bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism‐based selective gelatinase inhibitor
Authors: Bonfil R. Daniel , Sabbota Aaron , Nabha Sanaa , Bernardo M. Margarida , Dong Zhong , Meng Hong , Yamamoto Hamilto , Chinni Sreenivasa R. , Lim Int Taek , Chang Mayland , Filetti Lusia C. , Mobashery Shahriar , Cher Michael L. , Fridman Rafael
Published: December 2005

Metastasis to the bone is a major clinical complication in patients with prostate cancer (PC). However, therapeutic options for treatment of PC bone metastasis are limited. Gelatinases are members of the matrix metalloproteinase (MMP) family and have been shown to play a key role in PC metastasis. Herein, we investigated the effect of SB‐3CT, a covalent mechanism‐based MMP inhibitor with high selectivity for gelatinases, in an experimental model of PC bone metastases. Intraperitoneal (i.p.) treatment with SB‐3CT (50 mg/kg) inhibited intraosseous growth of human PC3 cells within the marrow of human fetal femur fragments previously implanted in SCID mice, as demonstrated by histomorphometry and Ki‐67 immunohistochemistry. The anti‐osteolytic effect of SB‐3CT was confirmed by radiographic images. Treatment with SB‐3CT also reduced intratumoral vascular density and bone degradation in the PC3 bone tumors. A direct inhibition of bone marrow endothelial cell invasion and tubule formation in Matrigel by SB‐3CT in vitro was also demonstrated. The use of the highly selective gelatinase inhibitors holds the promise of effective intervention of metastases of PC to the bone. © 2005 Wiley‐Liss, Inc.
LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase‐type plasminogen activator system
Authors: Bagheri‐Yarmand Rozita , Mazumdar Abhijit , Sahin Aysegul A. , Kumar Rakesh
Published: December 2005

Mammalian LIM kinase 1 (LIMK1) phosphorylates and inactivates the actin‐binding and ‐depolymerizing factor cofilin and induces actin cytoskeletal changes. LIMK1 is reported to play an important role in cell motility, but the mechanism of induction of cell motility and the role of LIMK1 in tumor growth, angiogenesis and invasion are poorly understood. Here we show that expression of LIMK1 in MDA‐MB‐435 human breast cancer cells enhanced cell proliferation and cell invasiveness and promoted in vitro angiogenesis. Since tumor metastasis requires degradation of the extracellular matrix by the serine protease urokinase type plasminogen activator (uPA), we examined the role of LIMK1 in the regulation of uPA/uPAR system. LIMK1 overexpression in breast cancer cells upregulated the uPA system, increased uPA promoter activity, induced uPA and uPAR mRNA and protein expression and induced uPA secretion. In contrast, cells transfected with the catalytically inactive LIMK mutant D460N‐LIMK1 did not exhibit these phenotypic changes. Blocking antibodies against uPA and uPAR suppressed LIMK1‐induced cell invasiveness. In addition, LIMK1 overexpression increased tumor growth in female athymic nude mice, promoted tumor angiogenesis and induced metastasis to livers and lungs, possibly by increasing uPA expression in the tumors. Finally, LIMK1 and uPAR were coordinately overexpressed in human breast tumors. These results suggested an important role for LIMK1 signaling in breast cancer tumor growth, angiogenesis and invasion and a regulatory connection between LIMK1 and the uPA system. © 2005 Wiley‐Liss, Inc.
Ectopic expression of neutrophil gelatinase‐associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells
Authors: Lee Ho‐Jeong , Lee Eun‐Kyoung , Lee Kong‐Ju , Hong Soon‐Won , Yoon Yeup , Kim Jang‐Seong
Published: December 2005

Neutrophil gelatinase‐associated lipocalin (NGAL), also known as lipocalin 2, is a 25‐kDa lipocalin initially purified from neutrophil granules. It is thought to play a role in regulating cellular growth since its expression is highly upregulated in a variety of proliferative cells such as cancer cells. However, experimental evidence showing a clear causal relationship between NGAL expression and the proliferation of tumor cells is lacking. Here, we found NGAL expression in highly and poorly metastatic colon cancer cell lines of the same genetic origin correlated inversely with the metastatic potential of these cells, which suggests NGAL participates in the metastatic process. To explore the role NGAL plays in tumor growth and metastasis, the KM12SM human colon cancer cell line, which is highly metastatic while showing decreased NGAL expression, was genetically manipulated to overexpress NGAL. The effects of this on tumor growth and liver metastasis were then analyzed using experimental animal models established by injecting BALB/c nude mice with tumor cells subcutaneously or intrasplenically. Ectopic expression of NGAL in the colon cancer cells had little effect on the growth and viability of the tumor cells both in vitro and in vivo. However, NGAL expression not only suppressed the ability of the colon carcinoma cells to invade Matrigel in vitro, it also substantially inhibited liver metastasis in an experimental animal model. Collectively, these results indicate that NGAL may be a candidate metastasis suppressor in colon cancer cells. © 2005 Wiley‐Liss, Inc.
Lifetime occupational and recreational physical activity and risk of benign prostatic hyperplasia
Authors: Maso Luigino Dal , Zucchetto Antonella , Tavani Alessandra , Montella Maurizio , Ramazzotti Valerio , Polesel Jerry , Bravi Francesca , Talamini Renato , La Vecchia Carlo , Franceschi Silvia
Published: December 2005

To investigate the relation between occupational and recreational physical activity (PA) in different periods of life and the risk of benign prostatic hyperplasia (BPH), we conducted a hospital‐based, case‐control study in Italy. The study included 1,369 histologically confirmed BPH and 1,451 controls, admitted to the same hospitals for acute, nonneoplastic diseases. Odds ratios (ORs) and 95% confidence intervals (CIs) of BPH, according to lifetime PA, were obtained by unconditional multiple logistic regression models, including terms for age, study center and education. Compared to the lowest level of occupational PA, the multivariate ORs for BPH for the heavy/strenuous level were 0.6 (95% CI, 0.4–0.8) at age 15–19, 0.6 (95% CI, 0.4–0.8) at age 30–39 and 0.7 (95% CI, 0.5–0.9) at age 50–59. Moreover, compared to <2 hr/week of recreational PA, the ORs for BPH for the highest level (≥≥5 hr/week) were 0.5 (95% CI, 0.4–0.7) at age 15–19, 0.6 (95% CI, 0.5–0.8) at age 30–39, and 0.7 (95% CI, 0.5–0.8) at age 50–59. All inverse trends in risk were significant, and no heterogeneity was found by reason of BPH‐diagnosis, age at diagnosis, and body mass index (BMI). The inverse association between PA and BPH risk may be due to favorable hormonal correlates of PA, but residual confounding by socioeconomic covariates cannot be excluded. A moderate PA at any ages may help reducing a sizeable number of BPH. © 2005 Wiley‐Liss, Inc.
Selenium binding protein 1 in ovarian cancer
Authors: Huang Kuan‐Chun , Park Dong Choon , Ng Shu‐Kay , Lee Ji Young , Ni Xiaoyan , Ng Wing‐Chung , Bandera Christina A. , Welch William R. , Berkowitz Ross S. , Mok Samuel C. , Ng Shu‐Wing
Published: December 2005

Selenium binding protein 1 (SELENBP1) was identified to be the most significantly down‐regulated protein in ovarian cancer cells by a membrane proteome profiling analysis. SELENBP1 expression levels in 4 normal ovaries, 8 benign ovarian tumors, 12 borderline ovarian tumors and 141 invasive ovarian cancers were analyzed with immunohistochemical assay. SELENBP1 expression was reduced in 87% cases of invasive ovarian cancer (122/141) and was significantly reduced in borderline tumors and invasive cancers (p < 0.001). Cox multivariate analysis within the 141 invasive cancer tissues showed that SELENBP1 expression score was a potential prognostic indicator for unfavorable prognosis of ovarian cancer (hazard ratio [HR], 2.18; 95% CI = 1.22–3.90; p = 0.009). Selenium can disrupt the androgen pathway, which has been implicated in modulating SELENBP1 expression. We investigated the effects of selenium and androgen on normal human ovarian surface epithelial (HOSE) cells and cancer cells. Interestingly, SELENBP1 mRNA and protein levels were reduced by androgen and elevated by selenium treatment in the normal HOSE cells, whereas reversed responses were observed in the ovarian cancer cell lines. These results suggest that changes of SELENBP1 expression in malignant ovarian cancer are an indicator of aberration of selenium/androgen pathways and may reveal prognostic information of ovarian cancer. © 2005 Wiley‐Liss, Inc.
Tumor shedding of laminin binding protein modulates angiostatin production in vitro and interferes with plasmin‐derived inhibition of angiogenesis in aortic ring cultures
Authors: Moss Britney L. , Taubner Lara , Sample Yekaterina K. , Kazmin Dmitri A. , Copié Valérie , Starkey Jean R.
Published: December 2005

The growth of solid tumors is largely controlled by the process of angiogenesis. A 67 kDa protein, the laminin binding protein (LBP), is shed from malignant cells in significant amounts and binds to laminin‐1 (Starkey et al., Cytometry 1999;35:37–47; Karpatová et al., J Cell Biochem 1996;60:226–34). However, the functions of shed LBP are not fully understood. We hypothesize that matrix‐bound LBP could modulate local tumor angiogenesis. In support of this hypothesis, we demonstrate that shed LBP exhibits sulfhydryl oxidase‐like activities, and modifies the production of angiostatins from plasmin in vitro. The molecular weights of the autocatalytic products of lys‐plasmin incubated with LBP in vitro suggest that PMDs (plasmin A chains attached to degraded B chains) (Ohyama et al., Eur J Biochem 2004;271:809–20) are preferentially generated. Using rat aortic ring assays, we also show that shed LBP reverses plasmin‐dependent inhibition of vascular outgrowth. To elucidate which LBP region(s) are active in modulating angiogenesis, limited proteolysis experiments were conducted to determine stable rLBP domains likely to fold correctly, and these were cloned, expressed and purified. The stable LBP fragments were tested for binding to laminin‐1 and for competition with shed LBP activity in the aortic ring assay. Results of these studies suggest that the active LBP domains lie within the 137–230 amino acid sequence, a region known to contain 2 bioactive sequences. Since this fragment binds to laminin‐1 and modulates angiogenesis, it appears likely that binding of shed LBP to matrix laminin‐1 is related to its functions in tumor angiogenesis. The findings presented in this manuscript suggest that LBP shedding could provide a useful therapeutic target. © 2005 Wiley‐Liss, Inc.
Hypoxia inducible factor‐1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response
Authors: Kronblad Åsa , Jirström Karin , Rydén Lisa , Nordenskjöld Bo , Landberg Göran
Published: December 2005

Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor‐1α (HIF‐1α), and HIF‐1α has been associated with an impaired prognosis in breast cancer and down‐regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF‐1α regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF‐1α using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF‐1α was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki‐67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF‐1α expressing tumours. In lymph node‐positive patients as well as NHG 1/2 tumours, high HIF‐1α protein expression was significantly associated with an impaired recurrence‐free survival (p = 0.014, 0.018). When analyzing the subgroup of NHG 1/2 tumours, a high HIF‐1α expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF‐1α might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis. © 2005 Wiley‐Liss, Inc.
Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC–EURGAST)
Authors: González Carlos A. , Pera Guillem , Agudo Antonio , Bueno‐de‐Mesquita H. Bas , Ceroti Marco , Boeing Heiner , Schulz Mandy , Del Giudice Giuseppe , Plebani Mario , Carneiro Fátima , Berrino Franco , Sacerdote Carlotta , Tumino Rosario , Panico Salvatore , Berglund Göran , Simán Henrik , Hallmans Göran , Stenling Roger , Martinez Carmen , Dorronsoro Miren , Barricarte Aurelio , Navarro Carmen , Quiros José R. , Allen Naomi , Key Timothy J. , Bingham Sheila , Day Nicholas E. , Linseisen Jakob , Nagel Gabriele , Overvad Kim , Jensen Majken K. , Olsen Anja , Tjønneland Anne , Büchner Frederike L. , Peeters Petra HM. , Numans Mattijs E. , Clavel‐Chapelon Françoise , Boutron‐Ruault Marie‐Christine , Roukos Dimitrios , Trichopoulou Antonia , Psaltopoulou Theodora , Lund Eiliv , Casagrande Corinne , Slimani Nadia , Jenab Mazda , Riboli Elio
Published: December 2005

It is considered that fruit and vegetable (F&V) protect against oesophagus and gastric cancer (GC). However, 2 recent meta‐analyses suggest that the strength of association on GC seems to be weaker for vegetables than for fruit and weaker in cohort than in case‐control studies. No evidence exists from cohort studies about adenocarcinoma of oesophagus (ACO). In 521,457 men and women participating in the EPIC cohort in 10 European countries, information of diet and lifestyle was collected at baseline. After an average of 6.5 years of follow‐up, a total of 330 GC and 65 ACO, confirmed and classified by a panel of pathologists, was used for the analysis. We examined the relation between F&V intake and GC and ACO. A calibration study in a sub‐sample was used to control diet measurement errors. In a sub‐sample of cases and a random sample of controls, antibodies against Helicobacter pylori (Hp) were measured and interactions with F&V were examined in a nested case‐control study. We observed no association with total vegetable intake or specific groups of vegetables and GC risk, except for the intestinal type, where a negative association is possible regarding total vegetable (calibrated HR 0.66; 95% CI 0.35–1.22 per 100 g increase) and onion and garlic intake (calibrated HR 0.70; 95% CI 0.38–1.29 per 10 g increase). No evidence of association between fresh fruit intake and GC risk was observed. We found a negative but non significant association between citrus fruit intake and the cardia site (calibrated HR 0.77; 95% CI 0.47–1.22 per 100 g increase) while no association was observed with the non‐cardia site. Regarding ACO, we found a non significant negative association for vegetable intake and for citrus intake (calibrated HRs 0.72; 95% CI 0.32–1.64 and 0.77; 95% CI 0.46–1.28 per 100 and 50 g increase, respectively). It seems that Hp infection does not modify the effect of F&V intake. Our study supports a possible protective role of vegetable intake in the intestinal type of GC and the ACO. Citrus fruit consumption may have a role in the protection against cardia GC and ACO. © 2005 Wiley‐Liss, Inc.
Msh2 deficiency increases susceptibility to benzo[a]pyrene‐induced lymphomagenesis
Authors: Zienolddiny Shanbeh , Ryberg David , Svendsrud Debbie H. , Eilertsen Einar , Skaug Vidar , Hewer Alan , Phillips David H. , te Riele Hein , Haugen Aage
Published: December 2005

DNA mismatch repair (MMR) is essential for repair of single‐base mismatches and insertion/deletion loops. MMR proteins also participate in cellular response to DNA damaging agents such as various alkylating agents. Mice deficient in the MMR gene Msh2 develop tumors earlier after exposure to alkylating agents when compared to unexposed mice. The interaction between the MMR system and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (B[a]P) has not been investigated in vivo. Here, we show that treatment of Msh2‐deficient mice with B[a]P enhances susceptibility to lymphomagenesis. Carrying at least one intact copy of the Msh2 gene had a protective effect. B[a]P treatment only induced lymphomas in 3 of the 40 (7.5%) mice with at least one intact copy of the Msh2 gene as compared to 13 of the 17 (76.5%) Msh2‐deficient mice and occurs only after a much longer time period. The B[a]P‐DNA adduct levels measured in lung, liver, spleen and forestomach of B[a]P‐treated Msh2−/− mice were not significantly different from B[a]P‐treated Msh2+/+ mice. In summary, the results suggest that B[a]P accelerates lymphomagenesis in Msh2‐deficient mice. Furthermore, Msh2 deficiency does not have any significant effect on B[a]P‐DNA adduct levels. © 2005 Wiley‐Liss, Inc.
Vitamin E succinate suppresses prostate tumor growth by inducing apoptosis
Authors: Malafa Mokenge P. , Fokum Frida D. , Andoh Jennifer , Neitzel Leslie T. , Bandyopadhyay Sucharita , Zhan Rui , Iiizumi Megumi , Furuta Eiji , Horvath Elizabeth , Watabe Kounosuke
Published: December 2005

Prostate cancer is a major cause of cancer death and morbidity in western countries. However, because of its intrinsic nature of chemoresistance, there is only limited systemic therapy available for the patients. Vitamin E (VE) has been under intensive study as a chemopreventive agent for various types of cancers. Preclinical studies suggest that vitamin E succinate (VES) is the most effective antitumor analogue of VE, yet there are scarce studies of VES in prostate cancer. In this study, we investigated the effects of VES on a panel of prostate cancer cells, and a xenograft model of prostate cancer. Our results indicate that VES significantly inhibited proliferation and induced apoptosis of prostate cancer cell lines in a dose and time dependent manner. The results of microarray analysis followed by real‐time RT‐PCR and inhibitor analyses indicated that the VES‐induced apoptosis is mediated by caspase‐4 in prostate tumor cells. In our animal model of prostate cancer in SCID mouse, daily injection of VES significantly suppressed tumor growth as well as lung metastases. These results suggest a potential therapeutic utility of VES for patients with prostate cancer. © 2005 Wiley‐Liss, Inc.
Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations. Part A. Chemically‐induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors
Authors: Smith Lee P. , Thomas Giovana R.
Published: December 2005

Understanding the complex histological, genetic and molecular changes that lead to malignant transformation of squamous epithelia of the head and neck will likely guide the development of methods for improved diagnosis, monitoring and treatment of head and neck squamous cell carcinoma (HNSCC). The development and use of animal models that closely mimic the histopathology and molecular pathogenesis of HNSCC in humans would greatly expand the research possibilities and provide a means of testing potential therapeutic agents. However, many available animal models of HNSCC fall short of this objective. In order for investigators to select the appropriate model to answer scientific questions, it is important to understand the benefits and limitations of available animal models for the study of HNSCC. The purpose of this work is to give an overview of the most pertinent animal models of HNSCC, and to discuss future directions of research in this field. © 2005 Wiley‐Liss, Inc.
Extra‐tumoral breast tissue in breast cancer patients: Variations with steroid contraceptive use
Authors: Vamre Tone B. Aaman , Stalsberg Helge , Thomas David B. ,   The WHO Collaborative Study of Neoplasia and Steroid Contraceptives
Published: December 2005

The association between oral contraceptive (OC) use and benign breast changes in extra‐tumoral breast tissue was studied histologically in 1,503 breast cancer patients from The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. The occurrence of ductal hyperplasia, ductal atypia, sclerosing adenosis, cysts, apocrine metaplasia, apocrine hyperplasia, apocrine atypia, adenosis, lobular atypia, duct ectasia, calcifications, inflammatory reaction, lactational metaplasia and a high epithelial‐stromal ratio was graded semi‐quantitatively. Prevalence odds ratio (POR) for each histologic variable was calculated by logistic regression analyses. Patients who had ever used OC had lower occurrence of ductal hyperplasia than never users (POR 0.72 (95% CI 0.52–0.99)). Current use and more than 8 years of use was also associated with a lower prevalence of ductal hyperplasia (POR 0.40 (0.20–0.81) and POR 0.33 (0.17–0.64), respectively). Age > 35 years at first use was associated with increased prevalence of ductal carcinoma in situ (POR 2.15 (1.05–4.40)), but not of atypical ductal hyperplasia. Our results show that the effects of OC use on ductal hyperplasia in non‐neoplastic breast tissue of breast cancer patients are similar to what others have found in patients with benign breast disease only. The increased prevalence of extra‐tumoral ductal carcinoma in situ in breast cancer patients who started OC use at high age may possibly be explained by a longer preinvasive phase in these patients. © 2005 Wiley‐Liss, Inc.
Contact of high‐invasive, but not low‐invasive, melanoma cells to native collagen I induces the release of mature cathepsin B
Authors: Klose Anke , Wilbrand‐Hennes Astrid , Zigrino Paola , Weber Ekkehard , Krieg Thomas , Mauch Cornelia , Hunzelmann Nicolas
Published: December 2005

Metastasis of malignant tumor cells involves cell–cell and cell–matrix interactions, which regulate the expression and localization of proteolytic enzymes. In the present study, we investigated the expression and localization of the lysosomal cysteine proteinase cathepsin B and its natural inhibitors cystatin A, B and C in high‐ (MV3), intermediate‐ (SKmel28) and low‐invasive (SKmel23, WM164) human melanoma cell lines grown on plastic or in contact with monomeric or fibrillar collagen type I. Neither the transcript levels of cathepsin B nor those of the natural inhibitors, cystatin B and C, were altered by the interaction of melanoma cells with collagen type I. However, protein expression and cellular localization of cathepsin B and its inhibitors were markedly affected. In contrast to low‐invasive cells, high‐invasive cells constitutively released procathepsin B when cultured on plastic. In addition, contact of invasive cells with fibrillar collagen type I resulted in the release of both mature forms of the protease. Perturbation studies using inhibitory antibodies against the β1 subunit of the integrin receptor indicated a role for the β1 integrin receptor family in the regulation of cathepsin B release. Cystatin B protein expression was much lower in high‐invasive cells in both culture conditions, when compared to low‐invasive cells. Cystatin C expression was comparable in all cells, but cell contact to fibrillar collagen type I induced its expression. These results strongly implicate a pivotal role of cell–matrix interactions for the regulation of cathepsin B localization and activity in melanoma cells. © 2005 Wiley‐Liss, Inc.
BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non‐mucinous colorectal cancer
Authors: Tanaka Hirofumi , Deng Guoren , Matsuzaki Koji , Kakar Sanjay , Kim Grace E. , Miura Soichiro , Sleisenger Marvin H. , Kim Young S.
Published: December 2005

Mucinous colorectal cancer (CRC) has been reported to have distinct clinicopathological and genetic characteristics. However, the incidence and the relationship among microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF and KRAS mutations in mucinous and non‐mucinous CRC are not known. Activating mutations of BRAF and KRAS and their relationship with MSI and CIMP were examined in 83 sporadic CRC specimens (26 mucinous and 57 non‐mucinous CRC). MSI, CIMP, BRAF and KRAS mutation were observed in 17, 24, 25 and 36% of the tumors, respectively. BRAF mutation was highly correlated with MSI (p < 0.001) and CIMP (p < 0.001). A higher incidence of MSI (27% vs. 12%), CIMP (38% vs. 18%, p < 0.05) and BRAF mutation (46% vs. 16%, p < 0.01) was observed in mucinous CRC. KRAS mutation (27% vs. 40%) was observed more frequently in non‐mucinous CRC. Significantly higher percentages of mucinous CRC (54%, p < 0.05) had MSI or CIMP or BRAF mutations. Concordant occurrence of 2 or more of these alterations was observed in 39% of mucinous CRC and only 11% of non‐mucinous CRC (p < 0.01). The more frequent occurrence and closer association among MSI, CIMP and BRAF mutation in mucinous CRC observed in our study further supports the idea that its pathogenesis may involve distinct genetic and epigenetic changes. © 2005 Wiley‐Liss, Inc.
Cancer risk among Finnish food industry workers
Authors: Laakkonen Aarne , Kauppinen Timo , Pukkala Eero
Published: December 2005

Occupational cancer risks suggested among food industry workers are inconclusive. The objective of our study was to assess associations between different cancers and working in the food industry in Finland. The carcinogenic exposures are mainly inhalatory, and we were therefore interested in respiratory cancers in particular. We followed up a cohort of all economically active Finns born between 1906 and 1945 for 30 million person‐years during 1971–95. The 1970 Census data on occupations were linked with data on subsequent incident cancer cases. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated for each occupation using the economically active population as the reference. A total of 2,526 incident cancer cases were observed. Elevated risks were observed among male food industry workers for pancreatic (SIR = 1.50, CI = 1.13–1.96) and kidney cancers (1.51, 1.16–1.94). With respect to specific occupations, there was an excess of lung cancer among female bakers (1.38, 1.01–1.85) and laryngeal cancer among male grain millers (2.60, 1.05–5.36). Occupational exposure is unlikely to be a major risk factor for cancer among Finnish workers employed in typical food industry occupations. © 2005 Wiley‐Liss, Inc.
Alcohol consumption and mammographic density in a multiethnic population
Authors: Maskarinec Gertraud , Takata Yumie , Pagano Ian , Lurie Galina , Wilkens Lynne R. , Kolonel Laurence N.
Published: December 2005

This report examined the association between alcohol intake and breast cancer risk as assessed by mammographic densities in a multiethnic population. Information for this analysis was available from 2 previous investigations: a nutritional intervention study (The Breast, Estrogens, and Nutrition Study; BEAN) with 217 premenopausal women and a nested case‐control study within The Multiethnic Cohort (MEC) with 1,250 primarily postmenopausal women. On the basis of self‐reported alcohol intake from a validated food frequency questionnaire, women were categorized into abstainers (<1 drink/month), low (<1 drink/day) and high (≥1 drink/day) alcohol consumers. On average, 3 mammograms were available per woman. Using mixed models, we calculated mean percent densities for each alcohol consumption category while adjusting for covariates. Mean alcohol intakes for women in the BEAN study and for cases and controls in the MEC study were 2.0, 2.7 and 1.8 drinks/week, respectively. Overall, the difference in densities between abstainers and the highest alcohol intake category was only 1–2% and the differences were not statistically significant. However, the difference was 3–5% for women aged 55–65 years and for breast cancer cases. In postmenopausal women without hormone replacement therapy (HRT), breast density increased by 2% for each higher alcohol intake category. Breast densities were also elevated for high alcohol consumers on estrogen‐only therapy as compared to abstainers and low consumers, whereas combined HRT use was associated with higher mammographic densities independent of alcohol use. In conclusion, despite the low alcohol intake in our population, alcohol consumers had higher percent breast densities than did abstainers. The larger difference in some subgroups suggests that women with certain characteristics may be more susceptible to the influence of alcohol on breast density than others. © 2005 Wiley‐Liss, Inc.
Decreased expression of phosphorylated JNK in breast infiltrating ductal carcinoma is associated with a better overall survival
Authors: Yeh Yao‐Tsung , Hou Ming‐Feng , Chung Yueh‐Fang , Chen Yi‐Jiun , Yang Sheau‐Fang , Chen Da‐Chung , Su Jinu‐Huang , Yuan Shyng‐Shiou F.
Published: December 2005

Phosphorylation/activation of c‐jun NH2‐terminal kinase (JNK) has an ambivalent role, pro‐proliferation or antiproliferation, in human cancers, which is determined by different cell types and by its crosstalk with other kinases. So far, the role of phosphorylated JNK (p‐JNK) in breast cancer is mostly undefined. In this study, we analyzed the expression of p‐JNK, as well as p‐ERK1/2 and p‐38, in the pair of cancer and noncancer breast tissues, by using immunoblotting techniques. These results were further correlated with the clinicopathological characteristics and overall survival. Decreased p‐JNK1/2 expression in cancer tissues was observed in 48.5% of breast infiltrating ductal carcinoma (IDC) cases and was correlated significantly with the increased tumor grade and the decreased age at diagnosis (p = 0.030 and 0.029). Interestingly, the Kaplan–Meier survival curve showed that the decreased p‐JNK1/2 expression was associated with a better overall survival of IDC (p = 0.004). The expression of p‐JNK1/2 was positively correlated with p‐p38 (p = 0.002), but not p‐ERK1/2. Furthermore, co‐expressed p‐JNK1/2 and p‐p38 was associated with a poor overall survival of IDC (p = 0.007). In conclusion, our results indicate that the aberrant p‐JNK1/2 expression and the co‐expressed p‐JNK1/2 and p‐p38 in breast tissues may play a role in the carcinogenesis of breast IDC. © 2005 Wiley‐Liss, Inc.
CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: A population‐based study in Shanghai, China
Authors: Hou Lifang , Xu Jianfeng , Gao Yu‐Tang , Rashid Asif , Zheng Síqun Lilly , Sakoda Lori C. , Shen Ming‐Chang , Wang Bing‐Sheng , Deng Jie , Han Tian‐Quan , Zhang Bai‐He , Meyers Deborah A. , Fraumeni Joseph F. , Hsing Ann W.
Published: December 2005

Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile duct and ampulla of Vater, are rare but highly fatal malignancies. Other than gallstones, little is known about the risk factors for biliary tract cancers. Endogenous estrogens are thought to play a role in the etiology of gallstones and gallbladder cancer, since both conditions predominate in females and are associated with parity and obesity. In view of reports linking the CYP17 MspA1 polymorphism to high circulating levels of estrogens and a predisposition to other hormonally related cancers, we examined the relationship between CYP17 MspA1 variants and risk of biliary disease in a population‐based case‐control study in Shanghai. The study included 446 cancer cases (254 gallbladder, 139 extrahepatic bile duct, 53 ampullary cancers), 929 biliary stone cases (691 gallbladder, 238 bile duct) and 818 population controls. Genomic DNA from peripheral blood lymphocytes was used for genotyping. Relative to those with the A2/A2 genotype, A1 carriers (A1/A1 and A1/A2 genotypes) had an increased risk of gallbladder cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1–2.1). In addition, women with the A1 allele and high parity (≥3) had a 3‐fold risk of gallbladder cancer (OR = 3.3, 95% CI = 1.6–6.9), compared to those with the A2/A2 genotype and lower parity, with the highest risk seen for those also having biliary stones (OR = 4.6, 95% CI = 1.8–11.7, Pinteraction = 0.04). The A1 allele was not associated with a higher risk of gallstones except among those with body mass index (BMI) greater than 25 kg/m2 (OR = 3.1, 95% CI = 2.0–4.8, Pinteraction = 0.02) and among those with a history of diabetes (OR = 2.5, 95% CI = 1.4–4.3, Pinteraction = 0.09). No clear relation was seen between the CYP17 polymorphism and cancers of the bile duct or ampulla of Vater. The association of the CYP17 MspA1 polymorphism with an increased risk of gallbladder cancer, as well as biliary stones among overweight and diabetic individuals, suggests an interplay between genetic and hormonal risk factors in gallbladder disease. © 2005 Wiley‐Liss, Inc.
Monitoring of disseminated tumor cells in bone marrow in high‐risk breast cancer patients treated with high‐dose chemotherapy
Authors: Drageset Vilde , Nesland Jahn M. , Erikstein Bjorn , Skovlund Eva , Sommer Hilde , Anker Gun , Wist Erik , Lundgren Steinar , Bergh Jonas , Kvalheim Gunnar
Published: December 2005

The present study aimed to investigate the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients before and after high‐dose adjuvant chemotherapy with or without progenitor stem‐cell support. One hundred and eighteen high‐risk stage II breast cancer patients entering the Scandinavian Study Group multicenter trial were randomized to 9 cycles of tailored and dose‐escalated FEC (5‐flurouracil, epirubicin, cyclophosphamide) or 3 cycles of standard FEC followed by high‐dose chemotherapy. Bone marrow (BM) samples at diagnosis and 6 months after completion of chemotherapy were assessed for the presence of cytokeratin positive (CK+) cells. Before treatment, 29% of the patients were CK+ (21% in the dose‐escalated group and 36% in the high‐dose‐group). Six months after treatment, 17% of the patients were CK+ (17 and 16% respectively). Of the 95 patients who were evaluated 6 months after treatment, 60% were consistently CK−. CK+ cells in BM was evaluated as a prognostic and predictive marker and compared to other defined prognostic factors of the primary tumor. Monitoring BM changes at the time of diagnosis and 6 months posttreatment is an independent predictive factor for breast‐cancer‐specific survival (BCS) (p = 0.001). Those who have consistent CK negative (−) BM findings constitute a group of patients with good prognosis. Our results suggest that changes in CK+ cells in BM before and after chemotherapy can be used clinically as a surrogate maker to predict outcome in breast cancer patients. © 2005 Wiley‐Liss, Inc.
Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers
Authors: Jung Barbara , Smith E. Julieta , Doctolero Ryan T. , Gervaz Pascal , Alonso Julio C. , Miyai Katsumi , Keku Temitope , Sandler Robert S. , Carethers John M.
Published: December 2005

High‐frequency microsatellite unstable (MSI‐H) colon tumors develop as a consequence of mutations at repetitive sequences in target genes. TGFBR2 and ACVR2, encoding TGFβ superfamily receptors, and the proapoptotic gene BAX are frequent targets for frameshift mutation. We analyzed the effect of these mutations on survival and histology in 2 separate cohorts. Forty‐eight MSI‐H Dukes B2 colon tumors from a cohort of 172 patients had mutations in TGFBR2, BAX and ACVR2 correlated with patient survival. Further, 54 population‐based MSI‐H colon cancers of all stages from a cohort of 503 patients had mutations correlated with tumor stage, grade and size. Of 44 amplifiable MSI‐H Dukes B2 tumors, 70% harbored TGFBR2, 63% BAX and only 4.5% ACVR2 mutations. While mutation alone did not influence survival, concomitant mutation of TGFBR2 and BAX was associated with an improved prognosis in Dukes B2 patients (p = 0.05). ACVR2 mutations were more frequent in the second, population‐based cohort (stage II: 32.5%, p < 0.05). While no target gene mutation correlated with stage in this cohort, poor histological grade and large tumor volume were associated with mutant ACVR2, but not TGFBR2 or BAX mutations, and likely accounts for the lower prevalence of ACVR2 mutations in the first, well‐differentiated Dukes B2 cohort. Because target gene mutations did not correlate with stage, they likely occur early in the pathogenesis of MSI‐H cancers. Mutations in TGFBR2 and BAX may improve survival in MSI‐H Dukes B2 patients, and mutations of ACVR2 may augment histological changes consistent with poor tumor grade that is characteristic of MSI‐H colon cancers, and increase tumor size. © 2005 Wiley‐Liss, Inc.
Cancer incidence in a cohort of Ontario and Quebec women having bilateral breast augmentation
Authors: Brisson Jacques , Holowaty Eric J. , Villeneuve Paul J. , Xie Lin , Ugnat Anne‐Marie , Latulippe Louis , Mao Yang
Published: December 2005

The possibility that women, who receive breast implants for cosmetic purposes, have increased long‐term risks of developing cancer continues to be debated. The objective of our study was to prospectively examine cancer incidence among women who received breast implants. A cohort was assembled of 24,558 women, 18 years of age and older, who underwent bilateral cosmetic breast augmentation, and 15,893 women who underwent other cosmetic procedures in Ontario or Quebec between 1974 and 1989. These plastic surgery patients were selected from the same clinics as the implant population. Incident cancers were identified by linking to Canadian registry data up to December 31, 1997. In total, 676 cancers were identified among women who received breast implants compared to 899 expected based on general population rates (standardized incidence ratio (SIR) = 0.75; 95% confidence interval (CI) = 0.70–0.81). Overall cancer incidence rates among women who received breast implants were similar to that of the other plastic surgery patients (relative risk (RR) = 0.91, 95% CI = 0.81–1.02). However, women who received breast implants had lower breast cancer rates than the plastic surgery patients (RR = 0.64, 95% CI = 0.53–0.79). No increased risks were observed among the implant population for any of the other cancer sites examined. Comparisons involving only women who received breast implants found no association between long‐term breast cancer incidence and implant site (submuscular vs. subglandular), fill (saline vs. silicone) or envelope (polyurethane‐coated or not). In conclusion, women undergoing cosmetic breast augmentation do not appear to be at an increased long‐term risk of developing cancer. © 2005 Wiley‐Liss, Inc.
Near infrared thoracoscopy of tumoral protease activity for improved detection of peripheral lung cancer
Authors: Figueiredo Jose‐Luiz , Alencar Herlen , Weissleder Ralph , Mahmood Umar
Published: December 2005

Improvement in tumor detection using “smart” probes in combination with microcatheter fluorescence thoracoscopy was evaluated in a mouse model. These imaging probes increase in fluorescence intensity after protease activation; cathepsin B is a major activator of the probes used in this study. Lewis lung carcinoma cells were orthotopically implanted in the subpleural lung parenchyma. Two activatable near infrared (NIR) probes with different excitation and emission wavelength were administered intravenously to determine whether wavelength would modulate target to background ratio (TBR). Mice were selectively intubated and thoracoscopy performed. A 0.8 mm outer diameter imaging catheter was used to record simultaneous white‐light (anatomic) and NIR (protease expression) images. At both wavelength pairs evaluated (680/700 and 750/780 nm excitation/emission), the intrinsic luminosity differences between tumors and normal lung in uninjected animals was low (p > 0.3 and p = 0.4, respectively and TBR near 1). In mice receiving protease probes IV, tumors were significantly more fluorescent than adjacent lung (p < 0.0005 for 680/700 and p < 0.006 for 750/780) and TBR increased to approximately 9‐fold. Confirmatory fluorescence microscopy and immunohistochemistry were similar and revealed that normal lung had very low levels when compared to tumors of cathepsin B and probe fluorescence. In conclusion, protease sensitive imaging probes selective for cathepsin B, imaged with NIR microcatheters, significantly increase the TBR, making small peripheral lung tumors more readily apparent. Such an approach may be a useful adjunct in staging or restaging patients with lung cancer to find minimal disease in the pleural and subpleural space. © 2005 Wiley‐Liss, Inc.
Fruit consumption reduces the effect of smoking on bladder cancer risk. The Belgian case control study on bladder cancer
Authors: Kellen Eliane , Zeegers Maurice , Paulussen Aimée , Van Dongen Martien , Buntinx Frank
Published: December 2005

We have hypothesized that consumption of fruit and vegetables may be associated with reduced risk of bladder cancer and that this may interact with cigarette smoking and metabolic genetic polymorphisms. A population‐based case–control study was performed in the Belgian province of Limburg among 200 cases and 385 controls. Logistic regression was performed to calculate odds ratios (ORs) for bladder cancer occurrence with corresponding 95% confidence intervals (95% CI). Effect modification by smoking was investigated. We also evaluated interaction between fruit intake and GSTM1, GSTT1, NAT2 and SULT1A1 amongst “ever‐smokers.” Total vegetable intake was not significantly associated with the risk of bladder cancer (OR 1.15, 95% CI: 0.70–1.88 for the highest compared to the lowest tertile). However, total fruit intake was negatively associated with bladder cancer risk (OR 0.61, 95% CI 0.37–0.99 comparing the same tertiles). Among individuals with low daily fruit consumption, ever smokers had a highly increased risk of bladder cancer risk (OR: 4.23, 95% CI: 1.91–9.40). By increasing the daily fruit consumption, the risk of “ever‐smokers” for developing bladder cancer decreased, however it remained significant (OR: 2.15; 95CI%: 1.15–4.05). No interaction was identified between the different genotypes and fruit consumption. We conclude that fruit consumption may decrease the effect of smoking on developing bladder cancer. Antioxidants, found in fruit, may protect against the damage caused by free radicals found in cigarette smoke. Metabolic polymorphisms appear not to modify this relation. © 2005 Wiley‐Liss, Inc.
Are mammotropic hormones mainly permissive for the development of breast cancer?
Authors: Trichopoulos Dimitrios , Bamia Christina , Lagiou Pagona , Trichopoulou Antonia
Published: December 2005

In a case–control study nested within the Greek EPIC cohort, serum levels of estrone, estradiol, androstenedione, dehydroepiandosterone sulfate, testosterone and IGF‐1 were measured for 29 breast cancer patients and 58 control women, matched for age and menopausal status. There was little difference in breast cancer risk when values of 4–6—as compared to values of 1–3—hormones were elevated, a finding arguing against a positive interaction among these hormones. Breast cancer risk, however, was significantly and substantially lower among women with levels of all hormones below the corresponding age‐ and menopausal‐status‐predicted means, compared to women with levels of at least 1 hormone above the predicted mean (odds ratio = 0.11 with 95% confidence interval 0.01–0.90; p = 0.04). Our results suggest that the studied mammotropic hormones may act as permissive factors for breast cancer occurrence, and that the levels of some of them above the mean suffice for sustaining growth of a developing tumor. A corollary is that studies of mammotropic hormones in relation to breast cancer risk may also need to focus on the lower end of the distributions of these growth‐enhancing hormones. © 2005 Wiley‐Liss, Inc.
The norepinephrine‐driven metastasis development of PC‐3 human prostate cancer cells in BALB/c nude mice is inhibited by β‐blockers
Authors: Palm Daniel , Lang Kerstin , Niggemann Bernd , Drell Theodore L. , Masur Kai , Zaenker Kurt S. , Entschladen Frank
Published: December 2005

The development of metastases is a decisive step in the course of a cancer disease. The detection of metastases in cancer patients is correlated with a poor prognosis, and over 90% of all deaths from cancer are not due to the primary tumor, which often can be successfully treated, but are due to the metastases. Tumor cell migration, a prerequisite for metastasis development, is not merely genetically determined, but is distinctly regulated by signal substances of the environment including chemokines and neurotransmitters. We have shown previously that the migration of breast, prostate, and colon carcinoma cells is enhanced by the stress‐related neurotransmitter norepinephrine in vitro, and that this effect can be inhibited by the β‐blocker propranolol. We now provide for the first time evidence for the in vivo relevance of this neurotransmitter‐driven regulation using PC‐3 prostate carcinoma cells. The development of lumbar lymph node metastases in athymic BALB/c nude mice increased with the application of norepinephrine via microosmotic pumps, while propranolol inhibited this effect. However, the growth of the primary tumor was not affected by either treatment. Additionally, experiments using human tissue microarrays showed that 70–90 percent of breast, colon, and prostate carcinoma tissues express the relevant β2‐adrenoceptor. Thus, our work contributes to the understanding of the basic cellular mechanisms of metastasis development, and furthermore delivers a rationale for the chemopreventive use of clinically established β‐blockers for the inhibition of metastases. © 2005 Wiley‐Liss, Inc.
Combined therapy of an established, highly aggressive breast cancer in mice with paclitaxel and a unique DNA‐based cell vaccine
Authors: Chopra Amla , Kim Tae Sung , O‐Sullivan InSug , Martinez Don , Cohen Edward P.
Published: December 2005

Here, we describe the enhanced benefits of treating a highly aggressive breast cancer in mice with a combination of paclitaxel and immunization with a unique DNA‐based cell vaccine. An adenocarcinoma was isolated from a spontaneous neoplasm that arose in the mammary gland of a C3H/He mouse (H‐2k) (SB5b cells). The vaccine was prepared by transfer of genomic DNA‐fragments (25 kb) from the breast cancer cells into a mouse fibroblast cell line (LM), modified to enhance its immunogenic properties. As the transferred DNA is integrated, and replicated as the recipient cells divide, the vaccine could be prepared from relatively small numbers of cancer cells (107 = 4 mm tumor). SB5b cells were injected into the mammary fat pad of naïve C3H/He mice, which are highly susceptible to the growth of the cancer cells. When the tumors reached ˜3 mm, the mice were injected s.c. with a noncurative dose of paclitaxel. Six days later, when immune competence returned, the mice received the first of 3 weekly s.c. injections of the vaccine. The combined therapy induced robust cellular immunity to the breast cancer, mediated by CD8+ and NK/LAK cells, which resulted in prolonged survival. The immunity was specific, as immunization with a vaccine prepared by transfer of DNA from B16 melanoma cells into the fibroblasts failed to induce immunity to the breast cancer. This type of vaccine raises the possibility that an analogous strategy could be used in the treatment of breast cancer patients at an early stage of the disease. © 2005 Wiley‐Liss, Inc.