bluuebunny/crossref_metadata_2025_split 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

Abstract
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

Abstract
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&lt; 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

Abstract
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

Abstract
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

Abstract
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 &gt;32 to 35% (p43 to 47% (p25 to 30% (p44% (p53% (p60% (p&lt;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

Abstract
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

Abstract
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

Abstract
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