bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2085: Interleukin 33 promotes tumor development, progression, and metastasis in colorectal cancer
Authors: Zhang Yu , Davis Celestia , Pena Maria Marjorette
Published: May 2015

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States, and the major cause of death is metastasis which is frequently targeted to the liver. Metastasis progression typically occurs without symptoms, and is often diagnosed at the final stage when little can be done to help the patient. Understanding the genetic and molecular mechanisms at the early stages can lead to the identification of bio-molecular markers that might be useful for early diagnosis or as therapeutic targets to alleviate morbidity and mortality from the disease. To identify factors that promote CRC progression and liver metastasis, we utilized an orthotopic mouse model of CRC metastasis to the liver that we had developed by cecal implantation of CT26 colon adenocarcinoma cells followed by sequential in vivo selection to isolate a highly liver metastatic CRC cell line, CT26-FL3. A whole genome microarray analysis was performed to compare the genetic signature of CT26-FL3 to its isogenic parental cell line CT26. We identified interleukin (IL) 33 a one of the genes that was highly overexpressed in CT26-FL3 as compared to CT26 cells. We found that increased IL-33 expression was associated with advancing stages of CRC in patient samples and that its expression was already elevated in nascent adenomas in the ApcMin/+ mouse, a genetic mouse model of intestinal tumorigenesis. To determine its role in promoting tumor progression, the murine colon cancer cell line MC38 was stably transfected with an Il33-expressing plasmid. We found that overexpression of IL-33 in MC38 cells promoted faster growth of the primary tumor and enhanced its metastasis into the liver. Taken together, the data suggest that IL33 might play an important role in the early development and progression to metastasis of CRC. IL-33 can function as a conventional cytokine or as a transcriptional regulator. It signals through a membrane bound ST2 receptor, as well as a soluble ST2 receptor that can act as a molecular sink to block its signaling pathway. Its potential as a viable marker for diagnosis or as a therapeutic target will be further determined in this study.

Citation Format: Yu Zhang, Celestia Davis, Maria Marjorette Pena. Interleukin 33 promotes tumor development, progression, and metastasis in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2085. doi:10.1158/1538-7445.AM2014-2085
Abstract 2088: Kindlin-3 enhances breast cancer metastasis through upregulation of Twist-mediated tumor angiogenesis
Authors: Sossey-Alaoui Khalid , Pluskota Elzbieta , Davuluri Gangarao , Bialkowska Katarzyna , Das Mitali , Lindner Daniel , Plow Edward F.
Published: May 2015

The FERM domain containing protein, Kindlin-3, has been recognized as a major regulator of integrin function in hematopoietic cells but its role in neoplasia is totally unknown. We have examined the relationship between Kindlin-3 and breast cancer in mouse models and human tissues. Human breast tumors showed a ∼7-fold elevation in kindlin-3 mRNA compared to non-neoplastic tissue by quantitative polymerize chain reaction. At the protein level, Kindlin-3 was found to be expressed abundantly in breast cancer tissue, and its expression increases with the advancing stage of tumor development. Mining of the Oncomine database (www.oncomine.com) confirmed this association: Kindlin-3 was in the top 3 % of gene products elevated in breast cancer (p< 10-12). When Kindlin-3 was over-expressed in a breast cancer cell line, primary tumor growth and lung metastasis increased by 2.5- and 3-fold, respectively when implanted into mice compared to cells expressing vector alone. Mechanistically, the Kindlin-cells displayed a 2.2-fold increase in Vascular Endothelial Growth Factor (VEGF) secretion and B1 integrin activation. Increased VEGF secretion resulted from enhanced production of Twist, a transcription factor which promotes tumor angiogenesis. Knockdown of Twist diminished VEGF production and knockdown of B1 integrins diminished Twist and VEGF production by Kindlin-3 cells while non-targeting si-RNA had no effect on expression of these gene products. The activation of this signaling cascade resulted in the enhancement of breast cancer cell invasion, and tumor angiogenesis and metastasis. Hence, our studies established the pathway in which cross-talk between Kindlin-3 and B1 integrins activates the nuclear translocation of TWIST, which leads to enhanced VEGF-A production and secretion, macrophage infiltration as well as activation of the Epithelial-to-mesenchymal-transition (EMT) program. The activation of this signaling cascade culminates in enhanced breast cancer cell migration, invasion and tumor angiogenesis, all of which are required for tumor progression and metastasis.

In summary, by analysis of human tissue samples and in vitro and in vivo studies, we have identified a novel role for Kindlin-3 in the progression of breast cancer. To our knowledge, this is the first demonstration of the presence and implication of Kindlin-3 in breast cancer or any cancer.

Citation Format: Khalid Sossey-Alaoui, Elzbieta Pluskota, Gangarao Davuluri, Katarzyna Bialkowska, Mitali Das, Daniel Lindner, Edward F. Plow. Kindlin-3 enhances breast cancer metastasis through upregulation of Twist-mediated tumor angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2088. doi:10.1158/1538-7445.AM2014-2088
Abstract 2097A: The role of Lipocalin-2 in colorectal cancer metastasis
Authors: Hughes Daniel Titus
Published: May 2015

Colorectal cancer, the third leading cause of cancer deaths in America, has a poor clinical outcome once the disease has progressed to stage IV metastatic cancer. Five-year survivorship of stage IV is only 10%, but survivorship of stage I is drastically higher at 90%. Therefore, understanding the early stages of colorectal cancer metastasis is critical to develop therapeutic strategies for treating and preventing stage IV colorectal cancer. Using an orthotopic model for colorectal cancer metastasis, we have observed that our highly metastatic cell line produces a pre-metastatic upregulation of Lipocalin-2 both in circulation and in the liver. Overexpression of Lipocalin-2 in our highly metastatic cell line led to an overall reduction of circulating iron. Lipocalin-2 is upregulated in many primary tumors of epithelial origin, but the role of Lipocalin-2 in metastasis remains unclear. The full effects and implications of Lipocalin-2 in colorectal cancer metastasis remain to be elucidated.

Citation Format: Daniel Titus Hughes. The role of Lipocalin-2 in colorectal cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2097A. doi:10.1158/1538-7445.AM2014-2097A
Abstract 2129: Effects of talactoferrin on lung adenoma prevention in A/J mice
Authors: Seabloom Donna , Galbraith Arthur , Haynes Anna , Antonides Jenny , Fujita Alisha , Wuertz Beverly R. , Steele Vernon , Ondrey Frank , Wattenberg Lee
Published: May 2015

Talactoferrin is a promising non-toxic solid tumor cancer agent which has met with some success in the treatment of early stage lung cancer clinically in humans. It is well tolerated and early phase clinical trials with this agent demonstrated efficacy and immune stimulation as an oral dendritic cell-mediated immunotherapy agent. We felt the nature of this agent would be suitable in the chemoprevention setting in experimental lung carcinogenesis in a B[A]P mouse model. We utilized 120 seven week old female A/J mice. All groups received Benzo[a]pyrene by oral gavage in three doses of 3mg/kg body weight over the course of one week. Animals were then randomized into 5 groups of 24 mice per group based on weight. Experimental diets, talactoferrin (Agennix Inc., Indianapolis, IN) at 1.40 and 0.42% of diet, were started one week or eight weeks after last dose of B[a]P. Animals were continued on the feeding schedule, weighed weekly, and monitored for weight loss, attenuation, rough hair coat, or other signs of ill health. The study was concluded 16 weeks after administration of B[a]P. The agent was well tolerated for the duration of the experiment and there was no observable toxicity. The average number of adenomas per animal was 14.04 ± 0.9315 (N=24) in the control group, 18.14 ± 1.448 (N=22) in the early low dose group, 16.70 ± 1.295 (N=23) in the late low dose group, 15.09 ± 1.408 (N=23) in the early high dose group and 14.46 ± 1.213 (N=24) in the late high dose group. We conclude talactoferrin is well tolerated in the A/J mouse model. We also conclude talactoferrin did not inhibit carcinogenesis in A/J mice at a dose range of 420mg/kg/day to 1400mg/kg/day.

Citation Format: Donna Seabloom, Arthur Galbraith, Anna Haynes, Jenny Antonides, Alisha Fujita, Beverly R. Wuertz, Vernon Steele, Frank Ondrey, Lee Wattenberg. Effects of talactoferrin on lung adenoma prevention in A/J mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2129. doi:10.1158/1538-7445.AM2014-2129
Abstract 2135: Chemoprevention of tobacco carcinogen-induced lung cancer by DFMO and Licofelone administered individually or in combination in female A/J mice
Authors: Patlolla Jagan Mohan Reddy , Kopelovich Levy , Qian Li , Biddick Laura , Zhang Yuting , Sadeghi Michael K. , Desai Dhimant , Amin Shantu , Lightfoot Stan , Steele Vernon E. , Rao Chinthalapally V.
Published: May 2015

Lung cancer is the leading cause of cancer death among both men and women in the US. Inflammatory eicosanoids and leukotrienes derived from cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) pathway positively influences lung tumor growth. Overexpression of ornithine decarboxylase (ODC) enzyme activity and polyamines has been associated with proliferation and progression of lung cancer. Thus, targeting both tumor inflammatory molecules and polyamines synthesis may provide additive/synergistic antitumor effects. To overcome clinical toxicity of high dose difluoromethyl ornithine (DFMO), an inhibitor of ODC; and to target both COX-2/5LOX, we tested low dose DFMO combined with Licofelone, a novel dual inhibitor COX-2/5-LOX, in lung cancer model. At 7 weeks of age, mice (25 mice/group) were treated with 10 μmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) /mouse to induce the lung tumors. Three weeks after the NNK treatment, mice were fed either control or experimental diets containing 200, 400 ppm licofelone or 1500 and 3000 ppm DFMO or low-dose combinations of both agents. Mice were killed at 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) after NNK-treatment for lung tumor evaluation. Administration of 200 and 400 ppm licofelone significantly suppressed lung tumor (adenoma + adenocarcinoma) formation by >32 to 35% (p43 to 47% (p25 to 30% (p44% (p53% (p60% (p<0.0001) respectively at 17 and 34 weeks exposure. These results suggest that low-dose combinations of licofelone and DFMO inhibit the NNK-induced lung adenocarcinoma formation synergistic/additive manner. Immunohistochemistry analysis revealed that lung tumors from mice exposed to licofelone plus DFMO showed significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of TUNEL positive cells as compared to lung tumors from NNK-treated mice fed with control diet. These results demonstrate the targeting lung tumor COX-LOX with ODC may provide better efficacy when compared to individual targets on tobacco carcinogen-induced lung adenocarcinomas formation. {Supported by NIH, NCI grants NO1-CN-53300 and Kerley-Cade Chair}.

Citation Format: Jagan Mohan Reddy Patlolla, Levy Kopelovich, Li Qian, Laura Biddick, Yuting Zhang, Michael K. Sadeghi, Dhimant Desai, Shantu Amin, Stan Lightfoot, Vernon E. Steele, Chinthalapally V. Rao. Chemoprevention of tobacco carcinogen-induced lung cancer by DFMO and Licofelone administered individually or in combination in female A/J mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2135. doi:10.1158/1538-7445.AM2014-2135
Abstract 2137: Prevention of HER2 overexpressing early stage breast disease progression by lapatinib
Authors: Xu Jia , Jain Shalini , Yu Dihua
Published: May 2015

Currently, Tamoxifen and Aromatase inhibitors are used for prevention of estrogen receptor positive (ER+) breast cancer; however, there is no effective prevention strategy for ER- breast cancer. HER2 overexpression (HER2+) can be detected in up to 60% early stage breast lesions, such as atypical hyperplasia (ADH) and ductal carcinoma in situ (DCIS). Up to 40% of ER- breast cancers are HER2+. Thus, targeting HER2 signaling may be an effective chemoprevention strategy for these ER- and HER2+ breast cancer. Here, we stable introduced ErbB2-expressing retroviruses into the ER-, non-transformed MCF10A cells (MCF10A.B2) to establish an ER- and HER2+ early breast disease model. We show that Lapatinib, a FDA-approved dual tyrosine kinase inhibitor for both HER2 and EGFR, reduced the proliferation rate and increased the apoptosis in MCF10A.B2 cells. In 3D culture, Lapatinib treatment starting at day 6 prevented the MCF10A.B2 cells from forming abnormal acini, and the numbers of DCIS-like acini have been significantly decreased compared to control group. Untreated MCF10A.B2 cells forms DCIS-like acini in 3D culture by day 10, which have been reverted to normal or ADH-like acini when lapatinib treatment started by day 10. Furthermore, MMTV-neu mouse model develop ER- mammary tumors in 6.4 months, whereas lapatinib treatment (30mg/kg/day, six days per week) starting at 10 weeks of age significantly delayed the tumor initiation and progression in this mouse model as detected by mammary gland biopsy and fiber optic micro-endoscope (FOME) imaging. Mice treated with lapatinib had fewer premalignant lesions and reduced noninvasive tumors in their mammary glands, which are correlated with reduced proliferation rate and increased apoptosis rate, indicating that lapatinib is a promising agent for the prevention/intervention of ER- and HER2+ breast cancers. To identify effective and reliable biomarkers to assess the risk of ER-/HER2+ lesions and efficacy of lapatinib for prevention and intervention, cDNA microarray and reverse phase protein array (RPPA) were performed on MCF10A.B2 cells and control MCF10A cells. We have identified several molecular pathways activated by HER2+ in this model which will be tested for their roles in the initiation of mammary tumors and as potential targets for prevention of ER-/HER2+ breast disease. Our study brings better understanding of the mechanism underlying ER-/HER2+ early stage breast disease progression to cancer and could be rapidly translated into the clinic for prevention of ER-/HER2+ breast cancers.

Citation Format: Jia Xu, Shalini Jain, Dihua Yu. Prevention of HER2 overexpressing early stage breast disease progression by lapatinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2137. doi:10.1158/1538-7445.AM2014-2137
Abstract 2149: Novel compound 1, 3-bis (3, 5-dichlorophenyl) urea inhibits lung cancer progression
Authors: Singhal Sharad S. , Figarola James , Singhal Jyotsana , Nagaprashantha Lokesh , Berz David , Rahbar Samuel , Awasthi Sanjay
Published: May 2015

The successful clinical management of lung cancer is limited by frequent loss-of-function mutations in p53 which cooperates with chronic oxidant-stress induced adaptations in mercapturic acid pathway (MAP) which in turn regulates critical intracellular signaling cascades that determine therapeutic refractoriness. Hence, we investigated the anti-cancer effects and mechanisms of action of a novel compound called 1, 3 bis (3, 5-dichlorophenyl) urea (COH-SR4) in lung cancer. Treatment with COH-SR4 effectively inhibited the survival and clonogenic potential along with inducing apoptosis in lung cancer cells. COH-SR4 treatment caused the inhibition of GST activity and G0/G1 cell cycle arrest and inhibited the expression of cell cycle regulatory proteins CDK2, CDK4, cyclin A, cyclin B1, cyclin E1, and p27. The COH-SR4 activated AMPK pathway and knock-down of AMPK partially reversed the cytotoxic effects of COH-SR4 in lung cancer. COH-SR4 treatment lead to regression of established xenografts of H358 lung cancer cells without any overt toxicity. The histopathology of resected tumor sections revealed an increase in pAMPK, a decrease in the nuclear proliferative marker Ki67 and angiogenesis marker CD31. Western-blot analyses of resected tumor lysates revealed a decrease in pAkt and anti-apoptotic protein Bcl2 along with an increase in pAMPK, pro-apoptotic protein Bax and cleaved PARP levels. Importantly, COH-SR4 lead to decrease in the mesenchymal marker vimentin and increase in the normal epithelial marker E-cadherin. The results from our in-vitro and in-vivo studies reveal that COH-SR4 represents a novel candidate with strong mechanistic relevance to target aggressive and drug-resistant lung tumors (Supported by NIH grant CA 77495 and Beckman Research Institute of the City of Hope).

Note: This abstract was not presented at the meeting.

Citation Format: Sharad S. Singhal, James Figarola, Jyotsana Singhal, Lokesh Nagaprashantha, David Berz, Samuel Rahbar, Sanjay Awasthi. Novel compound 1, 3-bis (3, 5-dichlorophenyl) urea inhibits lung cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2149. doi:10.1158/1538-7445.AM2014-2149
Abstract 2151: Evaluation of a citrus flavonoid as a chemopreventive agent against breast cancer
Authors: Ke Jia-Yu , Tian Min , Kliewer Kara L. , Schwartz Steve J. , Reidl Ken M. , Tsai Shin-yu , Yee Lisa D. , Belury Martha A.
Published: May 2015

Naringenin is a flavonone found in citrus fruits and tomatoes that may have anti-tumor properties. Previously, our lab discovered that naringenin induced the activity of AMP-activated protein kinase (AMPK) and reduced phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP) in MCF-7 human breast cancer cells. These properties have been linked with anti-tumor actions of drugs such as metformin and mTOR inhibitors. Based on these findings, we tested the ability of naringenin (0 uM - 200 uM) to modulate growth of MCF-7 human breast cancer cells and E0771 murine mammary tumor cells. In both models for cancer cell growth, naringenin dose-dependently decreased live cell number in a time-dependent manner. Furthermore, results of flow cytometry and propidium iodide staining assays showed accumulation of apoptotic cells after naringenin treatment. Naringenin also decreased expression of cyclin D1 and elevated expression of pro-apoptotic protein Bax suggesting that naringenin may inhibit the proliferation of mammary tumor cells by inducing cell cycle arrest and promoting apoptosis. To test for dose-dependent accumulation of naringenin in mammary gland tissue, female mice were fed varying doses of naringenin (control, 0%; low dose,1.0 wt%; or high dose, 3.0 wt% naringenin) in a high saturated fat diet for 11 weeks. Body weights and cumulative food intake were not different between diet groups. Dietary naringenin resulted in dose-responsive accumulation in mammary gland. Relative accumulation of naringenin in tissues was greatest in liver (low dose, 7.61 ± 1.14 umol/kg tissue and high dose, 37.04 ± 8.33 umol/kg tissue) followed by mammary gland and muscle which had a similar magnitude of naringenin accumulation (low dose ∼ 0.4 umol/kg tissue and high dose naringenin, 2.5 umol/kg tissue) of accumulation. Naringenin and monoglucuronide naringenin were two of the main forms of accumulated flavonoid in mammary gland raising the possibility that naringenin and/or metabolites are the active form of flavonoid responsible for anti-tumor activity against mammary cancer. Evaluating the species of naringenin metabolites in mammary gland that exert pro-apoptotic actions will be important to evaluate in order to understand the potential of naringenin-rich foods to contribute to prevention of breast cancer in women.

Citation Format: Jia-Yu Ke, Min Tian, Kara L. Kliewer, Steve J. Schwartz, Ken M. Reidl, Shin-yu Tsai, Lisa D. Yee, Martha A. Belury. Evaluation of a citrus flavonoid as a chemopreventive agent against breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2151. doi:10.1158/1538-7445.AM2014-2151
Abstract 2153: Metformin and aspirin synergistically inhibit mTOR and JAK/STAT3 signaling pathway and induce cell death in pancreatic cancer cells
Authors: Yue Wen , Lin Yong , Chen Chunxia , Carpizo Darren R. , DiPaola Robert S. , Tan Xiang-Lin
Published: May 2015

Epidemiological studies have correlated a decreased risk of pancreatic cancer with patients who take either metformin or aspirin. In addition, animal studies have shown that either metformin or aspirin inhibits pancreatic tumor formation as well as the progression of pancreatic intraepithelial neoplasia (PanIN). Since the combination of metformin and aspirin and their potential synergistic effects on pancreatic cancer cells have not been investigated, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis in pancreatic cancer cell lines PANC-1 and BxPC3. Cell viability and migration were determined using the MTT assay, colony formation, and the wound-healing assay, and the molecular changes in the mTOR and JAK/STAT3 and apoptotic signaling pathways were evaluated. The synergistic effects of the combination of metformin with aspirin were assessed using a method based on isobologram analyses. We observed that the combination of metformin and aspirin at low concentrations showed significant synergistic effects on the inhibition of cell viability, migration and colony formation in both PANC-1 and BxPC-3 cells. We also found that the combination of metformin and aspirin significantly inhibited the phosphorylation of mTOR, S6K, JAK2 and STAT3. Furthermore, the combination of metformin and aspirin significantly inhibited the expression of Bcl-2 and Mcl-1, which are the downstream targets of STAT3, in both mRNA and protein levels. We also observed increased apoptosis as measured by caspase 3 and poly (ADP-ribose) polymerase (PARP) cleavage in PANC-1 cells treated with the combination of metformin and aspirin. These results suggest that metformin and aspirin synergistically induce cell death in pancreatic cancer cells associated with down-regulating Bcl-2 and Mcl-1 through the STAT3 pathway. Our results support the continued investigation of the combination of metformin and aspirin as chemopreventative or therapeutic agents in pancreatic cancer tumor models.

Citation Format: Wen Yue, Yong Lin, Chunxia Chen, Darren R. Carpizo, Robert S. DiPaola, Xiang-Lin Tan. Metformin and aspirin synergistically inhibit mTOR and JAK/STAT3 signaling pathway and induce cell death in pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2153. doi:10.1158/1538-7445.AM2014-2153
Abstract 2154: Notoginseng suppresses azoxymethane/dextran sulphate sodium-induced colitis and colitis-associated colorectal carcinogenesis
Authors: Wang Chong-Zhi , Yuan Chun-Su
Published: May 2015

Colorectal cancer remains one of the most prevalent cancers and a leading cause of cancer related death in the US. Many currently used chemotherapeutic agents are derived from botanicals. Identifying the herbal sources, including those from ginseng family, to develop better preventive or therapeutic agents remains an essential step in advancing the management of the cancer. Patients suffering from inflammatory bowel disease are at a high risk of developing colorectal cancer. To evaluate the anti-cancer potential of botanicals, we evaluated the effects of notoginseng on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis. One week after A/J mice received AOM, the animals received DSS for 8 days, or were supplemented with notoginseng extract, at 30 or 90 mg/kg. DSS-induced colitis was scored with the disease activity index (DAI). The severity of the inflammatory lesions was evaluated by a colon tissue histological assessment. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were also investigated. We observed that the effects of notoginseng on the reduction of colon inflammation, expressed in the DAI score, were in a dose-related manner (p < 0.01). Notoginseng inhibited the reduction of colon length and loss of bodyweight in a dose-related manner (all p < 0.05). The histological assessment of colitis and the inflammatory related immunohistochemical data of iNOS and COX-2 also supported the pharmacological observations. Our data suggest that notoginseng is a promising candidate in preventing and treating colitis and inflammation-associated colon carcinogenesis. (This work was supported in part by the NIH/NCCAM grants AT004418 and AT005362).

Citation Format: Chong-Zhi Wang, Chun-Su Yuan. Notoginseng suppresses azoxymethane/dextran sulphate sodium-induced colitis and colitis-associated colorectal carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2154. doi:10.1158/1538-7445.AM2014-2154
Abstract 2165: Parents' ages at birth and risk of hormone-related cancer among women in the California Teachers Study
Authors: Lu Yani , Luo Jianning , Wang Sophia , Ma Huiyan , Sullivan-Halley Jane , Reynolds Peggy , Bernstein Leslie
Published: May 2015

Childbearing age has increased in Western countries over the last several decades. The immediate effects of advanced parental age on the health of offspring have been extensively studied. However, few studies have examined the effect of parental age at birth on the risk of adult-onset cancer. We explored the association between parental age at birth and the risk of adult-onset hormone-related cancers (i.e., breast cancer, ovarian cancer and endometrial cancer) in the prospective California Teachers Study cohort of 133,479 female teachers and administrators. Between 1995 and 2010, 5359 women were diagnosed with breast cancer, 515 women were diagnosed with ovarian cancer, and 1110 women were diagnosed with endometrial cancer. Multivariate adjusted relative risks (RR) and 95% confidence intervals (CI) were estimated by fitting Cox proportional hazards models. After mutual adjustment for paternal age/maternal age at birth, no association was observed for maternal age at birth for any of the three types of cancer. However, compared to those born to a father whose age at his daughter's birth was 25-29 years, women born to a father under age 20 years had 35% greater risk of breast cancer (RR=1.35, 95% CI=1.03-1.76) and more than 2 times greater risk of ovarian cancer (RR=2.26, 95% CI=1.14-4.50); women born to a father whose age at childbirth was 30-34 years had 25% greater risk of endometrial cancer (RR=1.25, 95% CI=1.05-1.48) than women whose father was 25-29 years. In an interaction model, relative to daughters born to a mother younger than 25 year and a father between 25-29 years, relative risk was elevated for those born to a mother younger than 25 and a father younger than 20 years (RR=1.37, 95% CI=1.07-1.76), or to a father older than 34 years old regardless of mother's age (mother <25 or ≥25 years old; RR=1.31 and 1.12 respectively). Lower ovarian cancer risk was observed among women born to a mother ≥25 years and a father between 25-29 years (RR=0.66, 95% CI=0.48-0.90); no association was observed for endometrial cancer. These findings indicate that parental age at birth, especially paternal age at birth, may affect the adult-onset cancer risk of daughters, especially breast cancer.

Citation Format: Yani Lu, Jianning Luo, Sophia Wang, Huiyan Ma, Jane Sullivan-Halley, Peggy Reynolds, Leslie Bernstein. Parents' ages at birth and risk of hormone-related cancer among women in the California Teachers Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2165. doi:10.1158/1538-7445.AM2014-2165
Abstract 2168: Components of metabolic syndrome and total cancer mortality
Authors: Gathirua-Mwangi Wambui G. , Zhang Jianjun
Published: May 2015

Metabolic syndrome becomes more and more common primarily due to the epidemic of overweight and obesity in both developed and developing countries. Epidemiologic studies have shown that obesity increases the risk of several cancers. However, it largely remains unclear whether the components of metabolic syndrome are associated with total cancer mortality. Therefore, we sought to evaluate this important question in the Third National Health and Nutrition Examination Survey (NHANES). Data on demographics, socioeconomics, lifestyle factors, and the components of metabolic syndrome were collected among 19,296 men and women aged 18 years or older (pregnant women excluded). Cancer mortality outcomes of these subjects were determined by linkage to the National Death Index (NDI), and the most recent year of the linkage was in 2010. A total of 1,111 cases of all sites of cancer have been documented during this period of time. Weighted Cox proportional hazards regression was used to compute relative risks (RR) with 95% confidence intervals (CIs) for total cancer mortality in relation to the components of metabolic syndrome. After adjustment for age, sex, race, education, marital status, and cigarette smoking, subjects in the highest quartile (Q) of serum glucose experienced a 25% increased risk of total cancer when compared with those in the lowest quartile [RR (95% CI): 1.250 (1.247-1.253)]. The significant positive association was also observed for systolic blood pressure [Q4 vs. Q1: RR (95% CI): 1.278 (1.274-1.282)]. Conversely, a reduced risk of total cancer was found for high-density lipoprotein (HDL) cholesterol [Q4 vs. Q1: RR (95% CI): 0.798 (0.796-0.800)]. No apparent effect was detected for waist circumference and serum triglyceride. To our knowledge, the present study is among the first to demonstrate that some components of metabolic syndrome modulate the risk of total cancer among a representative population in the US. Our findings offer novel evidence for the potential role of metabolic syndrome in cancer carcinogenesis and mechanistic data for the associations between obesity and the risk of some cancers.

Citation Format: Wambui G. Gathirua-Mwangi, Jianjun Zhang. Components of metabolic syndrome and total cancer mortality. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2168. doi:10.1158/1538-7445.AM2014-2168
Abstract 2174: Association of diabetes and obesity with risk of esophageal and gastric adenocarcinoma in the Iowa Women's Health Study (IWHS)
Authors: LaBore Bryan P. , Prizment Anna E. , Ondrey Frank G. , Anderson Kristin E.
Published: May 2015

Incidence rates of esophageal and gastric cancers have increased rapidly in developing countries during the past four decades. The rate of esophageal adenocarcinomas has approximately tripled among US whites and now exceeds that of esophageal squamous cell carcinomas. Incidence of gastric cardia adenocarcinomas has also risen significantly during this period, though to a lesser extent. These cancers often respond poorly to treatment, highlighting the importance of identifying modifiable risk factors with a view to prevention. The association between diabetes and gastroesophageal adenocarcinoma has been examined in only a few studies and findings are inconsistent. While obesity is a significant risk factor for esophageal and gastric adenocarcinomas, few analyses have been conducted in prospective cohorts. We examined the association between diabetes, BMI, and waist circumference and incidence of esophageal, non-cardia gastric and gastric cardia adenocarcinomas in a large prospective cohort of postmenopausal women. A mailed survey at baseline (1986) collected information on self-reported diabetes and anthropometric measures and included a detailed food-frequency questionnaire. The 34,466 initially cancer free women were followed for 24 years with annual cancer incidence obtained through the State Health Registry of Iowa, part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program; 83 women developed gastroesophageal adenocarcinoma. Associations were examined using proportional hazards regression models: hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Significant associations were observed in age-adjusted models for diabetes (yes/no) [HR: 2.09, 95% CI: 1.01-4.34], body mass index (kg per meters squared) [HR: 1.09, 95% CI: 1.03-1.15], and waist circumference (cm) [HR: 1.24, 95% CI: 1.01-1.53]. Additionally, a positive association between diabetes and adenocarcinoma of the gastroesophageal junction was found in both age-adjusted [HR: 3.43, 95% CI: 1.32-8.90] and multivariate-adjusted models [HR: 3.00, 95% CI: 1.13-7.99]. An inverse association was found with increasing daily fiber intake (g/day) and all gastroesophageal adenocarcinomas [HR: 0.84, 95% CI: 0.73-0.96]. These findings support the view that diabetes, body mass index and waist circumference increase risk of gastroesophageal adenocarcinoma while increased fiber intake may decrease risk.

Citation Format: Bryan P. LaBore, Anna E. Prizment, Frank G. Ondrey, Kristin E. Anderson. Association of diabetes and obesity with risk of esophageal and gastric adenocarcinoma in the Iowa Women's Health Study (IWHS). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2174. doi:10.1158/1538-7445.AM2014-2174
Abstract 2178: Rotating night shift work and cancer mortality in the nurses' health study
Authors: Gu Fangyi , Han Jiali , Hankinson Sue , Schernhammer Eva , Group Nurses' Health Study
Published: May 2015

Rotating night-shift work is common in western societies, but epidemiological studies on shift work and cancer mortality are limited.

In a prospective closed cohort of 74,914 registered US nurses, the Nurses' Health Study, we examined the impact of rotating night-shift work on total-cancer and cancer-specific mortality. Rotating night-shift work was defined as having worked at least 3 nights per month. Cox proportional hazards models adjusting for age, smoking, BMI, and other important confounders, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

During 22 years of follow-up, we documented 5,123 cancer deaths. Overall, we observed no association between rotating night-shift work and total-cancer mortality (HR15+years=1.07; 95% CI, 0.97-1.19; Ptrend=0.17). However, women with 15 or more years of night-shift work had a significant increase in lung cancer mortality (multivariable HR=1.25; 95% CI, 1.04-1.50) and a borderline significant increase in colorectal cancer mortality (MV HR=1.32; 95% CI, 0.97-1.81). The increase in lung cancer mortality was limited to current smokers. We observed no increase in breast cancer mortality (HR15+years=1.03; 95%CI, 0.76-1.38; Ptrend=0.97). For cancers with fewer than 200 deaths, we observed a non-significant increase in mortality from kidney cancer, myeloma and leukemia among women with 6-14 and 15+ years of rotating night-shift work: the HRs were 1.58 (95% CI, 0.92-2.71) and 1.36 (95% CI, 0.72-2.56) for kidney cancer, 1.66 (95% CI, 0.98-2.81) and 1.47 (95% CI, 0.79-2.77) for myeloma, 1.25 (95% CI, 0.70-2.23) and 1.53 (95% CI, 0.83-2.83) for leukemia, respectively.

We conclude that after adjusting for important confounders, the impact of rotating night-shift work on cancer mortality appears modest. Women working rotating night-shifts for more than 15 years had modestly increased colorectal and lung cancer mortality but the increase in lung cancer mortality was largely limited to current smokers and it is possible that these observations remain residually confounded by smoking. Additional studies are warranted to confirm our findings.

Citation Format: Fangyi Gu, Jiali Han, Sue Hankinson, Eva Schernhammer, Nurses' Health Study Group. Rotating night shift work and cancer mortality in the nurses' health study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2178. doi:10.1158/1538-7445.AM2014-2178
Abstract 2203: Pathway analysis of genome-wide association study data highlights taste transduction and metabolic pathways and esophageal squamous cell carcinoma susceptibility
Authors: Hyland Paula L. , Zhang Han , Yang Qi , Lin Shih-Wen , Maeder Dennis , Hu Nan , Tang Ze-Zhong , Su Hua , Wang Lemin , Wang Chaoyu , Ding Ti , Fan Jin-Hu , Qiao You-Lin , Wheeler William , Giffen Carol , Burdett Laurie , Wang Zhaoming , Chanock Stephen J. , Dawsey Sanford M. , Freedman Neal D. , Abnet Christian C. , Goldstein Alisa M. , Yu Kai , Taylor Philip R.
Published: May 2015

Background: In China, esophageal cancer is the fourth leading cause of cancer death and essentially all cases are histologically esophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses applied to GWAS data can identify biological pathways and/or groups of genes enriched with disease-associated variants whose individual effect sizes may be too small to be detected by standard single locus methods. Methods: We used the adaptive rank-truncated product (ARTP) method to analyze 1,827 pathways containing 69,420 genes in GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. Pathways were retrieved from five databases: KEGG, BioCarta, Reactome, HumanCys and NCI-Nature curated. Statistical significance was determined by permutation. Results: Associations with ESCC risk (P<0.001) were observed for 60 pathways, which included overlapping pathways from different sources predominantly associated with cell cycle control and signaling, DNA repair, and apoptosis. After excluding genes with previous GWAS hits from the pathway analysis, the KEGG taste transduction pathway and the KEGG metabolic pathways were significantly associated with risk of ESCC (P<0.001). The most significant genes (P<0.001) in these pathways were TAS2R13, TAS2R42, TAS2R14, TAS2R46 and TAS2R50, and MTAP, GAPDH, DCTD, POLD2 and AMDHD1, respectively. Significance: This approach provides new insights into the collective role of genetic variants and ESCC risk in Han Chinese and suggests that genetic alterations associated with taste transduction and metabolic pathways may contribute to cancer susceptibility.

Citation Format: Paula L. Hyland, Han Zhang, Qi Yang, Shih-Wen Lin, Dennis Maeder, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Stephen J. Chanock, Sanford M. Dawsey, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor. Pathway analysis of genome-wide association study data highlights taste transduction and metabolic pathways and esophageal squamous cell carcinoma susceptibility. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2203. doi:10.1158/1538-7445.AM2014-2203
Abstract 2213: Uncommon CHEK2 missense variant and reduced risk of pancreatic cancer
Authors: Scelo Ghislaine , McKay James , Holcatova Ivana , Janout Vladimir , Foretova Lenka , Fabianova Eleonora , Chabrier Amelie , Gaborieau Valerie , Brennan Paul
Published: May 2015

CHEK2 is a cell cycle control gene encoding for checkpoint kinase 2, which acts as a tumor suppressor by causing arrest or apoptosis in response to unrepaired DNA damage. Inherited mutations in the CHEK2 gene have been reported to increase the risk of several cancers, although a paradoxical decrease in risk of tobacco-related lung and head and neck cancers was reported. An association between CHEK2 mutations and pancreatic cancer risk has not been reported. Missense variant rs17879961 (replacement of T by C, resulting in the change of Isoleucine by Threonine at position 157 of the protein [I157T]) has been shown to be very rare in the US and western Europe populations (<1%) while more common in central Europe countries (∼5%). We genotyped 585 pancreatic cancer cases and 664 controls recruited in central Europe (Czech Republic and Slovakia). The heterozygous (T/C) genotype was observed in 2.1% of cases and 4.4% of controls. After adjustment for age, sex, and center of recruitment, T/C genotype was associated with a significantly lower incidence of pancreatic cancer than the common T/T genotype (odds ratio [OR]=0.41, 95% confidence interval [CI] 0.20-0.83, p=0.0132). ORs were of similar magnitude by smoking status, diabetes history, and body mass index categories, while an apparent difference by drinking status with observed: OR=0.24 (95% CI 0.09-0.64) for non-drinkers versus OR=0.88 (95%CI 0.31-2.53), p for heterogeneity=0.078. This counter-intuitive halving of the pancreatic cancer risk for CHEK2 rs17879961 T/C carriers warrants replication and functional studies to elucidate mechanisms involved.

Citation Format: Ghislaine Scelo, James McKay, Ivana Holcatova, Vladimir Janout, Lenka Foretova, Eleonora Fabianova, Amelie Chabrier, Valerie Gaborieau, Paul Brennan. Uncommon CHEK2 missense variant and reduced risk of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2213. doi:10.1158/1538-7445.AM2014-2213
Abstract 2227: An automatic pipeline to find and annotate rare subclonal somatic variants in a paired tumor/normal sample
Authors: Joecker Anika , Pearson Nathan , Boysen Cecilie , Thomson Naomi , Hein Anne-Mette , Oster Bodil , Arens Anne , Knudsen Bjarne , Knudsen Thomas , Richards Dan , Forsberg Roald
Published: May 2015

Identifying and characterizing somatic variants in deep genome sequence data from tumor samples remains challenging and time-consuming. Of special interest in cancer research and diagnostics is the detection and annotation of rare subclonal somatic variants found only in a small proportion of primary tumor cells. Such variants can drive tumor spread and recurrence, but are often neglected in choosing treatments.

Currently, few tools reliably distinguish such rare subclonal variants from sequencing errors. And even among real somatic variants, drivers (of tumor growth, spread, or resistance) are hard to distinguish from passengers. Doing so entails integrating diverse information on variants, genes, pathways, cancer-relevant phenotypes, and treatments (including insights on population allele frequencies and broader evolutionary conservation; known/likely effects on gene product structure, function, expression, and interaction; and relations among gene products, phenotypes, and drugs). Software for effectively integrating such data in light of genomic variation in samples, to highlight relevant findings through clear visualization, has been a pressing need.

Here we present an end-to-end analysis workflow for finding and functionally characterizing rare subclonal variants, using the newly developed CLC Cancer Research Workbench to feed the interpretive platform of Ingenuity Variant Analysis, to identify cancer driver mutations in paired tumor/normal samples. We will show new interesting results from this analysis, which were not shown beforehand on this publicly available cancer dataset (Case Reports in Oncological Medicine, Volume 2013 (2013), Article ID 270362) from a patient with massive acinic cell carcinoma.

Citation Format: Anika Joecker, Nathan Pearson, Cecilie Boysen, Naomi Thomson, Anne-Mette Hein, Bodil Oster, Anne Arens, Bjarne Knudsen, Thomas Knudsen, Dan Richards, Roald Forsberg. An automatic pipeline to find and annotate rare subclonal somatic variants in a paired tumor/normal sample. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2227. doi:10.1158/1538-7445.AM2014-2227
Abstract 2230: Gene mutations and deletions inactivates PTEN tumor suppressor in Chilean colon cancer patients
Authors: Encina Gonzalo , Alvarez Karin , Orellana Paulina , Wielandt Ana María , Villarroel Cynthia , Simian Daniela , Contreras Luis , Kronberg Udo , López Francisco , Carvallo Pilar
Published: May 2015

Introduction. Tumor suppressor PTEN acts as a negative regulator of the PI3K/AKT/mTOR pathway, thus controlling cell survival and proliferation. Mutations or deletions inactivating PTEN function lead to over-activation of the PI3K/AKT/mTOR pathway in cancer. PTEN gene alterations have been described in different types of tumors. In colon cancer these mutations range from 1% to 29% of the cases. The aim of this study was to determine the prevalence of PTEN mutations and/or deletions in Chilean colon cancer patients. Methods: ninety-one colon cancer patients were recruited for this study. Genomic DNA from normal and tumor tissue was obtained, and the deletion of PTEN locus was determined by PCR amplification of three STR markers flanking PTEN, and two intragenic markers. To search point mutations we amplified exons 7 and 8 by PCR, and sequenced. PTEN expression was evaluated through immunohistochemistry. Results: We observed deletion events in 9.8% (9/91) of tumors, and inactivating mutations in 5.5% (5/91). Two tumors presented a deletion in one allele and a mutation in the other. Immunohistochemistry detected a very weak expression of PTEN in 55/76 tumors. Conclusions: 15.4 % (12/91) of tumors have PTEN gene inactivated. We observed that deletion was a frequent mechanism for PTEN inactivation in Chilean colon cancer patients.

Note: This abstract was not presented at the meeting.

Citation Format: Gonzalo Encina, Karin Alvarez, Paulina Orellana, Ana María Wielandt, Cynthia Villarroel, Daniela Simian, Luis Contreras, Udo Kronberg, Francisco López, Pilar Carvallo. Gene mutations and deletions inactivates PTEN tumor suppressor in Chilean colon cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2230. doi:10.1158/1538-7445.AM2014-2230