bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B40: Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk
Authors: Chen Meng , Cassidy Adrian , Gu Jian , Yang Hushan , Lin Jie , Ye Yuanqing , Hildebrandt Michelle , Dinney Colin , Wu Xifeng
Published: May 2012

B40

Bladder cancer is a complex disease involving multiple genes interacting with each other and/or with environment factors in the tumorigenesis process. We examined 245 SNPs of 22 genes of PI3K-AKT-mTOR pathway which is an essential cellular pathway controlling cell growth, proliferation and survival. We used a case-control design with 803 cases and 803 controls systematically evaluate single nucleotide polymorphisms (SNPs) in this pathway as predicators of bladder cancer risk, in close interaction with environmental factors. In individual SNP analysis, increased bladder cancer risk was significantly associated with 20 SNPs (AKT3: rs12045585, RHEB: rs1920978, RPS6KA5: rs8018757, IRS2: rs9515120, TSC2: rs2073636 and rs8063461, and Raptor: rs11653499, rs9890502, rs8071015, rs7211818, rs9915378, rs9674559, rs7208536, rs7219896, rs4969444, rs2672890, rs7212142, rs9897968, rs2271608, and rs1062935) adjusting by age, gender and smoking status using logistic regression. We grouped the unfavorable SNPs into four categories based on the distribution of the control. Compared to the reference group, the second, third and fourth category showed 1.01 (95%CI: 0.76-1.34), 1.16 (95%CI: 0.89-1.50), and significantly 1.53 (95%CI: 1.14-2.07, P=0.005) fold increased risk of bladder cancer respectively (P for the trend: <0.0001). Classification and regression tree (CART) analysis was performed to explore the high order gene-gene and gene-environment interaction. Further stratification, haplotype and diplotype analysis are still ongoing. This is the first study to address the role of germline genetic variation in this pathway as cancer susceptibility factors. The identification of novel genetic susceptibility markers for bladder cancer etiology will not only help understand the biology of bladder carcinogenesis, but also help identify high risk individuals for bladder cancer. These findings warrant further replication in independent populations.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B40.
Abstract B41: Serum MIS and breast cancer risk
Authors: Dorgan Joanne , Stanczyk Frank , Egleston Brian , Shaw Christiana , Kahle Lisa , Spittle Cynthia , Adams Gregory , Brinton Louise
Published: May 2012

B41

Mullerian inhibiting substance (MIS) is a member of the transforming growth factor β family of growth and differentiation factors known primarily for its role in regulating in-utero sexual differentiation of males. In the female breast, MIS inhibits elongation and branching of mammary ducts. In vitro and in animal models, MIS inhibits growth of mammary tumors. Thus, we hypothesized that MIS may be a novel biomarker of decreased breast cancer risk. The objective of this study was to prospectively determine if MIS levels in serum are related to breast cancer risk. A case-control study was performed nested in the Columbia, Missouri Serum Bank. Each of 129 cases with prediagnostic serum collected before menopause were matched to 2 controls on age, date, menstrual cycle day, and time of day of blood collection. MIS was measured in serum by ELISA. Data analysis was performed using conditional logistic regression. Contrary to expectations, results of preliminary analysis indicate that premenopausal women with elevated serum MIS levels are at an increased risk of breast cancer. Median MIS concentrations in cases and controls were .3 ng/ml and .1 ng/ml, respectively (p=.002). Women in the highest MIS quartile had a RR = 6.6 (95% CI = 2.5 - 17.4; trend-p <.0001). Tests for interaction with OC use were significant. In analysis restricted to women not taking OC’s (117 matched sets) the comparable RR=4.3 (95% CI = 1.5 - 12.1; trend-p=.006). Adjustment for serum estradiol and testosterone concentrations did not materially alter results. MIS could increase breast cancer risk via direct effects on the breast or correlation with other ovarian hormones associated with risk. MIS declines with ovarian aging and women with higher MIS levels may have a later age of menopause contributing to their increased breast cancer risk. Further research on the association of MIS with breast cancer is clearly needed.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B41.
Abstract B57: UBE3A (E6AP) auto antibodies in hepatocellular carcinoma
Authors: Gebreselassie Daniel , Lan R. , Loffredo C. , Goldman R. , Abdel-Hamid M.
Published: May 2012

B57

UBE3A (E6AP) auto antibodies in hepatocellular carcinoma

1Gebreselassie, D., 1Lan, R., 1Loffredo, C.A., 2Abdel-Hamid, M., 1Goldman, R.

1Lombardi Comprehensive Cancer Center Georgetown University Washington, D.C. & 2National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt

Patients with cancer produce auto antibodies that could serve as biomarkers for detection and classification of the disease. To identify auto antibodies associated with hepatocellular carcinoma (HCC), we used a protein array of 5,000 human proteins (Invitrogen) to compare sera of ten cancer free controls and ten patients with HCC matched on age, gender, and viral infection. Thirty six proteins significantly associated with HCC (p<0.05) were spotted on a custom array. The array experiments confirmed increased auto antibodies in HCC for 20 of the 36 candidates. The frequency of increase was as high as 45% for some of the auto antibodies in a comparison of 20 HCC cases and 10 matched controls. To further validate the observed auto antibody response to Ubiquitin protein ligase E3A (UBE3A), we fused cDNA for the protein, with an N-terminal FLAG tag and an enzyme reporter gene, humanized Renilla luciferase (hRluc). The construct was expressed in the Cos-1 mammalian cell line and crude cell lysates were used for quantification of auto antibodies in serum of the same individuals used in the protein array experiment. The assay is based on immunoprecipitation (IP) of the antigenic protein-construct on protein G beads followed by the quantification of hRluc chemiluminescence. Antibodies to the FLAG tag and the antigen of interest were used to optimize the assay. We found that HCC patient sera contain significantly elevated auto antibodies to UBE3A (t-test P<0.01). The autoantibody response to UBE3A was observed in approximately 20% of the HCC patients and correlates with the results of the protein array experiment.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B57.
Abstract B6: Vegetable and fruit intakes and risk of Barrett’s esophagus in men and women
Authors: Thompson Olivia , Beresford Shirley , Kirk Elizabeth , Vaughan Thomas
Published: May 2012

B6

Background

Barrett’s esophagus (BE) is a risk factor for esophageal adenocarcinoma (EA). Modifiable risk factors for BE are largely unknown.

Objective

The purpose of this study was to determine if vegetable and fruit intakes were associated with BE risk.

Design

In a case-control study based in western Washington State, we compared the vegetable and fruit intakes of 170 patients newly diagnosed with BE to those of 182 controls from the general population. Relationships between vegetable and fruit intakes and BE were examined using unconditional logistic regression to compute odds ratios (ORs) and corresponding 95% confidence intervals (CIs).

Results

Participants in the second and third tertiles of vegetable intake appeared to be at lowered BE risk (multivariate-adjusted OR=0.40 (95% CI=0.22, 0.74); OR=0.35 (95% CI=0.18, 0.70) respectively; Ptrend=0.047) compared to participants in the first tertile of vegetable intake. Similarly, participants in the second and third tertiles of combined vegetable and fruit intake were at lowered BE risk (multivariate-adjusted OR=0.53 (95% CI=0.29, 0.96); OR=0.47 (95% CI=0.24, 0.93) respectively; Ptrend=0.094) compared to participants in the first tertile of vegetable and fruit intake. Similar results were obtained in subanalyses limited to BE cases with visible and with long-segment BE.

Conclusions

Data from our study support that increased intakes of vegetables and vegetables and fruits are associated with lowered risks of BE in men and women. Prospective data that examine relationships between diet and BE are needed.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B6.
Abstract B62: Estrogen receptors interacting proteins and female lung cancer prognosis
Authors: Zhukov Tatyana
Published: May 2012

B62

Introduction

The lung cancer death rate in women has doubled over the past 25 years, while the male lung cancer death rate has continued to decline. Although several lines of evidence suggest that women may be more susceptible to develop tobacco-induced lung cancer than men, we lack definitive results related to gender disparity in lung cancer survival. We hypothesize that estrogen through interaction with estrogen receptors (ERs) may mediate the centrosome amplification and affect their function. Potentially, centrosome abnormalities may lead to chromosomal instability and female lung cancer progression, that might be the reason for gender differences in lung cancer survival.

Materials and Methods

The NSCLC lung tumor specimens from male and female patients treated surgically at the Moffitt Cancer Center between 2000 and 2005 were used in this study.We developed quantitative methods for detection of centosome abnormalities and expression of γ- tubulin and Aurora A (markers of centrosome amplification) in archived tissue specimens and in lung cancer cell lines. We detected centosome markers and ER with immunocyto- histolabeling and assessed marker expression at sub-cellular locations, using bright field and confocal microscopy. Centrosomes are apical to the nucleus and appear to colocalize with ERα signal.

Results

We have found promising novel data on interaction of ERα, MUC1 and γ- tubulin and Aurora A. We observed significant increases in expression of ERα and centrosome markers in a subgroups of malignant tumors compared to normal adjacent lung. Co-localization experiments on cell culture encourage us to consider centrosome modification as the downstream effect of estrogen modification in lung cancer.

Conclusion

Correlation analysis of clinical data on differential lung cancer survival (after adjustment for patient’s gender, age, race, histology type, tumor stage at diagnosis, follow-up for recurrence and smoking history) with criteria of centrosome abnormalities is underway. These data may open a new way to look on mechanisms of chromosomal instability under estrogen control in female lung cancer progression, and introduce an attractive, novel therapeutic target.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B62.
Abstract B68: Emblica officinalis, a citrus flavonone, protects against radiation-induced chromosomal damage in Swiss albino mice bone marrow
Authors: Sharma Abhilasha , Soyal Dhanraj , Singh Inder , Sharma Nidhi , Goyal P.
Published: May 2012

B68

Free radicals are responsible for the induction of damage to the cellular DNA that leads to the formation of chromosome aberrations.

Antioxidants are known to scavenge free radicals,thereby decreasing the degree of such effects.Radiation is a well-known inducer of free radicals and compounds that can scavenge free radicals may reduce radiation-induced DNA damage. Emblica officinalis (Amla) a bioflavonoid predominant in citrus fruits, has been found to scavenge free radicals, therefore it may also reduce radiation-induced damage. The aim of the present study was to evaluate the radioprotection action of 100 mg/kg Emblica in the bone marrow of mice exposed to different doses of Co60 gamma radiation by scoring the frequency of asymmetrical chromosomal aberrations.The irradiation of mice resulted in a dose-dependent elevation in the frequencey of aberrent cells, acentric fragments,chromatid and chromosome breaks, dicentric and exchanges. All these aberrations were elevated with scoring time up to 24 hour post irradiation and declined thereafter, except chromatid breaks,which were maximum at 12 hour post-irradiation. Treatment of mice with 100 mg/kg b.wt. Emblica officinalis before exposure to various doses of gamma radiation resulted in a significant reduction in the frequencies of aberrent cells and chromosomal aderrations like acentric fragments,chromatid and chromosomal breaks, centric rings, dicentrics, and exchanges. The evaluation of free radical scavenging activity of Emblica officinalis revealed a dose-dependent scavenging of hydroxyal,superoxide and 2,2'-diphenyl-1-picrylhydrazyl radical.Our study demonstrates that Emblica officinalis can protects mouse bone marrow cells against radiation-induced chromosomal damage.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B68.
Abstract B72: Cancer chemopreventive potential of henna
Authors: Kapadia Govind , Sridhar Rajagopalan , Konoshima Takao , Takayasu Junko , Takasaki Midori , Tokuda Harukuni
Published: May 2012

B72

“Henna” is a powder of the leaves of Lawsonia inermis L. This powder is used mainly as a pigment for coloring skin, hair, fingernails, leather, silk and wool. The anticancer potential of henna powder was evaluated using in vitro and in vivo assays. Henna inhibited tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) - induced activation of Epstein-Barr virus early antigen in lymphoblastoid Raji cells. This indicated the anticancer potential of henna powder. The activity of henna powder was also studied in the ultraviolet B light (280-320 nm wavelength, 34.3 kJ/m2) - initiated and TPA- promoted two stage mouse skin carcinogenesis model. Topical application of a suspension of henna (0.5 mg/ml acetone) decreased tumor incidence in this model system by 70% and tumor multiplicity by 40% at ten weeks of treatment. Lawsone and its precursors 1, 2, 4-trihydroxynaphthalene-1,4-di-beta-glucopyranoside and 1, 2-dihydroxy-4-O-glucosyloxynaphthalene may be the pharmacologically active compounds in henna. In the present study lawsone inhibited TPA-induced activation of Epstein-Barr virus early antigen by 94%. The cancer inhibitory effect of topically applied henna powder was further demonstrated in the peroxynitrite (PN) -initiated and TPA - promoted two stage mouse skin carcinogenesis model system. In this model system, henna decreased tumor incidence by 55% and tumor multiplicity by 57% at 11 weeks of treatment. These data suggest that henna powder as well as its major coloring pigment, lawsone and/or its precursors may be useful as cancer preventive agents. The ability of lawsone and its precursors to perturb electron transfer reactions and free radical processes may partially account for their cancer preventive effects.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B72.
Abstract CN11-02: Cultural considerations in outcomes among prostate cancer patients
Authors: Halbert Chanita Hughes , Weathers Benita , Delmoor Ernestine , Mahler Brandon , Coyne James
Published: May 2012

CN11-02

Increasingly, cultural beliefs and values are being recognized as important to outcomes following cancer diagnosis. Although the way in which cultural beliefs and values are evaluated has implications for support programs that are developed to enhance survivorship, it is not known if cultural factors are best conceptualized as moderators or mediators of racial differences in psychological behaviors following prostate cancer diagnosis. Therefore, the purpose of this study was to determine if religiosity acted as a moderator or mediator of racial differences in coping efforts following prostate cancer diagnosis. Subjects were 224 African American and white men who were newly diagnosed with prostate cancer. Coping efforts and cultural factors were evaluated during a structured telephone interview. Overall, there were racial differences in religiosity (p=0.0001) and utilization of religious and spiritual coping (p=0.0001). African American men reported significantly greater levels of religiosity compared to white men and were most likely to use religion and spirituality to cope with their diagnosis. In the moderator analysis, the interaction between race and religiosity was not significant (p=0.22). However, in the mediation analysis, the effect for race became non-significant (p=0.36) when religiosity was entered into the model. Religiosity had a significant effect on religious and coping efforts (p=0.0001) in the final model; men with greater religiosity were most likely to use these strategies to cope with their diagnosis. These findings suggest that religiosity is not likely to be important to coping efforts only among African American men; rather, these beliefs and values are likely to influence how both African American and white men cope with their prostate cancer diagnosis.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN11-02.
Abstract CN14-01: A genome-wide association study identifies variation in nicotine acetylcholine receptors that influence risk for lung cancer and smoking behavior
Authors: Amos Christopher , Spitz Margaret , Wu Xifeng , Gorlov Ivan
Published: May 2012

CN14-01

In order to identify genetic factors that influence risk for developing lung cancer wer performed a genome-wide analysis using 315,450 SNPs queried on 1154 lung cancer cases and 1137 controls. Results from this analysis and follow-up studies involving 2714 lung cancer cases and 3694 controls identified a region on chromosome 15q that contains nicotinic acetylcholine genes as showing an extremely consistent and significant association with lung cancer risk. The genes that are implicated in this region play a role in signal transduction after exposure to nicotine or its metabolites. The associated SNPs were shown by us and others to play a role in smoking behavior, but further detailed analyses have demonstrated an independent effect of this locus on lung cancer risk beyond that which can be explained solely by smoking behavior. These findings support earlier biological studies suggesting a direct role of nicotine or its metabolites in promoting lung cancer development. Variations in the SNPs on chromosome 15 do not associate with lung cancer risk in nonsmokers, indicating a gene-environment interaction. Studies including cases with a family history of lung cancer show a higher risk for lung cancer in this subset of individuals. In a further study, 9531 lung cancer cases and 9674 controls have been queried to identify additional genetic factors that reliably increase lung cancer risk and additional loci on chromosomes 6 and 5 have been identified.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN14-01.
Abstract CN14-02: Proteomics strategies for lung cancer diagnostics
Authors: Massion Pierre
Published: May 2012

CN14-02

Proteomics strategies for lung cancer diagnostics

Pierre P. Massion, MD

Vanderbilt University Medical Center

To address the lung cancer epidemic, early detection and chemoprevention strategies are urgently needed. A better understanding of lung carcinogenesis is critical to improve chemoprevention strategies. The study of molecular abnormalities in preinvasive lesions represents one way to address the critical steps of lung tumor development. The identification of molecular events involved in preinvasive lesions progression could lead to clinical studies with new molecular-targeted agents and the development of surrogate biomarkers. Such biomarkers are essential to select high-risk patients, select chemoprevention strategies and monitor drug efficacy. While morphological features of the airway mucosa of high risk individuals are well established, by themselves do not provide a satisfying predictive model of lung cancer development. The hypothesis pursued here is that molecular characteristics of the airway mucosa would provide a powerful tool to classify subjects at high risk for lung cancer and should ultimately personalize the management of lung cancer and reduce the overall mortality associated with this disease. Bronchial specimen obtained from these high risk individuals lead to the report of a series of candidate biomarkers. These markers are being discovered through a series of methodologies advances that include proteomic strategies such as conventional immunhistochemical analyses, antibody arrays, matrix assisted laser desorption ionization mass spectrometry and shotgun proteomics. Advances in the understanding of the molecular biology of preinvasive lesions have helped identify many promising potential markers of early lesions which may lead to new effective biomarkers and chemopreventive strategies in high-risk populations.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN14-02.
Abstract ED02-01: Quantitative mass spectrometry for small molecules and gene mutations
Authors: Groopman John D.
Published: May 2012

ED02-01

Advanced Methods and Technologies for Biomarker Research

In recent years there have been enormous advances in the technologies and methods used to develop and validate biomarkers for use in understanding the etiology and pathogenesis of these diseases. Both genomic and proteomic research strategies have been used to understand cancer etiology, progression and metastasis. At the same time advances in mass spectrometry have helped to discern the continuing role that chemical carcinogens play in many human cancers. Collectively all of these advances in research are contributing to the translation of findings into epidemiology and prevention. This session will explore what our current state of knowledge about these technologies and methods with the goal that this will stimulate translational research in cancer prevention.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED02-01.
Abstract ED05-02: Discovering new drugs to inhibit prostate cancer metastasis
Authors: Bergan Raymond
Published: May 2012

ED05-02

Cancer chemoprevention offers a unique drug discovery opportunity. This is because at its core, chemoprevention involves the interface between pharmacologic agents that induce perturbations in biological systems and early stage cancer biology. The molecular aberrations in early stage cancer are more limited than those in advanced stage cancer. This provides a more permissive environment for understanding the complex relationships between drug, pharmacologic target, and therapeutic result. Thus, agents with therapeutically relevant activity represent important investigative tools that can be used to reveal important underlying biology, to identify new pharmacologic targets, and to develop pathophysiologically relevant models. Initial agents can then serve as starting blocks for new chemical synthesis, and these new compounds in turn can be evaluated for bioactivity in relevant model systems. The same considerations in the field of chemoprevention that facilitate this conventional bench-to-man approach to drug discovery can also be applied to the more novel approach of beginning drug discovery endeavors in man. The impetus for undertaking such an approach stems from the facts that our preclinical models have severe restrictions in emulating the biology in man, that the transition from preclinical to clinical represents a frequent point of failure, that the time to drug approval is not improving, and that the cost of drug discovery continues to rise. With the advent of new methods that permit robust system-wide measurement of cell and molecular parameters on limiting amounts of tissue, a practical barrier to beginning drug discovery efforts in man is now being lifted. Here too, chemoprevention offers a unique opportunity. This is because chemopreventive agent candidates are relatively non-toxic, and because they are tested in well defined risk cohorts. Thus, taken together, it now becomes possible to prospectively administer relatively non-toxic agents to at risk cohorts, and to screen for cell and molecular effects in a target organ harboring a limited spectrum of molecular aberrations. By definition, the resultant findings will have direct relevance to man, as well as to relevant underlying biology. An example of how an integrated approach was pursued by a single research group will be provided, and will serve to highlight the efficiency of interfacing chemoprevention with drug discovery. In particular, a natural product that possesses anti-motility properties has fostered the elucidation of pathways which regulated prostate cancer cell motility, has led to the identification of a pharmacologically relevant target protein, and has provided the chemical scaffold which supported new agent discovery. By coupling administration of the natural product to man, with gene expression profiling of target cells in man, new regulators of prostate cell motility have been identified and then confirmed by in vitro studies.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED05-02.
Abstract ED06-03: Tissue resources for translational research
Authors: Jacobson James
Published: May 2012

ED06-03

Biospecimens are required to support translational research leading to the development of biomarkers and clinical assays. Translational research encompasses projects from biomarker discovery through clinical assay development to ultimate validation of biomarkers and assays for clinical use. Each stage along this translational pathway requires appropriate biospecimens with different levels of annotation. The characteristics of biospecimens needed at each level of biomarker/clinical assay development will be discussed. The Cancer Diagnosis Program and other NCI programs support tissue resources that meet some of the need for biospecimens for translational cancer research. The types of resources available and the challenges of maintaining comprehensive biospecimen resources will be discussed.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED06-03.
Abstract ED08-01: How should we optimize technology to allow personalized medicine?
Authors: Meyskens Frank
Published: May 2012

ED08-01

TECHNOLOGY AND PREVENTION. What type of strategies should be followed to develop useful high technology in the service of preventing cancer in the individual?

There are many useful recommendations that have been suggested : screening, early detection, chemoprevention, but usage is relatively low, expensive in many cases, not without risk and with significant false positive and false negatives . This talk will explore a futuristic paradign that may lead to better results for the individual.

For those who want to be in the right mood for this presentation bring along a glass of red wine(preferably pinor noir) and beforehand read:

Meyskens FL.Jr. Cancer Prevention in the Year 2025: an anticipation. European J Cancer 36:1737-1740,2000.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED08-01.
Abstract ED09-01: Prevention of non-melanoma skin cancer with celecoxib
Authors: Elmets Craig
Published: May 2012

ED09-01

Cutaneous squamous cell and basal cell carcinomas are particularly common malignancies, the most common cause of which is overexposure to solar ultraviolet radiation. While physicians advise patients to apply sunscreens to prevent their occurrence, sunscreens are only modestly effective. In vitro studies and in vivo studies in animal models have suggested that prostaglandins and cyclooxygenase-2 (COX-2) play an important role in the development of non-melanoma skin cancers. In Skh-1 hairless mice, the cyclooxygenase inhibitor celecoxib has been reported to prevent UV-induced skin tumors. In addition, immunohistochemical examination of human actinic keratoses and squamous cell carcinomas has shown that COX-2 expression is increased, whereas expression of this enzyme is not observed in normal skin. In order to determine whether these experimental findings are applicable to humans, we have conducted a phase II/III double blind multicenter placebo controlled clinical trial examining the efficacy and safety of celecoxib in adult patients at risk for actinic keratoses and non-melanoma skin cancers. The studies offer the possibility of additional options for the prevention of this common malignancy.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED09-01.
Abstract PL01-04: The role of regulatory T cells in K-Ras driven lung cancer
Authors: Dennis Phillip
Published: May 2012

PL01-04

Background

K-Ras mutations occur in up to 30% of human lung adenocarcinomas (Salgia and Skarin 1998) and occur almost exclusively in patients with a history of smoking. These mutations confer resistance to commonly used cytotoxic chemotherapies as well as targeted agents (Eberhard, Johnson et al. 2005). In preclinical mouse models of lung cancer, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice (Johnson, Mercer et al. 2001). Inflammation is characteristic of smoking-related lung cancer and preclinical models of K-Ras-driven lung tumorigenesis. Specific components of the inflammatory response such as regulatory T cells (Treg) regulate inflammation and are thought to contribute to tumorigenesis. Because inhibitors of mTOR such as the immunosuppressant rapamycin can prevent K-Ras mediated murine lung tumorigenesis (Wislez, Spencer et al. 2005; Granville, Warfel et al. 2007), we hypothesized that the anti-tumor effects of rapamycin might be related to alterations in lung-associated inflammation.

Methods and Findings

Lung tumorigenesis was studied in three different murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Exposure of A/J mice to the tobacco-carcinogen NNK that causes K-Ras mutations (Belinsky, Devereux et al. 1989) tripled the fraction of lung-associated Treg prior to tumor development. Induction of lung tumors and induction of lung associated Foxp3+ cells by NNK was dose dependent. When administered to achieve trough levels comparable to that in humans, rapamycin prevented the induction of lung associated Foxp3+ cells by NNK, coincident with a 90% decrease in lung tumors. In A/J mice inoculated with syngeneic lung adenocarcinoma cells that were resistant to the anti-proliferative effects of rapamycin, rapamycin neither inhibited tumor growth nor decreased Treg. In contrast, depletion of Treg in inoculated mice using an anti-CD25 antibody prevented lung tumorigenesis by 80%. Transgenic mice that express mutant K-Ras (K-RasLA2) also develop lung tumors with infiltrating Foxp3+ cells, and when K-RasLA2 mice were crossed to genetically engineered mice that bear a loss of function mutation in Foxp3, lung tumorigenesis was inhibited by 75%.

Conclusions

These studies show that Treg are required for K-Ras-mediated lung tumorigenesis, and provide a strong rationale to clinically evaluate rapamycin or other agents that decrease Treg, to determine if decreasing Treg will inhibit K-Ras driven lung cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL01-04.
Abstract PL03-02: Inflammation-driven myeloid-derived suppressor cells: co-opting anti-tumor immunity to promote tumor progression
Authors: Ostrand-Rosenberg Suzanne , Sinha Pratima , Clements Virginia , Bunt Stephanie , Srivastava Minu
Published: May 2012

PL03-02

Inflammation facilitates tumor onset and promotes tumor progression through a variety of mechanisms. One of these mechanisms is by activating myeloid-derived suppressor cells (MDSC), a population of cells that block anti-tumor immunity. MDSC are present in most patients and experimental animals with primary and/or metastatic cancer. They inhibit adaptive anti-tumor immunity by preventing the activation of CD4+ and CD8+ T cells, and by blocking innate immunity by inhibiting natural killer cell cytotoxicity and polarizing immunity towards a tumor-promoting type 2 phenotype. Because of their extreme immune suppressive activity, MDSC will be a significant impediment to active immunotherapy in patients with established malignancies. The accumulation and retention of MDSC are driven by multiple pro-inflammatory factors that arise from chronic inflammation and that are produced by malignant cells and by the tumor microenvironment. Multiple pro-inflammatory mediators, including IL-1β, IL-6, prostaglandin E2 (PGE-2), and the S100A8/A9 proteins, accentuate the accumulation and retention of MDSC in tumor-bearing individuals. IL-1β mediates its effects indirectly, while IL-6, PGE-2, and S100A8/A9 proteins appear to directly interact with MDSC through their respective receptors. In addition to increasing the T cell suppressive activity of MDSC, IL-1β increases the cross-talk between MDSC and macrophages. This cross-talk enhances a type 2 immune response that favors tumor progression by increasing MDSC production of IL-10 and decreasing macrophage production of IL-12. MDSC not only respond to these pro-inflammatory molecules, but they also exacerbate an inflammatory tumor microenvironment by synthesizing and secreting proinflammatory mediators, including the S100A8/A9 proteins. As a result, once induced and activated, MDSC maintain an autocrine feedback loop that sustains their levels in the blood, lymph nodes, and at tumor sites. Multiple approaches are being developed to block the induction/activation of MDSC. Since both IL-1β and S100A8/A9 activate MDSC through the NF-κB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients. (Supported by NIH R01CA84232, RO1CA115880)

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PL03-02.
Abstract PR-1: A randomized factorial trial of vitamins E and C in the prevention of cancer in men: the Physicians' Health Study II
Authors: Buring Julie , Sesso Howard , Gaziano J , the Physicians' Health Study Research Group for
Published: May 2012

PR-1

Background

Basic science and observational studies support a potential role of antioxidants, including vitamins E and C, in the prevention of cancer. Previous trials have suggested a possible benefit of vitamin E, in particular on prostate cancer. Few long-term trials have evaluated vitamin C alone in the prevention of cancer. Despite uncertainty regarding long-term effects, use of vitamin supplementation remains highly prevalent in the US.

Methods

The Physicians’ Health Study II (PHS II) evaluated the roles of supplementation with vitamin E (400 IU every other day) and vitamin C (500 mg daily) on risk of cancer in a randomized, double-blind, placebo-controlled trial of 14,641 U.S. male physicians initially aged ≥50 years. The trial included 1,274 (8.7%) men with prevalent cancer at randomization. The randomized vitamin E and C trial components terminated as scheduled on August 31, 2007, and identification of cancer endpoints that occurred prior to that date will continue through September 30, 2008. The primary endpoint of the vitamin E component was prostate cancer, with total cancer (defined as excluding non-melanoma skin cancer) as a secondary endpoint. For vitamin C, the primary endpoint was total cancer. All endpoints were reviewed and confirmed by an Endpoints Committee of physicians blinded to randomized treatment assignment. High rates of morbidity and mortality follow-up have been maintained in the PHS II.

Results

During a median (interquartile range) follow-up of 7.6 (7.1 to 9.6) years among men with a mean baseline age of 64.3 years, there have been 1,929 cases of cancer, including 1,013 cases of prostate cancer. Based upon preliminary results, those randomized to vitamin E had a relative risk of prostate cancer of 0.95 (490 events in the active group vs. 523 in the placebo group; 95% CI, 0.84-1.07; p=0.39), and a relative risk of total cancer of 1.04 (978 vs 951; 95% confidence interval, 0.95-1.14; p=0.38). For those randomized to vitamin C, the relative risk of total cancer was 1.00 (964 events in the active group, 965 in placebo; 95% CI, 0.92-1.10; p=0.95).

In addition to updating the results above, we will also present the results for other site-specific cancers, as well as analyses that consider the effects of compliance, effect modification by baseline risk factors and baseline cancer, and potential adverse effects.

Conclusion

These preliminary data from a large-scale prevention trial of long duration indicate no beneficial effect of vitamin E supplementation on either prostate or total cancer, nor a beneficial effect of vitamin C supplementation on total cancer. These data will help inform clinical and public health recommendations regarding effects of vitamin E or vitamin C supplementation on risks of total and site-specific cancers.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-1.
Abstract PR-13: Inhibition of chronic colitis-induced carcinogenesis in IL-10 knockout mice by dietary supplementation of black raspberries
Authors: Liao Jie , Chung Yeon Tae , Wang Li-Shu , Yang Allison , Stoner Gary , Yang Guang-Yu
Published: May 2012

PR-13

Epidemiological and experimental studies indicate that inflammation is associated with the development of colon cancer. For example, it is known that patients with ulcerative colitis have an increased incidence of colon cancer, and anti-inflammatory drugs and bioactive food components that suppress colonic inflammation reduce the risk of colon cancer. IL-10 is an important regulatory anti-inflammatory cytokine associated with the development of colonic colitis. 100% of IL-10 knockout (KO) mice develop colitis after 3 months of age; histopathology reveals transmural inflammation, predominantly in the cecum. We have shown that the administration of a diet containing twice the recommended amount of iron leads to the development of colonic adenocarcinoma in more than 80% of IL-10 KO mice within 5 months. In the present study, we evaluated the effects of a dietary supplementation of black raspberries on spontaneous colitis-induced carcinogenesis in IL-10 KO mice. Beginning at 4 weeks of age, mice were administered black raspberry powder in AIN-93G diet at concentrations of 5% and 10% until termination of the experiment at 23 weeks. The colorectal tumor incidence in IL-10 KO mice fed control AIN-93G diet was 71.4% (10/14 mice with tumors). Significant reductions in colonic tumor incidence [38% (5/13 mice) and 30.8% (4/13 mice)] were observed in mice receiving 5% and 10% black raspberry diets, respectively. Histopathologic analysis of chronic inflammatory activity in the colon showed that the berries significantly inhibited the overall inflammatory index, including the extent of inflammation, ulcer formation and epithelial hyperplasia. Mechanistic studies suggest that inhibition of colitis-associated carcinogenesis by dietary berries might relate to their effects on modulation of myeloperoxidase-labeled inflammatory cells, nitro-oxidative stress, and cell proliferation. We conclude that black raspberries, as a food-based prevention agent, have potential for the prevention of inflammation-related carcinogenesis in the colon. (Supported by NIH grants R01-CA104741 and -CA103180).

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-13.
Abstract PR-7: A European genome-wide association study of urinary bladder cancer
Authors: Kiemeney Lambertus , Thorlacius Steinunn , Sulem Patrick , Geller Frank , Aben Katja , Kiltie Anne , Bishop Timothy , Matullo Giuseppe , Vineis Paolo , Porru Stefano , Zeegers Maurice , Buntinx Frank , Kumar Rajiv , Fletcher Tony , Koppova Kvetoslava , Rudnai Peter , Gurzau Eugene , Steineck Gunnar , Mayordomo Jose , Gulcher Jeffrey , Thorsteinsdottir Unnur , Kong Augustine , Rafnar Thorunn , Stefansson Kari
Published: May 2012

PR-7

We conducted a genome-wide SNP association study on 1,803

urinary bladder cancer (UBC) cases and 34,336 controls from

Iceland and the Netherlands using Illumina HumanHap300 and HumanCNV370-duo Beadchips. The 10 most significant SNPs were genotyped using Centaurus single track assays in 7 follow up case-control groups (2,165 cases and 3,800 controls) from Italy (Torino and Brescia), the UK, Belgium, Eastern Europe (Hungary, Romania and Slovakia), Sweden and Spain.

The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10-12). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on 3q28 (allele-specific OR = 1.19; P = 1.15 x 10-7).

No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. Individuals with low risk tumors (i.e. confined to the bladder mucosa and not poorly differentiated) had a higher frequency of rs9642880[T] than individuals with high risk tumors (OR = 1.15, P = 0.011). No difference was found in the frequencies of rs9642880[T] between ever-smoking and never-smoking cases.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-7.
Abstract A109: Intake of polyunsaturated fatty acids and distal large bowel cancer risk in whites and African Americans
Authors: Kim Sangmi , Sandler Dale P. , Galanko Joseph A. , Martin Christopher , Sandler Robert S.
Published: May 2012

Experimental and clinical data suggest anti-neoplastic properties of long-chain ω-3 polyunsaturated fatty acids in the colon. Epidemiologic evidence is inconclusive. We examined the association between intakes of different polyunsaturated fatty acids and distal large bowel cancer in a population-based case-control study of 1,509 whites (716 cases and 787 controls) and 369 African Americans (213 cases and 156 controls) in North Carolina (2001–2006). Dietary intake of 19 different polyunsaturated fatty acids was assessed using a validated food frequency questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for distal large bowel cancer risk in relation to quartiles of polyunsaturated fatty acid intake. Increased consumption of long-chain ω-3 fatty acids was associated with reduced risk of distal large bowel cancer. Compared to the lowest quartile, the multivariable odds ratios for the second, third and highest quartile were: OR=0.96 (95% CI: 0.71–1.31), OR=0.75 (95% CI: 0.54–1.04), and OR=0.61 (95% CI: 0.44–0.86), respectively; P for trend<0.01). Intake of individual eicosapentanoic acids and docosahexanoic acids was similarly inversely related to distal large bowel cancer risk, whereas the ratio of ω-6 to long-chain ω-3 fatty acids was associated with increased risk of distal large bowel cancer. These associations were limited to whites, and not observed among African Americans (likelihood ratio test for interaction p<0.01). There was no evidence of effect measure modification by nonsteroidal anti-inflammatory drug use, obesity, or tumor location. Our results support the hypothesis that long-chain ω-3 polyunsaturated fatty acids have beneficial effects in colorectal carcinogenesis. Whether or not the possible benefit of long-chain ω-3 fatty acids varies by race warrants further evaluation.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A109.
Abstract A118: The impact of participating in a team sport versus a group physical activity program on group cohesion in cancer survivors
Authors: Carter Cindy L. , Onicescu Georgiana , Cartmell Kathleen B. , Sterba Katherine R. , Tomsic Jim , Dunmeyer Erica , Taylor Chrissy , Fox Todd , Alberg Anthony J.
Published: May 2012

Objectives: Being a member of a cohesive group could provide a source of high-quality social support that could positively impact the quality of life in cancer survivors. In a nonrandomized trial, we compared group cohesion in a team-oriented (dragon boat paddling team) and non-team-oriented (group walking program) group physical activity intervention. We hypothesized that group cohesion would be stronger among those who participated in the team-oriented dragon boat paddling team compared to the group walking program.

Participants and Methods: 122/134 (91%) of participants who enrolled in the study completed the eight-week physical activity programs, dragon boat paddling team (n=68) or group walking program (n=54). Group cohesion was measured post-intervention using a modified 11 item version of the Group Environment Questionnaire. We tested differences in median cohesion scores between paddlers and walkers using the Wilcoxon Rank Sum test, a nonparametric equivalent of the t-test which is robust to deviations from the normality assumption.

Results: Following completion of the group physical activity program, the median group cohesion score for paddlers was statistically significantly higher than for walkers (paddlers=4.36, walkers=3.73, p=0.004).

Conclusions: Participating in a team sport was associated with significantly higher group cohesion even in comparison to a group physical activity program that was not team oriented. These novel findings suggest that team-oriented physical activity programs such as dragon boat paddling may provide a greater opportunity for social support through increased group cohesion than a group-based walking program. Future studies should examine the mechanisms underlying these differences and the outcomes associated with increased cohesion. Among cancer survivors, team membership may provide a natural source of social support.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):A118.