bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2133: Suppressing effect of a Kava fraction on two lineages of prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model
Authors: Tang Su-Ni , Datta Palika , Jiang Peixin , Leitzman Pablo , Xing Cheng-guo , Jiang Cheng , Lu Junxuan
Published: May 2015

Kava (Piper methysticum Forest) is a crop historically originating from west Pacific Islands. The epidemiologic studies for Pacific Island populations indicated that their cancer incidence rates were inversely related to the local consumptions of kava. Whereas chemopreventive efficacy of Kava ethanol extract has been shown in chemically-induced lung carcinogenesis models, its efficacy against prostate carcinogenesis is not known. In this study, we aim to evaluate the efficacy of Kava Fraction B, which is mostly kavalactones and free of flavokawains and most potent in lung carcinogenesis models, on prostatic carcinogenesis in the well-characterized C57BL/6 transgenic adenocarcinoma of mouse prostate (TRAMP) preclinical model. Previous studies by us (The Prostate, 2011) and others have suggested a paradigm of distinct lineages of carcinogenesis in this model: i.e., at least, androgen receptor (AR)-dependent glandular epithelia lesions (usually arise from the dorsal-lateral prostate [DLP] lobes) and AR-independent neuroendorine (NE)-like poorly differentiated (PD) carcinomas (usually derive from the ventral prostate [VP] lobe).

Experimentally, male C57BL/6 TRAMP mice were fed AIN93M purified diet without or with 0.4% of Kava fraction B from 8 weeks of age (WOA). Mice were euthanized at either 16 WOA or 28 WOA unless large tumors necessitated earlier sacrifice. The growth of the DLP in Kava-treated TRAMP mice were inhibited by 70% (P<0.05) from control TRAMP mice by 16 WOA. By 28 WOA, the inhibition of TRAMP DLP growth were 76% (P<0.001). Furthermore, Kava-fed TRAMP mice cohort had lower incidence of palpable and dissectable tumors (2 out of 14 mice) than control mice (7 out of 14 mice). Therefore, Kava fraction B appeared to inhibit both epithelial lineage lesions and NE-carcinogenesis. Future work will focus on 1) profiling cellular processes and molecular targets of Kava fraction B and 2) identifying active compounds in Kava Fraction B that inhibit epithelial lineage lesions and NE-carcinogenesis.

Supported in part by NCCAM AT007395 R01 and NCI CA142649 R01 grants.

Citation Format: Su-Ni Tang, Palika Datta, Peixin Jiang, Pablo Leitzman, Cheng-guo Xing, Cheng Jiang, Junxuan Lu. Suppressing effect of a Kava fraction on two lineages of prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model. [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 2133. doi:10.1158/1538-7445.AM2014-2133
Abstract 2136: Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study
Authors: Cho Soo-Jeong , Kim Young-Il , Kim So Young , Park Jong-Hyock , Choi Il Ju , Lee You Jin , Lee Eun Kyung , Kook Myeong-Cherl , Kim Chan Gyoo , Ryu Keun Won , Kim Young-Woo
Published: May 2015

Background: Metformin use has been associated with a decreased incidence and mortality of various cancers.

Aim: The aim of this study was to evaluate the association between metformin use and gastric cancer.

Methods: We randomy selected 100,000 type 2 diabetic patients from the 2004 Korean National Health Insurance claim database, and assessed gastric cancer incidence among 39,989 patients (aged 30-97 years) who were regularly treated with anti-diabetic drugs and followed-up from 2004 to 2010. In total, 26,690 patients had used metformin out of 32,978 diabetics who had not regularly used insulin (insulin non-users), and 5,855 patients had used metformin out of 7,011 regular insulin users.

Results: Patients who used metformin showed a lower incidence of gastric cancer than those who did not use metformin, in insulin non-users (P=0.047, log-rank test). However, in patients on regular insulin, there was no difference of gastric cancer incidence according to metformin use. In insulin non-users, the adjusted hazard ratio (AHR) for metformin use was 0.73 (95% confidential interval [CI], 0.53-1.01) with borderline statistical significance (P=0.059). Duration of metformin use was associated with the reduction of gastric cancer risk (AHR, 0.88; 95% CI 0.81-0.96, P=0.003), especially in patients that used metformin for more than 3 years (AHR, 0.57; 95% CI, 0.37-0.87; P=0.009).

Conclusion: Metformin use >3 years in type 2 diabetics who do not use insulin is associated with significantly reduced gastric cancer risk.

Citation Format: Soo-Jeong Cho, Young-Il Kim, So Young Kim, Jong-Hyock Park, Il Ju Choi, You Jin Lee, Eun Kyung Lee, Myeong-Cherl Kook, Chan Gyoo Kim, Keun Won Ryu, Young-Woo Kim. Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort 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 2136. doi:10.1158/1538-7445.AM2014-2136
Abstract 214: Androgen resistance in prostate cancer is associated with an enrichment of stem-like cells
Authors: Wu Lisa Y. , Bansal Nitu , Liu Tiancheng , Berkman Clifford E. , Bertino Joseph R.
Published: May 2015

Cancer Stem cells (CSCs) or tumor initiating cells (TICs) have recently been identified in solid tumors; however, the role of CSCs/TICs in metastasis remains poorly understood. In this study, we developed a pre-clinical model to study stem-like cells in prostate cancer metastasis. CS-5 and CS-10 cells were derived by growing parental LNCaP cells in androgen-depleted media for five and ten generations. The growth rate of CS-10 cells was similar to parenteral LNCaP cells while CS-5 cell growth was diminished. Interestingly, CS10 cells were the sole cells observed with CD44 expression, which also had the highest α2β1 expression. In addition, none of the cell lines expressed CD133. In contrast to parenteral LNCaP cells, CD44+ CS-10 cells displayed an increase in 5 min collagen-I attachment, cell migration, invasion, colony formation and sphere formation in an anchorage-independent environment, all attributes of TICs. Additional evidence for “stemness” was that CS-10 cells were capable of self-renewal in the secondary and tertiary spheroid assays. CS-10 cells expressed neuroendocrine and EMT markers and demonstrated resistance to anti-androgen drugs and most chemotherapeutic drugs compared to parenteral LNCaP cells.

In summary, the novel findings presented here provide evidence that castrate resistance may result in selection of CD44+/ α2β1+/CD24low/CD133 cells, which possesses stem cell properties. This cell line may serve as a model for evaluation of new targeted treatments in prostate CSCs.

Citation Format: Lisa Y. Wu, Nitu Bansal, Tiancheng Liu, Clifford E. Berkman, Joseph R. Bertino. Androgen resistance in prostate cancer is associated with an enrichment of stem-like 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 214. doi:10.1158/1538-7445.AM2014-214
Abstract 2140: Efficacy of aerosolized pioglitazone in lung carcinogenesis in A/J mice
Authors: Seabloom Donna , Galbraith Art , Wuertz Beverly , Haynes Anna , Antonides Jenny , fujita alisha , Steele Vernon , Wattenberg Lee , Ondrey Frank G.
Published: May 2015

Pioglitazone is a PPAR gamma agonist commonly utilized clinically in the treatment of diabetes. There have been clinical trials with this agent in oral cancer prevention and we sought to potentially expand its use in lung cancer in a B[a]P mouse model. Directed epithelial delivery in lung cancer is an attractive treatment approach and we felt pioglitazone would be amenable to aerosol delivery. Initially, a maximum tolerated dose experiment examining standard toxicity parameters, including animal behavior characteristics, weight, general health, and increases in markers of cytotoxicity in bronchoalveolar lavage was conducted. We found no statistically significant indications of increased toxicity in the animals with administration of aerosolized pioglitazone and proceeded with the prevention protocol. We utilized 192 seven week old female A/J mice. All groups received Benzo[a]pyrene by oral gavage in 3 doses of 3mg/kg body weight over the course of 1 week. Animals were then randomized into 8 groups of 24 mice per group based on weight. Experimental diets, 0, 50, 150, and 450µg/kg body weight pioglitazone formulated into 0.6µm average diameter respiratory particles, were started 1 week or 8 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 in the late treatment group was 10.69 ± 1.685 in the control, 12.27 ± 1.761 in the 50µg, 6.000 ± 0.6359 in the 150 µg, and 7.267 ± 1.071 in the 450µg groups but low control tumor counts in the early treatment group precluded analysis. The same tumor initation protocol was used with 72 mice. Animals were randomized into 3 groups of 24 animals and treated with 0, 150, or 450µg/kg body weight aerosol pioglitazone for 16 weeks starting 1 week after the last B[a]P dose. The average number of adenomas per animal was 9.217 ± 1.004 in the control, 7.957 ± 0.9440 in the in the 150 µg, and 6.304 ± 0.8653 in the 450µg groups. We conclude aerosol pioglitazone is well tolerated in the A/J mouse model and a promising chemoprevention agent in the aerodigestive tract.

Citation Format: Donna Seabloom, Art Galbraith, Beverly Wuertz, Anna Haynes, Jenny Antonides, alisha fujita, Vernon Steele, Lee Wattenberg, Frank G. Ondrey. Efficacy of aerosolized pioglitazone in lung carcinogenesis 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 2140. doi:10.1158/1538-7445.AM2014-2140
Abstract 2141: Dietary feeding of Kava root extract inhibits prostate carcinogenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model
Authors: Li Xuesen , Blair Christopher A. , Zi Xiaolin
Published: May 2015

Kava kava has been traditionally used to prepare beverages and herbal medicines in the Pacific Islands. Men living in Fiji and drinking kava have low incidence of prostate cancer (PCa). However, the PCa incidence among Fijian men who had migrated to Australia, increased by 5.1-fold. To determine the chemopreventive efficacy of kava root extracts, TRAMP mice were fed with commercial kava root extract supplemented food. In the prevention protocol, TRAMP mice were fed with 3 or 6 g (0.3% or 0.6%) kava root extract /kg food starting at 6 weeks of age and ending at 12 weeks of age, resulting in decreased numbers of high-grade prostatic intraepithelial neoplasia and moderately differentiated adenocarcinomas in kava root extract fed mice compared to the mice fed with control food (p<0.01). In the intervention protocol, in which TRAMP mice were fed with 0.3% or 0.6% kava root extract food starting at 6 weeks of age and ending at 24 weeks of age, the average genitourinary (GU) weight of 0.6% kava root extract fed mice was significantly reduced when compared to control food fed mice (1.98±2.07 gram vs.3.63±4.28 gram, p<0.05, Mann-Whitney U and Kolmogorov-Smirnov test). The percentages of large tumors (GU weight > 0.9 gram) were also decreased from 86.4% in the control group to 52.2% and 43.5% in 0.3 and 0.6 % kava food groups, respectively. In addition, we showed that kawain, the main component of kava root extracts, inhibited LSD1 enzyme activity, enhanced H3K9 dimethylation and decreased the mRNA expression of androgen receptor target genes, including PSA and TMPRSS2, in LNCaP cells. Taken together, these results suggested that dietary consumption of kava products have the potential to reduce the risk of prostate cancer development.

Citation Format: Xuesen Li, Christopher A. Blair, Xiaolin Zi. Dietary feeding of Kava root extract inhibits prostate carcinogenesis in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. [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 2141. doi:10.1158/1538-7445.AM2014-2141
Abstract 215: Aminoflavone exhibits in vivo efficacy on cancer stem cells in a spontaneous estrogen-dependent breast cancer murine model
Authors: Callero Mariana , Berardi Damian , Todaro Laura , Simian Marina , Brantley Eileen J. , Soto Ubaldo , Loaiza-Perez Andrea
Published: May 2015

Stem-cell populations have been identified in a range of solid tumors and possess the capacity to self renew. It is thought that these cancer stem cells (CSCs) play an important role in cancer establishment, progression, and resistance to current treatments. CSCs have been identified in primary breast cancer tissues and cell lines derived from metastatic tumors. Traditional cancer therapies are effective at debulking some tumors but often fail to produce long-term clinical remissions, presumably due to their inability to eradicate the cancer stem cell population. Therefore, novel treatments aimed at targeting this population can potentially enhance treatment of both primary and metastatic tumors. Aminoflavone (AF; NSC 686288) is a novel anticancer agent. Previous work from our research group demonstrated that AF is a ligand of the aryl hydrocarbon receptor (AhR) and displays cytotoxicity in the MCF-7 breast cancer cell line. A prodrug formulation of AF (AFP464, NSC710464), recently entered phase II clinical trials. Moreover, we previously found that AF disrupts MCF-7 mammosphere formation via AhR signaling activation to inhibit alpha 6-integrin expression. To investigate the efficacy of AF in vivo, we used an estrogen dependent, Tamoxifen-sensitive spontaneous M05 model system involving 1-year-old virgin female BALB/c mice developed in our animal facility. The M05 tumor is a semi-differentiated adenocarcinoma that expresses estrogen and progesterone receptors. After AF treatment (12 mg/kg, i.p., QD × 5 days) tumor size and growth rate decreased substantially compared to control animals. Cytometric analyses of cells obtained from AF-treated and control animals revealed that Lin (-)/ CD29 (Hi)/CD24 (+) cancer stem cells were lower in animals treated with AF than in the vehicle control group. We also observed a diminished capacity for mammosphere formation in cells obtained from tumors treated with AF. These data suggest AF diminishes the quantity of breast cancer stem cells as well as their integrity and capacity to form mammospheres in vitro and in vivo. These findings shed additional insight into the molecular mechanism of anticancer action for this novel anticancer agent to strengthen the rationale for its inclusion in breast cancer treatment regimens.

Citation Format: Mariana Callero, Damian Berardi, Laura Todaro, Marina Simian, Eileen J. Brantley, Ubaldo Soto, Andrea Loaiza-Perez. Aminoflavone exhibits in vivo efficacy on cancer stem cells in a spontaneous estrogen-dependent breast cancer murine model. [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 215. doi:10.1158/1538-7445.AM2014-215
Abstract 2150: Chemopreventive effects of black raspberries in endometrial cancer
Authors: Chen Jo-Hsin , Aguilera-Barrantes Irene , Kuo Chieh-Ti , Hilakivi-Clarke Leena , Stoner Gary D. , Rader Janet S. , Huang Yi-Wen
Published: May 2015

Endometrial cancer is the most common type of gynecologic cancer and annually comprises 3% of all cancer deaths of women in the United States. Additionally, ∼80% of cases are type I endometrial cancer, mainly associated with Pten abnormalities. It was estimated that up to 90% of type I endometrial cancer patients are overweight/obese. Therefore, a regimen to prevent obesity associated tumorigenesis is the most important for type I endometrial cancer. In the current study, the Pten heterozygous (+/-) female mice were used as the model, to study the potentially chemopreventive effects by black raspberries (BRBs). At 3-4 weeks old, Pten (+/-) and wild type female mice were divided into four treatment groups, fed with either AIN-93G control diet (CD), CD with 5% BRBs, 58% fat to induce obesity (HF),or HF with 5% BRBs. All of mice were euthanized at 28 weeks old. In wild type mice, no malignant lesion was identified. In Pten (+/-) mice, HF diet increased 10% focal glandular hyperplasia with atypia lesions when compared with CD diet. Dietary administration of BRBs decreased 19% focal glandular hyperplasia with atypia lesions when compared with CD group. Specifically, BRBs in HF diet inhibited 32% obesity-induced endometrial malignant lesions and significantly lowed lesion multiplicity. Furthermore, cytokine profiles in plasma by Bio-Plex Assay revealed dietary BRBs decreased IL-1β and IL-17A, and lowed TNF-α and GM-CSF when compared with CD and HF group, respectively. In conclusion, this study for the first time suggested BRBs are chemopreventive for obesity-induced endometrial tumorigenesis.

Citation Format: Jo-Hsin Chen, Irene Aguilera-Barrantes, Chieh-Ti Kuo, Leena Hilakivi-Clarke, Gary D. Stoner, Janet S. Rader, Yi-Wen Huang. Chemopreventive effects of black raspberries in endometrial 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 2150. doi:10.1158/1538-7445.AM2014-2150
Abstract 2152: Akt/survivin pathway inhibition synergizes the apoptotic cell death induced by A-santalol in prostate cancer cells
Authors: Bommareddy Ajay , Lockus Lauren , Seward Jonathan , Eggelston William , Prelewicz Stacy , Antal Andrea , Fillman Sarah , Castro Christian , VanWert Adam L. , Santha Sreevidya , Dwivedi Chandradhar
Published: May 2015

α-santalol, a major component of sandalwood oil inhibits growth of cultured prostate cancer cells in vitro by causing apoptosis. The present study was undertaken to investigate the mechanistic details associated with the induction of apoptosis by α-santalol in cultured prostate cancer cells (LNCaP and PC-3). Expressions of major proteins studied in the present investigation were determined using standard Western blot protocol and analyzed by LICOR-Odyssey infra-red scanner. Activity of survivin was confirmed employing survivin ELISA kit. The cell viability was determined by trypan blue dye exclusion assay and caspase-3 activity was confirmed using caspase-3 (active) ELISA kit. Treatment of prostate cancer cells with α-santalol (20, 40 µM) resulted in the down regulation of survivin, XIAP and p-AKT (s-473) levels. Furthermore, α-santalol significantly reduced the activity of survivin as evidenced by survivin ELISA assay. Inhibition of PI3K/Akt by pharmacological inhibitor LY294002 synergized the apoptotic cell death induced by α-santalol as determined by cell viability, active caspase-3 activity and expression of cleaved PARP, caspase-3 levels. In conclusion, the present study reveals that α-santalol downregulates activity and expression of survivin and that inhibition of PI3K/Akt pathway synergize the apoptotic cell death by downregulating survivin. This study was supported by Mentoring Task Force, Type I grant by Wilkes University and by Translational Cancer Research Center funded by South Dakota Governor's Office of Economic Development.

Citation Format: Ajay Bommareddy, Lauren Lockus, Jonathan Seward, William Eggelston, Stacy Prelewicz, Andrea Antal, Sarah Fillman, Christian Castro, Adam L. VanWert, Sreevidya Santha, Chandradhar Dwivedi. Akt/survivin pathway inhibition synergizes the apoptotic cell death induced by A-santalol in prostate 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 2152. doi:10.1158/1538-7445.AM2014-2152
Abstract 2155: Novel combinations of nano-formulated ferulic acid and aspirin show high potential for chemoprevention of pancreatic cancer
Authors: Thakkar Arvind , Wang Jeffrey , Prabhu Sunil
Published: May 2015

Pancreatic cancer ranks as the fourth most deadly form of cancer in the United States with about 37,000 deaths each year. This study evaluated the chemopreventive potential of combinations of free and nano-encapsulated mixtures of ferulic acid (FA) and aspirin (ASP) in low doses to human pancreatic cancer cells, MIA PaCa-2 and Panc-1. Cell lines were tested according to published protocols wherein cells were seeded in 96-well microplates and incubated with the unmodified and modified combinations for 72 h and analyzed using MTS cell viability assay method. Apoptosis was measured by flow cytometry. Results demonstrated that free FA (200 µM) and ASP (1 mM) combinations on average reduced cell viability by 60% (P<0.001), and also induced cell apoptosis by 47% (P<0.001) on the two cell lines. However, when individual agents (FA 200 μM; ASP 1mM) were tested, they were virtually ineffective in reducing cell viability, thus indicating an additive/synergistic effect of the two agents in combination. Subsequently, nano-formulations of FA and ASP (nano-FA and nano-ASP) were prepared by encapsulating the agents within solid lipid nanoparticles (SLNs) and tested on the same cell lines. Prior to this, nano-FA and nano-ASP were evaluated for particle sizes and encapsulation efficiencies. Initial particle sizes were 183± 46 nm (nano-FA) and 229±67 nm (nano-ASP), respectively. Furthermore, the encapsulation efficiencies were high for both nano-FA (86%) and nano-ASP (78%). The combination mixture of nano-FA (25 µM) and nano-ASP (25 µM) reduced the cell viability of MIA PaCa-2 and Panc-1 cells by 70% (P<0.001), and also induced cell apoptosis by 30% (P<0.01), thus reducing the dosage of FA by 8-fold and that of ASP by 40-fold to elicit a comparable response as the mixture of the free FA and ASP. Finally, a trans-AM NF-κB transcription factor assay kit was used to help understand the mechanism. Our results demonstrate that nano-FA and nano-ASP combinations significantly down-regulated NF-κB DNA binding activity in MIA PaCa-2 and Panc-1 cells. In conclusion, convincing evidence is provided of the chemopreventive potential of combinations of FA and ASP against pancreatic cancer, especially when formulated within a nanotechnology-based delivery system.

Citation Format: Arvind Thakkar, Jeffrey Wang, Sunil Prabhu. Novel combinations of nano-formulated ferulic acid and aspirin show high potential for chemoprevention 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 2155. doi:10.1158/1538-7445.AM2014-2155
Abstract 2163: Height, weight and weight changes during adulthood and thyroid cancer risk
Authors: Hwang Yunji , Lee Kyu-Eun , Park Young Joo , Park Do Joon , Youn Yeo-Kyu , Yeo Yohwan , Ma Seung-Hyun , Kang Daehee , Yoo Keun-Young , Park Sue K.
Published: May 2015

BACKGROUND: Incidence of thyroid cancer has been rapidly increased, in not only small sizes with improved detection devices but also large size of tumors whose underlying mechanisms remain unclear. Body size and weight change in adulthood were examined as the potential risk factors for thyroid cancer development.

METHODS: A large scale case-control study was conducted with constructed questionnaire for their height, weight (current, 2 years ago, at the age of 20 and 35 years old) and confounders. Medical charts were reviewed for cancer histology, tumor aggressiveness and BRAF mutation status. A total of 2,003 cases (1,611 females and 392 males) and individually matched 17,700 controls (13,983 females and 3,717 males) by age, sex, 12-year education and birth year were included. Logistic regression model were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

RESULTS: Having a tall height and heavy weight was associated with increased risk in both females [OR and 95%CI for height and weight: 1.46 (1.25-1.71) and 2.66 (2.24-3.15), respectably] and males [OR and 95%CI for height and weight: 1.71 (1.25-2.34) and 2.80 (2.00-3.92), respectably] compared to those in the lowest quartile for the body sizes. This study observed approximated tripled the risk of thyroid cancer [OR and 95%CI: 3.03 (2.10-4.37)] when female subjects gained 10kg or more within recent 2 years. Males who gained 10 kg or more after 35 years old were more likely to have a greater tumor size [<1cm vs. ≥1cm: 3.76 (2.62-5.38) vs. 6.87 (4.38-10.77)]. However, other factors were not significantly related to increased tumor aggressiveness (tumor size, lymph node metastasis, and mutlifocality) and BRAF mutation affected carriers.

CONCLUSION: The results support plausible hormonal and metabolic factors related height, weight, and rapid weight gain in adulthood increase thyroid carcinogenesis.

Citation Format: Yunji Hwang, Kyu-Eun Lee, Young Joo Park, Do Joon Park, Yeo-Kyu Youn, Yohwan Yeo, Seung-Hyun Ma, Daehee Kang, Keun-Young Yoo, Sue K. Park. Height, weight and weight changes during adulthood and thyroid cancer risk. [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 2163. doi:10.1158/1538-7445.AM2014-2163
Abstract 2179: Relationship between daily habits and risk of death in patients with biliary tract cancer: a large-scale cohort study in Japan
Authors: Otani Shinji , Kurozawa Youichi , Hosoda Takenobu , Mu Haosheng , Onishi Kazunari , Yokoyama Yae , Watanabe Joji , Sakamoto Teruhisa , Endo Kanenori , Ikeguchi Masahide
Published: May 2015

Objective: Biliary tract cancer is one of the deadliest diseases in East Asia. Death due to this disease comprises 5% of total cancer deaths in Japan. This study was conducted to evaluate the relationship between biliary tract cancer and daily habits using data from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk sponsored by the Japanese Ministry of Education (JACC study).

Methods: In the JACC study, a cohort of 110,792 subjects aged 40-79 from 19 prefectures in Japan completed the baseline survey during 1988-1990. The subjects were followed up until 2009. The endpoint for the present study was death due to biliary tract cancer, coded as C22.1 (intrahepatic bile duct carcinoma, CCC), C23 (malignant neoplasm of the gallbladder, GB cancer), and C24 (malignant neoplasm of other and unspecified parts of the biliary tract, BD cancer) in the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). The hazard ratio (HR) of biliary tract cancer mortality for smoking and drinking habits, high intake of fatty food, body mass index, and the job category (office job, field work, and others) was evaluated. All results were considered to be significant at the 5% critical level.

Results: High intake of fatty food, smoking habit, and field work showed a significant positive association with death in female patients due to BD cancer in females [HR = 1.87, 95% confidence interval (CI): 1.03-3.39; HR = 1.56, 95% CI: 1.02-2.39; and HR = 2.23, 95% CI: 1.03-4.84, respectively]. No significant relationship was observed between daily habits and death due to CCC and GB cancer.

Conclusion: High intake of fatty food is often a key factor in the risk of death due to biliary tract cancer, and it is well known that smoking can cause various other cancers. Our findings support the results of a previous research. Moreover, our results suggest that occupational differences may have an effect on mortality in female patients with biliary tract cancer. Therefore, a more detailed analysis of the job category is required for a more meaningful interpretation of the data.

Citation Format: Shinji Otani, Youichi Kurozawa, Takenobu Hosoda, Haosheng Mu, Kazunari Onishi, Yae Yokoyama, Joji Watanabe, Teruhisa Sakamoto, Kanenori Endo, Masahide Ikeguchi. Relationship between daily habits and risk of death in patients with biliary tract cancer: a large-scale cohort study in Japan. [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 2179. doi:10.1158/1538-7445.AM2014-2179
Abstract 2192: Defective calcium signaling pathway highlights the mutational landscapes of liver metastasis from colorectal and breast cancer
Authors: Song Fangfang , Li Miao , Liu Yuexin , Song Fengju , Zhang Wei , Chen Kexin
Published: May 2015

Few therapeutic options are currently available to treat metastasis to distant organs (e.g., liver) in colorectal cancer (CRC) and breast cancer (BC) patients. To gain insight into the genetic and molecular underpinnings of metastasis, we performed whole-exome sequencing on paired primary and metastasis samples from 5 CRC and 2 BC patients and focused sequencing on additional 13-paired tumors to identify and validate somatic genetic alterations. The results showed that the mutational spectra of metastases were highly heterogeneous. Nevertheless, genetic aberrations in calcium signaling pathway genes (GPR98, SYT6, TACR3, CYSLTR1, RYR3, and CACNA1A) were somatically mutated in liver metastases in 25% of CRC and BC cases, indicating that calcium-dependent signaling plays a key role in distant metastasis. These results begin to define the genetic basis underlying liver metastasis from CRC/BC and identify potential therapeutic targets.

Citation Format: Fangfang Song, Miao Li, Yuexin Liu, Fengju Song, Wei Zhang, Kexin Chen. Defective calcium signaling pathway highlights the mutational landscapes of liver metastasis from colorectal and 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 2192. doi:10.1158/1538-7445.AM2014-2192
Abstract 2198: A literature-based sum score of genetic variants in IGF genes modifies associations between indicators of energy balance and colorectal cancer risk
Authors: Simons Colinda CJM , Schouten Leo J. , Godschalk Roger , Schooten Frederik-Jan van , Brandt Piet A. van den , Weijenberg Matty P.
Published: May 2015

Background: Gene-environment interactions between variants in growth-regulating IGF genes and energy balance in colorectal cancer (CRC) were studied in the Netherlands Cohort Study (NLCS) after 16.3 years follow-up.

Methods: Using a systematic strategy, we selected 25 SNPs and a CA repeat in IGF genes that had repeatedly demonstrated significant associations with CRC risk, energy balance-related exposures or related endpoints in literature, and thus likely modify effects of energy balance on CRC development. Twenty-four SNPs were successfully genotyped in toenail DNA of NLCS subcohort members (n=3,203) and CRC cases (n=2,274) with adequate exposure data. Unfavorable alleles were aggregated into a sum score. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated in case-cohort analyses for linear combinations between tertiles of the genetic sum score and 8 energy balance-related exposures.

Results: Significant and increasingly higher risks were observed for men with more adverse profiles compared to men with the most optimal profile. In particular carrying more unfavorable alleles in combination with a larger adult trouser/skirt size, an increased height or the absence of early life energy restriction during the Dutch Hunger Winter (1944-45) was associated with distal colon cancer [highest vs. lowest linear combinations: HR (95% CI) = 2.03 (1.27-3.24), 2.05 (1.16-3.63) and 1.87 (1.11-3.16), respectively]. A combined effect of IGF polymorphisms and energy balance-related exposures on subsite-specific CRC risk was less convincing in women.

Conclusion: Combined effects of IGF polymorphisms and specific energy balance-related exposures are important in CRC development in men, and less convincingly in women. The availability of extensive environmental data and the aggregation of genetic variants were invaluable for interpreting the joint associations.

Note: This abstract was not presented at the meeting.

Citation Format: Colinda CJM Simons, Leo J. Schouten, Roger Godschalk, Frederik-Jan van Schooten, Piet A. van den Brandt, Matty P. Weijenberg. A literature-based sum score of genetic variants in IGF genes modifies associations between indicators of energy balance and colorectal cancer risk. [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 2198. doi:10.1158/1538-7445.AM2014-2198
Abstract 220: Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features
Authors: Tanaka Shinji , Ogawa Kousuke , Murakata Ayano , Mogushi Kaoru , Matsumura Satoshi , Aihara Arihiro , Ban Daisuke , Ochiai Takanori , Irie Takumi , Kudo Atsushi , Nakamura Noriaki , Tanaka Hiroshi , Arii Shigeki , Tanabe Minoru
Published: May 2015

Hepatocellular carcinoma (HCC) is known to demonstrate a morphological variety of macroscopic appearances, but their pathological and molecular differences remain unclear.

First, the clinicopathologic characteristics as well as genome-wide gene expressions were analyzed in relation to the gross morphology of HCC. Among the patients with nodular type HCC, significantly poor prognosis was recognized in confluent multinodular (CM) type in overall survival as well as recurrence-free survival. Analysis of the genome-wide expression patterns revealed significant deference of CM-type HCC from other types of HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM-type HCC.

Next, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU. Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13, VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13. In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control. Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control.

Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and specific approach for the treatment of HCC with the poor prognostic phenotype.

Citation Format: Shinji Tanaka, Kousuke Ogawa, Ayano Murakata, Kaoru Mogushi, Satoshi Matsumura, Arihiro Aihara, Daisuke Ban, Takanori Ochiai, Takumi Irie, Atsushi Kudo, Noriaki Nakamura, Hiroshi Tanaka, Shigeki Arii, Minoru Tanabe. Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features. [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 220. doi:10.1158/1538-7445.AM2014-220
Abstract 2210: Cumulative risks of gastric cancer by PSCA polymorphism, Helicobacter Pylori infection and smoking history in Japan
Authors: Ito Hidemi , Oze Isao , Hosono Satoyo , Watanabe Miki , Tanaka Hideo , Matsuo Keitaro
Published: May 2015

Appreciating lifetime risk of gastric cancer through established risk factors is one simple way to promote preventive behavior. We have estimated cumulative risks (CRs) of gastric cancer by genetic and environmental risk factors, PSCA-rs2294008 polymorphism, Helicobacter Pylori (HP) infection and smoking, based on a case-control study involving 697 cases and 1372 controls at Aichi Cancer Center. We estimated odds ratio (OR) and 95% confidence interval (CI) for groups by these factors using logistic regression model after adjustment for age, sex, family history of gastric cancer and intake of fruit and vegetable. The ORs were combined with gastric cancer incidence rates in Japan to calculate CRs using the Peto's method. The CRs by age of 75 varied according to the risk groups, from 0.9% (95% CI, 0.3%-3.3%) for never smokers without both HP infection and risk allele of rs2294008 to 13.4% (95% CI, 13.3%-13.4%) for ever smokers with HP infection and 1-2 risk alleles. Among those with 1-2 risk alleles, the CRs were reduced to 2.0% (95% CI, 1.9%-2.0%) in those without both smoking history and HP infection, 3.9% (95% CI, 3.8%-3.9%) for ever smokers without HP infection, 9.4% (95% CI, 9.4%-9.5%) for never smokers with HP infection, although it was 13.4% in those with both smoking history and HP infection. In conclusion, the findings based on genetic and environmental risk factors in this study would be important information for promoting primary and secondary prevention of gastric cancer.

Citation Format: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo. Cumulative risks of gastric cancer by PSCA polymorphism, Helicobacter Pylori infection and smoking history in Japan. [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 2210. doi:10.1158/1538-7445.AM2014-2210
Abstract 2215: Association between single-nucleotide polymorphisms of BRAF and papillary thyroid carcinoma in a Chinese population
Authors: Chen Kexin
Published: May 2015

Background: Papillary thyroid cancer (PTC) is a common malignancy that frequently harbors a high prevalence of somatic mutations in the oncogenic BRAF gene. As a novel prognostic molecular marker, this gene has drawn much attention in recent years for its potential utility in the risk prognosis and management of PTC. However, the contribution of the germline variants in this gene to PTC remains unclear. The study herein was aimed to investigate the potential association between the inherited BRAF variants and PTC based on a case-control study.

Methods: We selected four single-nucleotide polymorphisms (SNPs) and took a systematic step to interrogate whether these SNPs of BRAF are associated with PTC risk by genotyping these SNPs from 368 patients with PTC and 564 healthy controls.

Results: In comparison of cases and controls for the four SNPs, no differences were observed in the genotypic and allelic frequencies, nor was there evidence of an association between BRAF SNPs and overall risk of PTC. After stratification, however, we found a significantly increased risk of PTC attributed to the SNP variants rs17161747, rs1042179, and rs3748093 for those with a family history of cancer, for smokers, and for both those of age <45 years and nondrinkers, respectively. Further, in the PTC cases, those carrying the rs3748093 variant seemed to be less susceptible to developing lymph node metastases, but more likely to suffer from PTC at an earlier age (< 45 years).

Conclusions: These preliminary results may provide evidence for the involvement of the common genetic variants scattered throughout the BRAF oncogene in the prediction of PTC onset and progression. In the future, enlarging the number of samples and performing functional studies in this gene may help to validate whether the association truly exists.

Citation Format: Kexin Chen. Association between single-nucleotide polymorphisms of BRAF and papillary thyroid carcinoma in a Chinese population. [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 2215. doi:10.1158/1538-7445.AM2014-2215
Abstract 2219: STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas
Authors: Spaccarotella Elisa , Pupuleku Aldi , Pellegrino Elisa , Bandini Cecilia , Ferracin Manuela , Cantarella Daniela , Rinaldi Andrea , Provero Paolo , Cunto Ferdinando D. , Medico Enzo , Bertoni Francesco , Inghirami Giorgio , Piva Roberto
Published: May 2015

Anaplastic large cell lymphoma (ALCL) represents a category of T-cell Non-Hodgkin Lymphomas characterized by marked cellular pleomorphism, and expression of CD30. Two systemic forms of ALCL are defined by the presence or absence of chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene at 2p23 locus. Among several pathways triggered by ALK signaling, it has been widely shown that the constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival.

To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we performed gene and miRNA expression profiling experiments in association with functional validation approaches. The transcriptome of STAT3 was analysed in ALK positive ALCL cell lines using a tightly controlled time course experimental condition, in which the STAT3 signalling was abrogated by an inducible short hairpin RNA (shRNA).

Gene expression profiling analysis identified a selected number of genes (1730) specifically modulated by STAT3 silencing. A significant overrepresentation of putative STAT3 binding sites was found in regulatory regions of early down-regulated genes. Functional studies using a shRNA lentiviral library established that Interferon Regulatory Factor-4 (IRF4) targeting specifically affect cell viability of ALK+ ALCL cells. In contrast, forced expression of IRF4 partially rescued STAT3 knock-down sustaining the survival of ALK+ cells.

In a parallel experiment, genome-wide miRNA expression profiling identified 48 miRNAs concordantly modulated by the inducible knock down of ALK and STAT3. Among these, we demonstrated that expression of miR-17∼92 cluster significantly reverted STAT3 deprivation, sustaining both proliferation and survival of ALCL cells.

In conclusion, genes and miRNA expression profiling associated to functional screenings allowed the identification of new biologically relevant targets for ALK+ALCL. We speculate that IRF4 and miR-17∼92 cluster are involved in the lymphomagenesis of STAT3+ ALCL, and that their inhibition might represent an alternative avenue to interfere with ALK signaling in Anaplastic Large Cell Lymphomas.

Citation Format: Elisa Spaccarotella, Aldi Pupuleku, Elisa Pellegrino, Cecilia Bandini, Manuela Ferracin, Daniela Cantarella, Andrea Rinaldi, Paolo Provero, Ferdinando Di Cunto, Enzo Medico, Francesco Bertoni, Giorgio Inghirami, Roberto Piva. STAT3 network dissection in ALK positive Anaplastic Large Cell Lymphomas. [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 2219. doi:10.1158/1538-7445.AM2014-2219
Abstract 2221: A new promoter of Casp 8 in an esophageal squamous cell carcinoma susceptibility locus
Authors: Lin Zhengwei , Zhao Xiaohang , Xu Yang , Guo Zhimin , Zhao Nan , Sun Yulin
Published: May 2015

Our previous Genome wide associationstudy (GWAS) of esophagealsquamous cell carcinoma (ESCC) identified a susceptibility locus on chromosome 2q33.1 encompassing CASP8 gene. Caspase 8 is an essential initiator in cell apoptosis and is associated with many diseases. CASP8 has varieties of transcripts, which might exert distinct functions. However, the transcriptional determinants, which control CASP8 gene expression remain poorly defined. The present study focused on revealing the mechanism behind the GWAS signal and finding clues for the complex regulation of CASP8.We observed a secondary promoter in CASP8 using a series of luciferase reporter assays, which locates 25kb far away from the previously described CASP8 promoter. The ENCODE ChIP-seq data shows the promoter features at the epigenetic level, including high H3K27Ac, H3K4M3 and low CpG methylation around the novel promoter region. Though people have known lots of transcription factors, little research focuses on which factors exert the transcription function for a certain promoteron earth. To explore the transcription factors that contribute to the secondary promoter of CASP8, we developed an effective strategy based on DNA-protein affinity purification and mass spectrometry. PURα was identified from the eluted protein products that the secondary promoter fragment could bind specific. We validated the mass spectrometry result through western blot analysis and immunoprecipitation assay and confirmed that PURα was involved in the transcription machine and might exert the function by forming a complex together with E2F-1 and Pol II. Remarkably, we observed that if knocking down the expression of PURα, the transcription activity decreased significantly. Although the physiologicrole of the CASP8 secondary promoter and its correspondent transcripts remain unclear, the current data suggest that it could explain the complexity of CASP8's transcription in some degree and expand the GWAS results to the function level. We believe these two promoters have thecapacity to play a role in the very different functions of caspase 8 isoforms.

Note: This abstract was not presented at the meeting.

Citation Format: Zhengwei Lin, Xiaohang Zhao, Yang Xu, Zhimin Guo, Nan Zhao, Yulin Sun. A new promoter of Casp 8 in an esophageal squamous cell carcinoma susceptibility locus. [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 2221. doi:10.1158/1538-7445.AM2014-2221