastasizes to specific organs, including the regional lymph nodes, the lung and bone marrow. The mechanisms that guide organ‐specific metastasis and the molecular players that are involved remain to be established. To gain insight into this problem, we used an orthotopic model of breast cancer in which the MDA‐MB‐435 cells are implanted into the mouse mammary fat pad. Sublines that preferentially metastasized to specific sites were isolated by excising metastatic tumors and growing explants of these tumors in culture. Cells lines that preferentially metastasize to the lymph node and thoracic cavity were obtained. The gene expression profiles of primary tumors from these sublines were then compared with cDNA arrays containing 5,800 known genes. In tumors that preferentially metastasize to the lymph node, several genes encoding adhesion and matrix proteins were upregulated. Genes encoding proteins involved in metabolism were downregulated. One of the upregulated genes in lymph‐homing tumors was CD73. Immunohistochemistry showed that the CD73 protein is also upregulated in primary tumors of this cell line and that its expression is elevated in the lymph node metastases. CD73 is a transmembrane protein that has previously been implicated in the homing of normal lymphocytes to the nodes. This raises the hypothesis that tumors preferentially metastasize to lymph nodes by using CD73 to mimic part of the lymphocyte homing process. © 2003 Wiley‐Liss, Inc.
Occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons and other agents and K‐ras activation in human exocrine pancreatic cancer
Authors: Alguacil Juan , Porta Miquel , Kauppinen Timo , Malats Núria , Kogevinas Manolis , Carrato Alfredo ,   for the PANKRAS II Study Group
Published: September 2003

Abstractras genes are known critical DNA targets for chemical carcinogens. Exocrine pancreatic cancer (EPC) is the human tumor with the highest prevalence of K‐ras mutations at diagnosis. We analyzed the relationship between past occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons (PAHs) and other agents and mutations in codon 12 of the K‐ras gene in 107 incident cases of EPC. Information on occupational and life‐style factors was obtained from personal interviews conducted during hospital stay. Occupational exposures were examined using industrial hygienists (IH) assessment and the Finnish job‐exposure matrix (Finjem). Specific occupational exposures among K‐ras mutated EPC cases (n = 83) were compared to those of K‐ras wild‐type EPC cases (n = 24) (case‐case analysis). Multivariate‐adjusted odds ratios (OR) and their corresponding 95% confidence limits were estimated by unconditional logistic regression. Cases with K‐ras mutations were significantly more likely than wild‐type cases to have been exposed to dyes and organic pigments (OR 4.8; p<0.05). There was some indication of weaker associations between K‐ras mutations and occupational exposure to lead, PAHs, benzo[a]pyrene, gasoline, nickel, inhalatory exposure to chromium and sedentary work. The association with chromium compounds was stronger for G to T transversions, a finding compatible with experimental studies on mutation spectra for chromium. Results lend moderate support to the hypothesis of indirect relationships between occupational exposure to dyes and organic pigments and the activation of the K‐ras gene in the etiopathogenesis of human exocrine pancreatic cancer. © 2003 Wiley‐Liss, Inc.
Use of plasma MMP‐2 and MMP‐9 levels as a surrogate for tumour expression in colorectal cancer patients
Authors: Tutton Matthew G. , George Mark L. , Eccles Suzanne A. , Burton Sarah , Swift R. Ian , Abulafi A. Muti 
Published: September 2003

AbstractMatrix metalloproteinases, and notably the gelatinases MMP‐2 and MMP‐9, have important roles in tumour invasion, metastasis and angiogenesis. Our study investigates the distribution of MMP‐2 and MMP‐9 in colorectal cancer, the correlation with plasma levels, changes following surgical resection and whether plasma levels reflect clinical staging and disease course. MMP‐2 and MMP‐9 expression in 48 colorectal tumours and 13 adenomatous polyps was analysed by RT‐PCR, immunohistochemistry, and quantified by ELISA of tumour lysates. Concentrations of MMP‐2 and MMP‐9 in plasma samples from these patients and 36 other patients who underwent curative resections were measured by ELISA prior to and 6–12 months after surgery. MMP‐2 expression was significantly increased in colorectal cancer tissues compared to matched normal colon as measured by ELISA. Active MMP‐2 was localised by immunohistochemistry to regions where tumour cells invaded the muscularis with little staining in more superficial areas. Plasma MMP‐2 levels were also significantly elevated in patients with colorectal cancer, with significant reductions following curative resections at all stages. Similarly, MMP‐9 expression was significantly increased in colorectal cancer tissues, predominantly in the tumour stroma. Plasma levels of MMP‐9 were significantly elevated at all stages in colorectal cancer patients and a significant reduction was seen following curative resections. With both MMP‐2 and MMP‐9, the strongest correlation with clinical staging in colorectal cancer was represented by the total plasma concentration of the enzymes, both falling to within the normal range following curative surgery. Plasma levels of these enzymes may therefore have potential as a noninvasive indicator of invasion or metastasis in colorectal cancer or as a marker of disease status during follow‐up. © 2003 Wiley‐Liss, Inc.
Microsatellite instability in hereditary and sporadic breast cancers
Authors: Adem Camilo , Soderberg Cheryl L. , Cunningham Julie M. , Reynolds Carol , Sebo Thomas J. , Thibodeau Stephen N. , Hartmann Lynn C. , Jenkins Robert B. 
Published: September 2003

AbstractSporadic cancers and familial breast cancers are characterized by an increase in genetic instability. Little is known about whether mismatch repair defects accompany this genetic instability. We investigated invasive and/or in situ breast cancers from 30 women with deleterious BRCA1/2 mutations and unclassified variant BRCA1/2 alterations. Forty cases of sporadic breast cancers were also investigated, including 7 medullary carcinomas. Malignant and benign lesions were examined from all cases to better understand tumor progression. Automated immunohistochemistry, with antibodies directed against hMLH1 and hMSH2, was used to screen cases for possible mismatch repair defects. When loss of expression was noted, DNA ploidy was performed by cytomorphometry. DNA, after laser microdissection, was extracted from a majority of familial cases and their corresponding controls, and microsatellite instability analysis was performed. None of the familial or sporadic cases had loss of hMSH2 expression. All but one lesion, a DCIS arising in a deleterious BRCA2 mutation carrier, had loss of hMLH1 expression and a tetraploid profile by image cytomorphometry. There was no MSI in any explored lesions (n = 34), as determined by molecular analysis, including the DCIS with loss of hMLH1 expression. We conclude that DNA mismatch repair defects involving hMLH1 and hMSH2 underexpression are extremely rare events in sporadic and familial breast cancer. Mismatch repair gene mutations may be secondary random events in breast cancer progression. © 2003 Wiley‐Liss, Inc.
Increased expression of the mannose 6‐phosphate/insulin‐like growth factor‐II receptor in breast cancer cells alters tumorigenic properties in vitro and in vivo
Authors: Lee Jason S. , Weiss Jocelyn , Martin Janet L. , Scott Carolyn D. 
Published: September 2003

AbstractThe mannose 6‐phosphate/insulin‐like growth factor‐II receptor (M6P/IGF‐IIR) is thought to act as a suppressor of tumor growth by binding the mitogenic peptide IGF‐II and modulating its extracellular levels via degradation. This receptor has been found to be absent or nonfunctional in a high proportion of breast tumors as a result of LOH and mutation of the gene. In our study, we have examined the effect of increasing expression of M6P/IGF‐IIR on breast cancer cell tumorigenicity. MDA‐MB‐231 breast cancer cells stably transfected with M6P/IGF‐IIR cDNA exhibited not only a greatly reduced ability to form tumors but also a markedly reduced growth rate in nude mice. In vitro, increased M6P/IGF‐IIR expression resulted in 2‐fold reduced uptake of IGF‐II and was associated with reduced cellular invasiness and motility. Cells with increased M6P/IGF‐IIR expression exhibited reduced phosphorylation of IGF‐I receptor and p44/42 MAPK compared to vector transfectants, or wild‐type MDA‐MB‐231 cells. These results therefore suggest that M6P/IGF‐IIR levels can modulate breast cancer cell tumorigenicity by a mechanism that may involve altered IGF‐I receptor signaling. © 2003 Wiley‐Liss, Inc.
Suppression of peritoneal dissemination through protecting mesothelial cells from retraction by cancer cells
Authors: Hashimoto Shigenari , Takeoka Michiko , Taniguchi Shun'ichiro 
Published: September 2003

AbstractIn a previous study, we demonstrated that calponin h1 suppressed tumor growth of transformed cells and that the peritonitis carcinomatosa induced by mouse B16‐F10 melanoma (F10) cells was more extensive in calponin h1‐deficient (CN−/−) mice with fragility of mesothelial (MS) cells than in their calponin h1‐wild (CN+/+) counterparts. In our study, we assessed the therapeutic effect of calponin h1 on peritoneal dissemination. F10 cells were overlaid on the cultured CN+/+ or CN−/− MS cells and the effect of calponin h1 on retraction of MS cells was evaluated. Then, an adenoviral vector with the calponin h1 gene (AdGFP‐CN) inserted was constructed and was applied to CN−/− MS cells or CN−/− mouse peritoneum to investigate its suppressive effect on the peritoneal dissemination caused by F10 cells. Greater retraction and invasion of F10 cells were observed in CN−/− MS than in CN+/+ cells in vitro, while down‐regulation of calponin h1 was observed in CN+/+ MS cells prior to the invasion of F10 cells. Infecting CN−/− MS cells with AdGFP‐CN prevented their retraction and the invasion of F10 cells. Peritoneal dissemination was prominently suppressed in AdGFP‐CN‐infected CN−/− mice, and the survival of those mice was significantly prolonged. Thus, calponin h1 functioned to protect host MS cells from the invasion of F10 cells. © 2003 Wiley‐Liss, Inc.
Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers
Authors: Zöchbauer‐Müller Sabine , Lam Stephen , Toyooka Shinichi , Virmani Arvind K. , Toyooka Kiyomi O. , Seidl Sonja , Minna John D. , Gazdar Adi F. 
Published: September 2003

AbstractAn important method for silencing tumor suppressor genes in cancers is by aberrant methylation (referred to as methylation) of CpG islands in gene promoter regions. In lung cancer, methylation of the genes retinoic acid receptor β‐2 (RARβ‐2), CDH13 (H‐cadherin), p16INK4a (p16), RASSF1A (RAS association domain family I) is frequent. Thus, we investigated methylation of these genes in 4 different types of specimens (oropharyngeal brushes, sputum samples, bronchial brushes and bronchioloalveolar lavage [BAL] samples) of the upper aerodigestive tract epithelium from heavy smokers without evidence of cancer but with morphometric evidence of sputum atypia and compared the frequencies of methylation in the different types of specimens. In addition, we also analyzed sputum samples from 30 never smokers for methylation of these genes. Our major findings are: (i) At least one gene was methylated in one or more specimens from 48% of the smokers. However, methylation was statistically significant less frequently in never smokers compared to smokers. (ii) In general, methylation occurred more frequently in samples from the central airways (sputum, bronchial brushes) compared to the peripheral airways (BAL) and only occasionally in the oropharynx. (iii) RARβ‐2 was the most frequently methylated gene, whereas the frequency of methylation for the other genes was lower. (iv) Data from sputum samples and bronchial brushes were comparable. Our findings suggest that detection of methylation should be investigated as an intermediate marker for lung cancer risk assessment and response to chemopreventive regimens. © 2003 Wiley‐Liss, Inc.