bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 87: Differential effects of JNK1 and JNK2 on cell death in hypoxic colon cancer cell lines
Authors: Vasilevskaya Irina A. , Selvakumaran Muthu , Roberts David , O'Dwyer Peter J.
Published: February 2011

BACKGROUND: We previously showed that hypoxic colon cancer cell lines exhibit higher sensitivity to oxaliplatin when SEK1 function is impaired, and greater resistance when MKK7 is down regulated. The MKK7 mutant lines exhibit more profound inhibition of JNK activation than those lacking SEK1, and their effects on the activation of JNK1 and JNK2 differ. The HT29 cells do not die readily by apoptosis under these conditions, and both oxaliplatin and hypoxia induce autophagy in these cells.

PURPOSE: The purpose of this study is to investigate further how modulation of signaling through JNK1 and JNK2 influences cell death pathways in hypoxic HT29 cells treated with oxaliplatin. For that, we employed HT29-derived cell lines stably expressing empty vector (HT.LX) and dominant negative constructs for JNK1 (HTJ1.3) and JNK2 (HTJ2.2).

RESULTS: We observed higher induction and activation of c-Jun in cells with dnJNK1, while introduction of dnJNK2 caused the opposite effect. Resistance to oxaliplatin under hypoxic conditions was also higher in the cell line with lowest c-Jun activation level (IC50 of 2.1 μM for HT.LX, 3 μM for HTJ2.2 and 0.8 μM for HTJ1.3), suggesting a pro-survival role for JNK1 under these conditions. Both oxaliplatin- and hypoxia-induced formation of autophagosomes was reduced significantly in HT29 cells treated with the JNK inhibitor SP600125. We also found differential sensitivity of these cell lines to an inhibitor of autophagy, chloroquine (CQ): HTJ1.3 and HTJ2.2 cell lines were slightly more resistant to CQ under normal conditions, as compared to parental line, but under hypoxia all of the lines demonstrated higher sensitivity to the drug. Notably, in light of the role of JNK1 in activating autophagy, cells with diminished JNK1 activity were the most sensitive to CQ under hypoxia. Moreover, when we treated the cell lines with 5 μM of CQ under hypoxia/reoxygenation, inhibition of autophagy and induction of apoptosis were most significant in dnJNK1-expressing cells. This effect of JNK1 down-regulation is specific to hypoxia, since the constructs do not differ in sensitivity to CQ and oxaliplatin in combination.

CONCLUSIONS: Our data demonstrate the differential effects of JNK1/JNK2 modulation on cell death of hypoxic HT29 cells treated with oxaliplatin or chloroquine, and imply pro-survival function for JNK1 versus JNK2 under these conditions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 87.
Abstract 891: Association of genetic polymorphisms of SIPA1 with breast cancer risk and survival among Chinese women
Authors: Qu Shimian , Cai Hui , Long Jirong , Cai Qiuyin , Courtney Regina , Shu Xiao-Ou , Gao Yu-Tang , Zheng Wei
Published: February 2011

Signal-induced proliferation-associated gene 1 (Sipa1), encodes a GTPase-activating protein (GAP), was identified as a candidate host metastasis-regulatory factor in mice. Several epidemiological studies have shown that SIPA1 may play an important role in breast cancer risk and metastasis with inconsistent results. We evaluated functional single nucleotide polymorphisms (SNPs) in SIPA1 in relation to breast cancer risk and survival in Chinese women. Included in the study were 1,134 cases and 1,234 age frequency-matched community controls that participated in the Shanghai Breast Cancer Study, a large scale population-basd case-control study. Breast cancer patients were followed to determine intervals of overall survival and disease-free survival. Functional SNPs were genotyped using TaqMan assays. Additional SNPs in this gene region, both genotyped and imputed from a genome-wide association study, were also included in the analyses. The SIPA1 polymorphisms were not associated with breast cancer risk. We found SIPA1 polymorphisms were associated with breast cancer overall survival. Patients carrying the GA/AA genotypes in the synonymous exonic SNP rs746429 were associated with a marginally significant poor overall survival (HR =1.2, 95% CI, 0.9-1.6) as compared with the common GG genotype. Furthermore, this association was more evident among patients with an early stage cancer (HR =1.4, 95% CI, 1.0-1.9) than those with a late stage cancer (HR=1.2, 95% CI, 0.7-2.1). Patients carrying the AA genotype of rs3741378, a nonsynonymous exonic SNP, were associated with a better overall survival (HR =0.6, 95% CI, 0.4-1.0) as compared to those with the common GG genotype. We found that the SIPA1 polymorphisms were not associated with disease-free survival. Our findings suggested that common SIPA1 genetic polymorphisms may be associated with breast cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 891.
Abstract 916: Functional significance of sulfotransferase 1A1 polymorphisms in the 3’ untranslated region in determination of enzymatic activity
Authors: Yu Xinfeng , Beggs Marjorie L. , Dhakal Ishwori B. , Zhang Xuemei , Edavana Vineetha Koroth , Williams Suzanne , Mercer Kelly E. , Kadlubar Fred F. , Kadlubar Susan
Published: February 2011

SULT1A1 is the most highly expressed hepatic sulfotransferase and is involved in the biotransformation of a wide variety of endo-and xenobiotics. The inter-individual variation of SULT1A1 enzyme activity can markedly influence drug toxicity and/or treatment efficacy in the clinical setting. We and others have examined a common SNP in the coding region of SULT1A1 (Arg213His, SULT1A1*1/2), as well as several SNPs in the proximal promoter that were associated with altered enzymatic activity. However, the SNPs account for only a small proportion of variation of SULT1A1 activity in human populations. In order to identify SNPs that markedly affect SULT1A1 activity, we resequenced the 3’UTR of SULT1A1 in 97 liver samples. Direct sequencing revealed 2 SNPs (902A>G, 973C>T) in the 3’UTR and 1 SNP (1307G>A) in the 3’ flanking region. Interestingly, we found these SNPs are in absolute linkage disequilibrium and are closely associated with SULT1A1 expression and enzymatic activity. To further elucidate the important role of SNPs in 3’UTR, we performed haplotype analysis to predict the collective effects of functional genetic variants in the 3’ UTR regions, the SULT1A1*1/2 polymorphism and copy number variation on SULT1A1 enzymatic activity. Notably, two major haplotypes (ACGG and GTAA) were significantly correlated with SULT1A1 activity, Copy number did not influence on SULT1A1 activity in liver samples. 3’UTR SNPs are in linkage disequilibrium with SULT1A1*1/2 polymorphism, so to examine the effect of the SULT1A1*1/2 polymorphism, we performed haplotype-activity assay in 499 Caucasian and 129 African American subjects. Haplotype and regression analysis both strongly suggest that the 3’UTR SNPs are the pivotal predictor of SULT1A1 activity. MicroInspector predicts 3116C>T influences the binding of miR-631 to SULT1A1 3’UTR. Furthermore, in vitro luciferase reporter assays and overexpression of miRNA mimics and inhibitors indicated that SULT1A1 is a direct target of miR-631 and miR-631 differentially regulates the C and T alleles of rs1042157. The results suggest, for the first time, that allele-specific regulation of SULT1A1 by miR-631 contributes to the activity variation of SULT1A1 in population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 916.
Abstract 936: Phytoestrogen level modifies the association of ornithine decarboxylase-polyamine pathway related gene polymorphisms and gastric cancer risk
Authors: Cho Lisa Y. , Yang Jae Jeong , Ko Kwang-Pil , Park Boyoung , Shin Aesun , Gwack Jin , Chang Soung Hoon , Shin Hai-Rim , Yoo Keun-Young , Park Sue K.
Published: February 2011

Objective: We investigated the role of single nucleotide polymorphisms (SNP) ODC-polyamine pathway related genes (ODC1, AMD1, OAZ2, NQO1, NOS2A) for gastric cancer risk. Additionally, we examined whether phytoestrogen levels modify the association of ODC-polyamine pathway SNPs and risk of gastric cancer. Materials and Methods: Twenty-five SNPs in five genes were genotyped in 59 incident gastric cancer cases and 175 matched controls recruited from the Korea Multi-Center Cancer Cohort. Candidate genes were selected based on genotype databases, and genotype assay was performed using Goldengate platform (Illumina). We calculated the unadjusted Wald p-value between each SNP and phytoestrogen level, as well as the false discovery rate (FDR) corrected p-values of the 25 SNPs according to each phytoestrogen biomarker. Unconditional logistic regression model was used to calculate the adjusted odds ratios (OR) and 95% CI for smoking history. Results: There was a significant association for NQO1 (rs1800566, rs1437135) and daidzein, AMD1 (rs1279599, rs7768897, rs811921) and equol, AMD1 (rs1279599, rs7768897, rs811921) and enterolactone (FDR p-value<0.2). Conclusion: Certain phytoestrogens and ODC-polyamine related genes polymorphisms may interact to affect development of gastric cancer. Additional studies are needed to further elucidate the gene-environment interaction for gastric cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 936.
Abstract 941: Elucidation of chemopreventive effects of aerosolized rapamycin and dietary myoinositol by mechanistic biomarkers in mouse lung
Authors: Sharma Sheela , Lee Jin , Wong Brian , Sochaski Mark , Dennis Phillip A. , Steele Vernon E.
Published: February 2011

Rapamycin, an approved anti-rejection drug for patients undergoing organ transplantation, has shown antitumor activity in preclinical studies and clinical trials. However, concerns regarding the prevalence of pneumanitis in a small percentage of patients receiving the drug by injection have prompted us to test an alternative route of administration. Myoinositol is another agent that has shown excellent chemopreventive activity both in preclinical and clinical settings and is very well tolerated in humans. The objective of the current study is to investigate whether aerosolized rapamycin or myoinositol fortified diet can inhibit two key biomarkers of lung cancer, activated Akt and mTOR, in lungs and test the feasibility of two dosing regimens (continuous or intermittent dosing) on the same biomarker expression at multiple time points after the last dosing. Female A/J mice (8 wks old) were exposed to 5 different doses of myoinositol (0.01, 0.03, 0.1, 0.3 and 1% diet) or rapamycin by inhalation (0.001, 0.01, 0.1, 1 and 10 mg/kg) continuously for 5 days or every other day for 3 days in two separate experiments. After the last exposure, blood concentration (measured by GC-MS) and effect of each agent on phosphorylated-AKT (phospho-AKT at Thr308) and mTOR (phospho-S6 at Ser235/236) was assessed by immunohistochemistry. There was a good correlation between the dose-dependent increase in blood concentration of myoinositol (20 − 255 μM) or rapamycin (0.033-1.75 μM) and corresponding dose-dependent decrease in the expression of phospho-AKT (21-85%) and mTOR (10-69%) or phospho-AKT (54-60%) and mTOR (28-73%), respectively, in the lung compared to untreated controls. Interestingly, there was no significant difference between the two regimens in reducing the biomarker expression by either myoinositol or rapamycin and the expression levels continued to remain the same for up to 3 days after the last exposure or treatment. No toxicity was observed during or after the exposure and all animals showed normal body weight gain. In conclusion, this study showed that both rapamycin and myoinositol showed significant inhibition of phospho-AKT and phospho-mTOR expression from the basal level (AIN-76A diet control for myoinositol or air control for rapamycin) and that both these agents can be administered intermittently instead of continuously to observe similar effects. In addition, subsequent cancer prevention studies that are planned by administering agents at selected intervals should reduce or eliminate any associated toxicities from long term exposures (Supported by NCI #N01-CN-53301).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 941.
Abstract 942: Effects of maternal and postnatal folic acid supplementation on genomic DNA methylation in the mammary glands in a chemical rat model of mammary tumorigenesis
Authors: Ly Anna , Lee Hanna , Chen Jianmin , Sohn Kyoung-Jin , Sie Karen K. , Croxford Ruth , Renlund Richard , Thompson Lilian , Kim Young-In
Published: February 2011

Background: Widespread loss of genomic DNA methylation is an early and consistent epigenetic event in cancer development including breast carcinogenesis. Folate, an essential co-factor in the transfer of one-carbon units, has been shown to modulate both cancer risk and genomic DNA methylation. We recently observed that folic acid (FA) supplementation provided in utero and in early postnatal life significantly increased risk of mammary tumors in the offspring in the dimethylbenzanthracene (DMBA) rat model. To determine a potential underlying mechanism of FA-mediated mammary tumor development, we investigated the association between global DNA methylation, DNA methyltransferase (DNMT) activity, FA supplementation, and mammary tumor status in the offspring.

Methods: Female Sprague-Dawley rats were placed on a control diet (2 mg FA/kg diet) or a supplemented (5 mg) diet for 3 weeks prior to breeding and throughout pregnancy and lactation. At weaning, female pups were randomized to the control or supplemented diet. At 7 weeks of age, all pups received a single intragastric dose (5 mg) of DMBA to induce mammary tumors. At 28 weeks of age, plasma, mammary gland and liver folate and plasma homocysteine concentrations were determined and mammary tumors were enumerated and histologically confirmed. Genomic DNA methylation and DNMT activity were determined in non-neoplastic mammary glands.

Results: Plasma, liver, and mammary folate and homocysteine concentrations accurately reflected dietary FA levels at weaning and 28 weeks of age (p<0.05). A significant interaction was observed between genomic DNA methylation and mammary adenocarcinoma status in the offspring (p<0.001), indicating that among tumor-free offspring, genomic DNA methylation was significantly decreased by maternal FA supplementation. In addition, in offspring bearing at least one adenocarcinoma, genomic DNA methylation was significantly decreased regardless of dietary FA intervention. Postweaning FA supplementation independently decreased DNMT activity in the offspring (p=0.05).

Conclusions: Our data suggest that decreased genomic DNA methylation and DNMT activity associated with maternal and postweaning FA supplementation might be a mechanism by which maternal and postweaning FA supplementation increased mammary tumorigenesis in the offspring. Given the drastic increase in FA intake among women of childbearing age in North America, future studies are need to determine whether or not FA supplementation increases the risk of breast cancer through epigenetic mechanisms.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 942.
Abstract 953: Benzyl isothiocyanate suppresses pancreatic cancer angiogenesis and invasion by inhibiting Akt and MMP-2
Authors: Boreddy Srinivas Reddy , Pramanik Kartick C. , Kandala Prabodh K. , Srivastava Sanjay K.
Published: February 2011

We have shown in our previous studies that benzyl isothiocyante (BITC) suppress the growth of pancreatic cancer cells by inhibiting the activation of NF-kB and STAT-3 without affecting the viability of normal HPDE cells. Further, we demonstrated that oral administration of BITC significantly blocked the growth of pancreatic tumor xenografts in vivo. In the present study, we examined the effect of BITC on pancreatic cancer angiogenisis and invasion. Our results demonstrate that 5-10µM BITC almost completely blocked neovasculture formation in an ex vivo chick chorio-allantoic membrane (CAM) model. In agreement with these results, in vivo matrigel plug assay in athymic nude mice also reveal that the hemoglobin content in the implanted matrigel plug was reduced by 70% in the mice which were orally fed 12µmol BITC for 7 days as compared to controls, suggesting reduced blood vessel formation. In a matrigel tube formation assay using mouse brain endothelial cells, BITC treatment significantly inhibited VEGF-induced tube formation. As compared to controls, 5µM BITC treatment for 36h caused a drastic reduction in the number of cells that migrated into the wounding area in a wound healing assay. Our results also showed that the tumor cell invasion was effectively (p<0.001) inhibited by 50% in the BxPC-3 cells treated with 10 µM BITC for 24h in a transwell cell invasion assay. Since PI3K, Akt and MMP-2 are critically involved in tumor cell invasion, angiogenesis and metastasis we next evaluated the effect of BITC on these key signaling molecules. As expected, BITC treatment significantly reduced the expression as well as phosphorylation of PI3K at Tyr-458 and Akt at Ser-473 in BxPC-3 cells in a dose-dependent manner. In addition, the expression and mRNA level of MMP-2 was significantly down-regulated by BITC treatment in BxPC-3 cells. Furthermore, tissue inhibitor of metalloproteinases-2 (TIMP-2) level was also reduced by BITC. Taken together, our data strongly suggests the anti-angiogenic and anti-metastatic role of BITC in pancreatic cancer cells and warrants further clinical investigation. [Supported in part by RO1 grants CA 106953 and CA129038 (to SKS) awarded by National Cancer Institute].

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 953.
Abstract 956: Targeting prostate cancer chemoprevention via the androgen receptor in a preclinical mouse model
Authors: Koike Hiroyuki , De Velasco Marco A. , Miyazaki Yuka , Asahi Chiori , Ushida Hiroshi , Shimada Keiji , Yoshikawa Kazuhiro , Nishio Kazuto , Konishi Noboru , Uemura Hirotsugu
Published: February 2011

Prostate cancer is strongly associated with increasing age, with about 96 % of the cases occurring in men over 60 years of age. The high incidence and late age of onset make prostate cancer an ideal target for chemoprevention strategies as even a modest delay in carcinogenesis would significantly reduce the incidence of the disease. Chlormadinone acetate (CA) is one of the steroidal anti-androgen agents used in combined androgen blockade therapy as well as monotherapy for prostate cancer in Japan. However, no reports have been published for the chemopreventive potential of CA. We evaluated the efficacy of low-dose administration of CA to prevent or suppress prostate cancer using our PTEN conditional gene targeting mouse model.

Six-week-old mice were injected subcutaneously with CA (50 mg/kg 3X/week) until the age of 15 or 20 weeks. The genitourinary tracts (GUTs), consisting of the prostate, urethra, bladder, seminal vesicles and coagulating gland, were collected, weighed, fixed in formalin and imaged. GUT weights were significantly lower in CA-treated mice compared to untreated controls in a time dependent manner (P<0.01). Morphometric image analysis performed on the GUT to measure the prostate area revealed significant shrinkage of the prostate gland in CA-treated mice vs. the corresponding controls (P<0.001). Histopathological distribution analysis of normal, prostatic intraepithelial neoplasia (PIN) and tumor glands showed a decrease in the PIN but not normal or cancer glands in 15-week-old CA-treated mice compared to controls. However, similar analysis showed a dramatic decrease of cancer gland shrinkage in 20-week-old CA-treated mice with only marginal decreases of PIN compared to untreated controls. Immunohistochemical analysis of androgen receptor (AR) expression showed a significant decrease in nuclear localization and intensity CA-treated mice (P<0.001). Proliferation analysis of tumors by PCNA immunostaining showed a 30% reduction in 20-week-old mice treated with CA compared to untreated control mice (P<0.001). The apoptotic index in tumors if mice treated with CA increased three-fold to 3.16% compared to 1.12% on the corresponding control mice (P<0.004). Our data suggests that chemopreventive treatment with CA does not prevent the incidence of prostate cancer, however, it does inhibit the growth and progression of prostate cancer. Our findings may reveal a promising prophylactic strategy for the chemopreventive treatment of prostate cancer in high-risk individuals.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 956.
Abstract 957: Dietary flavonols protect against colorectal carcinogenesis in an AOM-DSS mouse model for colorectal cancer
Authors: Bobe Gerd , Young Matthew R. , Kim Young , Colburn Nancy H.
Published: February 2011

Background: Epidemiological studies suggest that a flavonol-rich diet inhibits colorectal carcinogenesis. Flavonols are a subgroup of polyphenols, which are found in fruits and vegetables usually glycosylated and are in particularly high concentrations in dry beans, onions, apples, and tea. The most consumed individual flavonols are in this order quercetin and one of its glycosylated forms rutin, kaempferol, myricetin, and isorhamnetin. Aim: To determine which individual flavonol is most protective against colorectal carcinogenesis in an inflammation-associated mouse colorectal carcinogenesis model (azoxymethane[AOM]/dextran sodium sulfate[DSS]-induced FVB mice). Methods: At 6 weeks of age, mice were injected intraperitoneally with AOM (10 mg/kg body weight). Mice then received for 1 week 2% DSS in the drinking water (1 or 1 and 4 weeks after AOM injection). Three days after the last DSS cycle, mice either remained on the AIN-93G diet or were switched to one enriched with 500 mg of kaempferol or equimolar concentrations of isorhamnetin, myricetin, quercetin, or rutin/kg of diet. Mice (n=32/group) remained for 85 days on the diets unless they had to be sacrificed earlier because of morbidity. A subset of mice was imaged using magnetic resonance imaging (MRI) at various times throughout the study. Results: Among the diets, mice on the control diet had the highest morbidity (50%) and mice on the isorhamnetin diet had the lowest morbidity (22%). Similarly, lesion number and size were lowest in mice on the isorhamnetin (16/mouse and 8.8 mm3/lesion) and the kaempferol (15/mouse and 7.4 mm3/lesion) diet compared to the control diet (21/mouse and 11.6 mm3/lesion). Image parameters detected different stages of colorectal carcinogenesis that can be modified by diet. Conclusion: All individual flavonols showed some protection against colorectal carcinogenesis with isorhamnetin and kaempferol being most efficacious. Studies are underway to identify serum, tissue, and imaging biomarkers of efficacy at earlier stages of colorectal carcinogenesis.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 957.
Abstract 958: Recruitment of tumor-associated macrophages by cooperation of PGE2 pathway and infectious stimulation
Authors: Oshima Hiroko , Oguma Keisuke , Oshima Masanobu
Published: February 2011

Gastric cancer development is tightly associated with Helicobacter infection, which induces expression of COX-2 and mPGES-1 resulting in activation of PGE2 pathway in gastric mucosa. It has been established that PGE2 pathway plays a key role in chronic inflammation and tumorigenesis in the stomach. However, mechanisms of PGE2 or PGE2-induced inflammation underlying tumorigenesis have not been fully understood yet. On the other hand, tumor associated macrophages play an important role in tumorigenesis through expression of growth factors, induction of angiogenesis, remodeling and suppression of acquired immunity. We previously showed that macrophage infiltration was enhanced in K19-C2mE transgenic mouse stomach, in which PGE2 pathway is induced by expression of COX-2 and mPGES-1. Moreover, accumulated macrophages in gastric mucosa were activated, which was suppressed by treatment of the mice with antibiotics. These results suggested that both PGE2 pathway and infectious stimulation are important for macrophage infiltration and activation during tumorigenesis. To investigate the effect of PGE2 and infectious stimuli in gastric tumorigenesis, we generated germfree colony of K19-Wnt1/C2mE transgenic mice and examined gastric phenotypes. K19-Wnt1/C2mE mice develop dysplastic gastric tumors caused by simultaneous activation of Wnt signaling and PGE2 pathway. Importantly, germfree K19-Wnt1/C2mE mice showed significant suppression of gastric tumor development with decreased macrophage infiltration. Moreover, Helicobacter infection to germfree K19-Wnt1/C2mE mice induced gastric tumor development. These results indicate that infectious stimuli to gastric mucosa are required for tumor formation. We also found that PGE2 pathway together with bacterial infection induced expression of monocyte-attractant chemokine CCL2 in the gastric mucosa and macrophage cell line. Notably, infiltrated macrophages showed “alternatively” activated M2 properties, which are characteristics of tumor-associated macrophages. Finally, inhibition of COX-2/PGE2 pathway in K19-Wnt1/C2mE mice caused significant suppression of macrophage infiltration and gastric tumorigenesis. These results suggest that PGE2 signaling and bacterial infectious stimulation cooperatively recruit protumorigenic macrophages through induction of chemokines, and that recruitment of tumor-associated macrophages is one of the important mechanisms of PGE2 signaling in tumorigenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 958.
Abstract 962: Similar preventive effects of naproxen and NO-naproxen in a chemically-induced model of urinary bladder cancer: Dose dependency, gene expression and toxicity
Authors: Grubbs Clinton J. , Wang Yian , You Ming , Steele Vernon , Boring Daniel , Lubet Ronald
Published: February 2011

Non-steroidal anti-inflammatory drugs (NSAIDs) have been highly effective in preventing colon, urinary bladder, and skin cancers preclinically; and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO-naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity, as well as the expectation that the production of NO itself might be therapeutically effective. We examined these agents in the hydroxybutyl(butyl)nitrosamine (OH-BBN) rat urinary bladder cancer model beginning 2 weeks after the last dose of carcinogen. Naproxen at doses of 400, 200, 128 or 75 ppm in the diet greatly decreased the development of large urinary bladder cancers. NO-naproxen at 183 or 550 ppm caused striking decreases in the incidence of large tumors implying that both agents are similarly effective. The lower doses of these agents are well below the human equivalent dose based on standard scaling factors. We are presently treating rats with naproxen by gavage and collecting serum to directly compare the pharmacokinetics of naproxen in the rat and human. To determine whether there was any indication of NO release in NO-naproxen treated rats, microarrays were performed with liver and bladder tissues from treated rats. Minimal differences in gene expression changes between the two agents were observed. Also, an ARE related response in the liver, which one would have expected from NO, was not seen. Thus, the data are compatible with limited direct effects of NO on urinary bladder cancer prevention. Supported by the NCI contract number HHSN261200433001C.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 962.
Abstract 965: Mechanistic studies of a dietary combination in cancer prevention: The effects of manganese superoxide dismutase on tumor suppressor gene activation
Authors: Robbins Delira F. , Morris Kerri , Zhao Yunfeng
Published: February 2011

Mechanistic Studies of a Dietary Combination in Cancer Prevention: The Effects of MnSOD on Tumor Suppressor Gene Activation

Reactive oxygen species can act as signaling transduction molecules modulating various pathways, such as the PI3K/Akt pathway. It is known that this pathway is constitutively activated in tumorigenesis contributing to protein synthesis, cell cycle progression, migration and survival. However, the PI3K/Akt pathway is negatively regulated by the major tumor suppressor protein PTEN. PTEN has dual specificity phosphatase activity regulating Akt phosphorylation as a lipid phosphatase; as well as, regulating cyclin D1 expression as a protein phosphotase. However, these are the roles of cytoplasmic PTEN. Recently, the nuclear roles of PTEN have received significant attention. Nuclear PTEN plays a major role in maintaining cellular homeostasis and stability by contributing to chromosome stability, DNA repair and cell cycle arrest. Previous studies have shown that PTEN nuclear localization is mediated by oxidative stress and may play a role in p53 stabilization. Nevertheless, MnSOD is considered to be a novel tumor suppressor gene. MnSOD has been defined as a nuclear encoded primary antioxidant enzyme localized in the mitochondria. We have shown in previous studies that the dietary combination Protandim reduced tumor incidence and multiplicity via the synergistic induction of superoxide dismutase enzymes. It has been shown that overexpression of MnSOD in in vivo models can suppress tumor formation via modulation of AP-1 binding. Therefore, it is imperative to look at how MnSOD may affect the process of apoptosis and the activation of tumor suppressor genes involved (i.e. PTEN and p53). Using our in vivo models (wildtype, MnSOD knockout, non-transgenic and MnSOD transgenic mice), we investigated how modulation of MnSOD expression may affect PTEN-mediated p53 stabilization, and how this contributes to chemoprevention. In addition, we explored how mutations in p53 may affect the PTEN-p53 interaction and its effects on tumor promotion via a gene transfection approach.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 965.
Abstract 970: Effect of feeding a high fat, high simple carbohydrate diet on serum prostate specific antigen (PSA) in cynomolgus monkeys
Authors: Mubiru James N. , Garcia-Forey Magdalena , Bauer Cassondra , Shade Robert E. , Comuzzie Anthony G. , Rogers Jeffrey
Published: February 2011

Introduction

The prostate specific antigen (PSA) test is used for screening and monitoring of prostate cancer. However, PSA has clinical limitations as it is elevated in other pathological conditions other than prostate cancer. PSA is also influenced by other physiological and environmental variables like genetics and diet. The aim of this study was to investigate the effect of feeding a high fat, high simple carbohydrate (HFHSC) diet on serum PSA in a nonhuman primate species.

Methods

Fifteen cynomolgus monkeys (Macaca fascicularis) were fed an HFHSC diet for 4 months. Body weight and Dual energy X-ray absorptiometry (DEXA) measurements were done at 0, 8 and 16 weeks. Blood was also drawn from these animals and used to assay serum PSA and serum insulin levels.

Results 0 weeks Mean ± SD8 -weeks Mean ± SD16 weeks Mean ± SDP value (0-16) weeksBody weight (kg)5.48 ± 1.095.89 ± 1.355.99 ± 1.440.018Calorie intake (kcal/day)421.8 ± 115.20705.07 ± 101.52684.07 ± 102.361.7 × 10−8Tissue Fat (%)5.57 ± 3.817.29 ± 5.508.04 ± 6.70.155Region fat (%)5.33 ± 3.677 ± 5.237.7 ± 6.480.16Fat (g)289 ± 264.37412.07 ± 375.72467.6 ± 462.890.14Soft tissue mass (g)4860.53 ± 1105.735199.06 ± 1338.795269.33 ± 1435.430.0488Lean mass (g)4571.6 ± 968.114787 ±1125.334801.87 ± 1162.970.056Bone mineral content (g)228.44 ± 44.71234.71 ± 48.74236.85 ± 49.470.031PSA ng/ml0.70 ± 0.570.91 ± 0.460.96 ± 0.620.04Insulin µU/ml14.92 ± 12.1930.87 ± 26.1161.36 ± 66.290.014

Conclusions Feeding cynomolgus monkeys with an HFHSC diet for 4 months resulted in a significant increase in serum PSA levels. The mechanisms underlying this change in serum PSA is still under investigation, however, chronic hyper-insulinemia as indicated in this study might be one of the contributing factors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 970.
Abstract 974: Fellowships in Research and Science Teaching (FIRST): Innovative postdoctoral training for aspiring academic scientists
Authors: Knight Brandi B. , Taliaferro-Smith LaTonia , Eisen Arri , Eaton Douglas
Published: February 2011

Fellowships in Research and Science Teaching (FIRST) is a successful, three-year postdoctoral program at Emory University that combines traditional postdoctoral research training with mentored teaching instruction. Supported by the Institutional Research and Academic Career Development Award (IRACDA, K12) in the Division of Minority Opportunities in Research (MORE), FIRST encourages teaching experiences at minority serving institutions (MSIs) in the Atlanta University Center (Clark-Atlanta University, Morehouse College, and Spelman College). Fellows receive formalized instruction in pedagogy through a course entitled A Class within a Class, which provides training in innovative teaching techniques, use of technology in the classroom, course development and assessment, as well as peer-evaluation of lecture styles. Participation in the FIRST program creates a unique training experience that prepares fellows to become successful biomedical researchers as well as effective instructors. Despite having dual responsibilities during postdoctoral training, a study comparing 114 FIRST fellows to 500 traditional postdocs showed that FIRST fellows continue to publish in peer-reviewed journals at the same rate or above traditional postdoctoral fellows. In addition, FIRST fellows continue to pursue academic research careers and receive NIH grant funding. Along with the goals of the IRACDA programs, FIRST fellows have established research affiliations with Emory University and MSIs thus creating a collaborative network between research-intensive intuitions and under-represented minority liberal arts colleges.

NIH/NIGMS IRACDA Grant 5K12GM000680

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 974.
Abstract 979: Understanding the relationship between race and nicotine dependence
Authors: Wilson Shondelle M. , Thorpe Roland J. , Ford Jean G. , LaVeist Thomas A.
Published: February 2011

Background: Mounting evidence continues to demonstrate that nicotine dependence is a growing public health issue among current smokers. While duration of smoking, number of cigarettes smoked per day (CPD) and cessation attempts are common indicators of nicotine dependence, African Americans tend to smoke less cigarettes per day (CPD; 10 or less), initiate smoking at a later age and experience greater failed quit attempts, compared to whites, yet develop nicotine dependence. However, no previous study has examined the possibility that race differences in the social context which African Americans and non-Hispanic whites live may contribute to disparities and the persistence of nicotine dependence. Social class and immediate personal interactions occurs in various social contexts, including the living space, workplace, institutions or other physical environments. This project examines the contributions of demographic, behavioral and environmental factors as social contextual factors that contribute to smoking behavior and the persistence of nicotine dependence.

Objective: We examined race disparities in nicotine dependence among 761 African American and white current smokers living in similar social and environmental risk exposures and compared these estimates to 1461 black and white current smokers in a national sample of adults aged 20 and over.

Methods: Data was assessed from Exploring Health Disparities in Integrated Communities-Southwest Baltimore (EHDIC-SWB; 2003) and National Health and Nutritional Examination Survey (NHANES; 2001-2004) to determine if race disparities in nicotine dependence would be attenuated in EHDIC-SWB. Time to first cigarette was used to assess nicotine dependence. Logistic regression was used to assess the association between race and nicotine dependence, controlling for known confounders.

Results: In multivariate analysis, race differences in nicotine dependence were greater among African-Americans in a representative sample of US adults. African Americans in a national sample have a lower odds of nicotine dependence (OR = 0.8; 95% CI 0.46, 0.93) compared to whites. However, no race difference were detected among participants in the EHDIC-SWB study (0.87; 95% CI 0.62, 1.22).

Conclusions: Examination of social and environmental factors may reveal important insights into the nature of inequalities between black and white adults in health outcomes such as nicotine dependence. Our results highlight the importance of examining social contextual factors and suggest that the promotion of targeted interventions may reduce the prevalence of nicotine dependence among current smokers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 979.
Abstract 980: Intrathecal methotrexate induces focal cognitive deficits and alters CNS folate physiology in rats
Authors: Li Yan , Vijayanathan Veena , Gulinello Maria , Cole Peter D.
Published: February 2011

Background: In order to reduce the persistent neurologic toxicity of therapy for childhood acute lymphoblastic leukemia (ALL), many treatment protocols avoid cranial radiation, relying instead on intrathecal chemotherapy to prevent central nervous system relapses. Nevertheless a significant subset of survivors treated without radiation manifest persistent focal deficits in cognitive function. The folate antagonist methotrexate (MTX), a key component of prophylactic intrathecal therapy, is suspected to contribute to treatment-induced cognitive dysfunction. Our goal was to establish a rodent model to isolate the cognitive and neurotoxic effects of MTX after direct administration into cerebrospinal fluid (CSF).

Methods: Adult Long-Evans rats were given either intrathecal MTX 0.5mg/kg or artificial CSF via transcutaneous puncture at the level of the cisterna magna. Three days later, all rats subsequently underwent a battery of behavioral tests designed to assess cognitive domains frequently impaired among children treated for ALL, including spatial memory, visual memory, and motor coordination. Indicators of folate physiology (folate and homocysteine) in CSF and serum were measured using high performance liquid chromatography. Concentrations of interleukin-1β, IL-6, and tumor necrosis factor-α were measured in CSF to assess whether intrathecal MTX induces an inflammatory response.

Results: Intrathecal MTX administration reliably produced both visual and spatial memory deficits, without altering general activity or motor coordination. MTX administration was associated with a significant reduction in both CSF and serum folate concentrations, along with an increase in CSF homocysteine. At 24 hours post-injection of MTX, CSF folate decreased by 75% and CSF homocysteine was increased 4-fold, relative to baseline. Intrathecal injection of both MTX and artificial CSF was associated with a significant rise in CSF IL-6 within 6 hours, which then returned to baseline by 24h.

Conclusion: We have established an animal model in which intrathecal MTX induces cognitive dysfunction that mimics clinically observed toxicity, in association with a rapid fall in CSF folate and increase in CSF homocysteine. A non-specific, transient increase was seen in the proinflammatory cytokine IL-6 within CSF. This proinflammatory response does not appear sufficient to cause cognitive deficits, as it was observed among both groups of rats, while toxicity was demonstrated among only those who received MTX. This model will allow us both to further investigate the pathophysiology of treatment-induced cognitive dysfunction and to test protective interventions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 980.
Abstract 987: Researching policy proposals aimed at placing cancer on the global health agenda
Authors: Kawahara Norie
Published: February 2011

Deaths caused by cancer continue to increase around the world. People living in low- and middle-income countries are in greater danger than people living in high-income countries of succumbing to risks that can be relatively easily avoided by man-made interventions. These risks include smoking, unhealthy eating and lifestyle, lack of exercise, excessive intake of alcohol, and chronic infections such as HPV or hepatitis. The World Health Organization projects that if the challenges facing low- and middle-income countries are not addressed, by 2015 an estimated 5.7 million people will die annually in those countries, rising to 8.9 million by 2030. With limited medical resources, the priority challenges for the global health agenda remain focused on HIV/AIDS and malaria. Now, however, is the time to transform global health policies. The U.S. Commitment to Global Health clearly states that “Cancer Should Be Raised Onto the Global Health Agenda” and yet cancer remains to be recognized by the global health community as a priority issue. What is the positioning given to cancer on the global health agenda? What factors are preventing is inclusion in global health? What are the primary mechanisms that inform and decide the global health agenda? In contrast to infectious diseases, cancer slowly yet perniciously attacks the very roots of people's lives. This long time-frame means that we must consider a wide-range of factors, including economic, cultural and domestic and international policies. This policy-based research was implemented in the form of interviews with people from various sectors, encompassing various perspectives, including social determinants of health, health equity and solidarity and human rights. The results and analysis of this research are broken down into: (1) Top-down mechanisms, (2) Bottom-up mechanisms, and (3) the formation of new values through an IT network that functions to meld (1) and (2) and promote them in tandem. The results will be used to present the challenges and outlook for raising cancer onto the global health agenda. In order to ensure the global advancement of cancer research, in accordance with the principles and theory enshrined in the Universal Declaration of Human Rights, which stipulates that all people have the right to enjoy the benefits of science and technology, an urgent prerequisite is to promote strategic analysis with the objective of including cancer in the United Nations Millennium Development Goals (MDGs). Achieving the inclusion of cancer in the MDGs would significantly raise the profile of cancer in the global health agenda.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 987.
Abstract LB-101: A novel role of semaphorin4a (sema4a) in genotoxin-induced DNA damage response in human lung fibroblasts
Authors: Bae Dongsoon , Chun Gina , Patierno Steven R. , Ceryak Susan M.
Published: February 2011

Dysregulation of DNA repair signaling after genotoxin exposure contributes to genomic instability and carcinogenesis. Hexavalent chromium [Cr(VI)] is a genotoxin of occupational and environmental concern. Protein tyrosine phosphatase (PTP) inhibitors (i.e., sodium orthovanadate (SOV)) activate key survival pathways. We reported that SOV enhances clonogenic survival after Cr(VI) exposure by overriding Cr-induced growth arrest in human lung fibroblasts (HLFs). PTP inhibition with SOV increased expression of DNA damage/repair genes as determined by microarray analysis. Kinetic analysis of DNA double-strand breaks (DSBs) by comet assay showed equal DSB formation 15 min after Cr(VI) exposure in the absence and presence of SOV. However, PTP inhibition significantly decreased DSBs 0.5-24 hr after Cr(VI) treatment. Aim of the present study was to determine the molecular mechanism(s) by which PTP inhibition affects DNA damage response during genotoxic stress. Gene expression was examined by DNA Damage Signaling Pathway PCR Array after 1 μM Cr(VI) treatment for 24 hr in the absence or presence of SOV. The PTP inhibitor reversed Cr-mediated changes in expression of several unique genes. Interestingly, the sema4a gene, known to be involved in T cell activation and endothelial cell proliferation and migration, was strongly induced by co-treatment of SOV and Cr(VI). Gene expression correlated with increased sema4a protein expression after co-treatment of SOV and Cr(VI). A potential role of sema4a in Cr-induced DNA DSB formation/repair in the absence or presence of SOV was assessed after sema4a siRNA transfection. Silencing of sema4a did not alter the effect of SOV on Cr-induced DSBs. However, sema4a silencing completely blocked Cr-induced DSBs 4 hr after exposure. These results suggest a novel role of sema4a in DNA DSB formation/repair in normal HLFs. Taken together, these data shed light on the emerging role of semaphorins as mediators of cell survival as well as potential therapeutic targets in carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-101.