bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-172: MicroRNAs mediate the inhibition of tumor cell invasion by sulindac
Authors: Li Xiaobo , Gao Lin , Taylor William , Shevde Lalita , Samant Rajeev , Dean-Colomb Windy , Piazza Gary A. , Xi Yaguang 
Published: August 2012

Abstract
A large body of evidence indicates that nonsteroidal anti-inflammatory drugs (NSAIDs) have strong antineoplastic properties against a broad range of cancer types in early or late stage animal models of tumorigenesis. However, their use in humans for chemoprevention is limited by toxicities resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. The anticancer properties of NSAIDs are generally attributed to the suppression of tumor cell proliferation and induction of apoptosis by inhibiting cyclooxygenase (COX), although numerous studies suggest that a COX-independent mechanism may either contribute to or be fully responsible for their activity. The effect of NSAIDs on tumor cell motility and invasion has not been well studied, despite clinical studies showing that certain NSAIDs can significantly increase the survival of patients with metastatic disease. Our results show that the NSAID, sulindac sulfide (SS) can potently inhibit the motility of human breast (MDA-MB-231 and SUM1315) and colorectal (HCT116 and HT29) tumor cells by a mechanism that is distinct from its tumor cell growth and COX inhibitory activity. To study the molecular basis for this activity, we investigated the involvement of microRNA (miRNA). A total of 132 miRNAs were found to be altered in response to SS treatment including miR-10b, miR-17, miR-21, and miR-9, which have been previously implicated in tumor invasion and metastasis. We confirmed that these miRNAs can stimulate tumor cell invasion and show that SS can attenuate their invasive effects (individual and cooperative) by down-regulating their expression. Employing luciferase and chromatin immunoprecipitation (ChIP) assays, NF-κB was found to bind the promoters of all four miRNAs to regulate their expression at the transcriptional level. Results from the immunofluorescence and Western Blotting assays show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB, which leads to down-regulation of these miRNAs. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB binding sites. Our results demonstrate that SS can inhibit tumor cell invasion by suppressing NF-κB mediated transcription of miRNAs, which illustrate the mechanistic basis of this novel anticancer property of sulindac on tumor progression and metastasis. We expect these results are capable of supporting future clinical trials of sulindac in patients with metastatic disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-172. doi:1538-7445.AM2012-LB-172
Abstract LB-176: Chemoprevention of NNK-induced lung adenoma and adenocarcinoma in A/J mice by p53 modulating agents, CP-31398 and Prima-1
Authors: Rao Chinthalapally V. , Patlolla Jagan Mohan R. , Qian Li , Zhang Yuting , Brewer Misty , Mohammed Altaf , Desai Dhimant , Amin Shantu , Lightfoot Stan , Kopelovich Levy 
Published: August 2012

Abstract
Lung cancer is a leading cause of cancer deaths worldwide. p53 Mutations including wild-type p53 nuclear localization due to excessive endogenous electrophilic molecules are highly prevalent in tobacco associated lung cancers. Here, we report the chemopreventive effects of direct-acting p53 modulating agents, CP-31398 and Prima-1 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma in female A/J mice. Seven weeks-old mice on a regular AIN-76A diet, received one dose of 10 μmol NNK /mouse by i.p. injection. Three weeks after NNK treatment, groups of mice (25 mice/group) were fed control AIN-76A or experimental diets containing 50 and 100 ppm CP-31398, or 150 and 300 ppm Prima-1. Mice were sacrificed after 20 weeks (10 mice/group) and/or 36 weeks (15 mice/group) following NNK-treatment and evaluated for lung adenomas and adenocarcinomas by histopathological methods. Administration of 50 and 100 ppm CP-31398 significantly suppressed lung tumor formation by 29% and 39.5% (P&lt;0.01-0.0001), respectively after 20 weeks and 32.2% and 40.1% (P&lt;0.01-0.0001), respectively after 36 weeks. Similarly, 150 and 300 ppm Prima-1 significantly suppressed lung tumor formation by 22.2% and 34% (P&lt;0.04-0.0001) after 20 weeks and 28.8% and 47.4% (P&lt;0.01-0.0001) after 36 weeks, respectively. Inhibition of NNK-induced lung adenocarcinoma by either agent was greater than 55-72% (p&lt;0.0001) after 20 weeks and about 40-57% after 36 weeks. These results suggest that restoring/activating wild-type p53 function by small molecules significantly inhibits NNK-induced lung tumor in A/J mice, most notably delaying progression of adenomas to adenocarcinoma. IHC analysis of lung tumors from NNK-treated mice exposed to either CP-31398 or Prima-1 showed a significantly reduced proliferating cell nuclear antigen (PCNA)-positive index, increased accumulation of nuclear wt-p53 including increased p21 and TUNNEL positive cells compared to lung tumors from NNK-treated mice fed with control diet. Incidentally, neither COX-1 nor iNOS were significantly affected by CP-31398 or Prima -1 in the NNK derived lung tumors. These results demonstrate, for the first time, the chemopreventive role of p53 modulating agents on tobacco specific carcinogen-induced lung adenocarcinomas. {Supported by NIH, NCI grants NO1-CN-53300}.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-176. doi:1538-7445.AM2012-LB-176
Abstract LB-180: Notch-1: A therapeutic target for breast cancer stem cells and breast cancer cells
Authors: Suman Suman , Das Trinath P. , Kurisetty Vittal , Gulappa Thippeswamy , Vadodkar Aditi Shirish , Lakshmanaswamy Rajkumar , Damodaran Chendil 
Published: August 2012

Abstract
In spite of early diagnosis and potent treatment modalities, breast cancer remains a leading cause of cancer related death among women. Studies have shown that breast cancer stem cells (BCSCs) are a subpopulation of tumor cells characterized by cell surface antigens CD44+/CD24-/low and high Aldehyde dehydrogenase (ALDH) enzyme activity. These cells are refractory to current treatment modalities, show higher risk of metastasis, a shorter time to recurrence, and relapse to death. Hence, it is imperative to find new effective treatments to target both BCSCs and breast cancer cells (BCs) in order to reduce mortality associated with this disease. Notch signaling is implicated in self-renewal of stem cells by transcriptional activation of its target genes such as Hes-1 and Hey-1. Hence, we screened small molecules, which target Notch signaling in ALDH+ and ALDH- breast cancer cells. We have identified a potent natural compound psoralidin that effectively inhibits ALDH+ and ALDH- breast cancer cells. Our results revealed, psoralidin significantly down-regulates Notch-1 and its target genes (Hes-1 and Hey-1), which resulted in growth inhibition and induction of apoptosis in both ALDH+ and ALDH- cells. Psoralidin significantly inhibited invasion and migration of ALDH+ (p&lt;0.004) and ALDH- (p&lt;0.001) cells. Interestingly, higher inhibition in invasion (MMPs, Laminin, ADAMs) and migration (E-cadherin, Vimentin, Snail, Slug, Zeb-1) was observed in case of ALDH- cells as compared to the ALDH+ cells. Our ongoing overexpression and inhibition studies on Notch-1 (in vitro and in vivo) may reveal the role of Notch-1 in ALDH+ and ALDH- cells. In addition, phenotypic and molecular analysis will help us to understand the mechanism behind tumor initiation, metastasis and recurrence of tumor growth in breast cancer. Our results may support psoralidin as a novel potent anticancer agent targeting both BCSCs and BCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-180. doi:1538-7445.AM2012-LB-180
Abstract LB-195: Immune responses against cancer stem cell-specific tumor antigens and tumor microenvironment
Authors: Torigoe Toshihiko , Hirohashi Yoshihiko , Morita Reina , Nishizawa Satoshi , Yasuda Kazuyo , Takahashi Akari , Tamura Yasuaki , Sato Noriyuki 
Published: August 2012

Abstract
Cancer stem cell (CSC) is a small population of cancer cells with stem cell-like phenotype and highly tumorigenic capacity. It is known that they are resistant to conventional chemotherapy and radiotherapy, therefore being responsible for cancer recurrence and metastasis. However, it has been unclear if immune responses against CSCs can overcome the therapeutic resistance of CSCs. In this paper, I would like to present unique immunopathological properties of CSCs, including (1) anti-stress genes expressed preferentially in CSCs, (2) immune responses against CSC-specific tumor antigens and (3) tumor microenvironment modulated by CSCs. We could isolate CSCs from a variety of solid cancer cell lines such as breast, lung, colon, kidney, ovarium and endometrium cancer lines by using Hoechst33342 staining assay and ALDH1 activity assay. Comparative gene expression analysis using DNA microarray revealed a number of stress responsive genes that are preferentially expressed in CSCs such as genes encoding heat shock proteins (HSPs), stress-activated protein kinases, ABC transporters, oxidoreductases, and detoxification enzymes. Interestingly, some of them are expressed exclusively in testis among normal adult tissues. DNAJB8 was one of the CSC-preferential HSPs. RNAi-mediated knockdown of DNAJB8 could reduce the tumor forming capacity of CSCs, while its overexpression enhanced the tumorigenic capacity. Our findings account for the molecular basis of stress-resistant property of CSCs and highlight a novel strategy and molecular targets for CSC-specific cancer therapy. We next examined if immune responses against CSCs could be induced by immunization with CSC-specific gene products such as SOX2, DNAJB8 and OR7C1. CSC-specific cytotoxic T-cell clones were established from peripheral blood lymphocytes of cancer patients and we confirmed that CSCs were susceptible to T-cell-mediated cytotoxicity in vitro. Our data indicated that CSC antigens might serve as potent tumor vaccines for CSC-targeted immunotherapy. However, some CSCs had the property of immunoescape through modulation of tumor microenvironment. CSCs could recruit stromal cells that produced immunosuppressive cytokines. The role of stromal cells that interact with CSCs would be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-195. doi:1538-7445.AM2012-LB-195
Abstract LB-196: Anti-DLL4 reduces tumor growth and tumorigenicity in B-RAF V600E melanomas including those with acquired resistance to B-RAF inhibitors
Authors: Beviglia Lucia , Yeung Pete , Fischer Marcus , Yen Wang-Ching , Gurney Austin , Lewicki John , Kapoun Ann , Hoey Timothy 
Published: August 2012

Abstract
Melanoma is frequently driven by oncogenic mutation in the B-RAF gene (V600E) and this mutation is found in approximately 60% of patients. These patients are highly sensitive to kinase inhibitors targeting B-RAF. However, recent clinical experience has shown that after an initial response, a high percentage of patients develop resistance to B-RAF inhibitors through various mechanisms. In our studies, we evaluated whether inhibition of DLL4-Notch signaling might be effective in B-RAF mutant melanoma. We utilized two patient-derived melanoma xenografts containing the B-RAFV600E mutation, OMP-M2 and OMP-M8. The OMP-M8 xenograft was derived from a patient who was treated with the B-RAF inhibitor Vemurafenib (PLX-4032) and showed an early response to treatment, but later became resistant. We performed combination efficacy experiments with the B-RAF inhibitor PLX-4720 (doses 20-80 mg/kg, oral gavage, qdx5) and anti-DLL4 antibodies (30 mg/kg, IP once a week), and found that PLX-4720 combined with anti-DLL4 treatment caused a significant inhibition of tumor growth in OMP-M2 tumors. In serial transplant limiting dilution assay (LDA) studies with the OMP-M2 model, PLX-4720 treatment induced a significant enrichment of tumor initiating cells. In contrast, anti-DLL4 reduced the frequency of tumor initiating cells compared to controls, as a single agent and in combination with PLX-4720. We also found that the OMP-M8 tumor xenografted in mice retained the lack of response to the B-RAF kinase inhibitor, showing that the xenografts responded to treatment similarly as the patient in the clinic. Interestingly, the B-RAF inhibitor resistant tumor OMP-M8 was sensitive to anti-DLL4, which inhibited the growth of the primary tumor and significantly reduced the frequency of tumor initiating cells as a single agent and in combination with a chemotherapeutic agent. These findings suggest that DLL4-Notch inhibition can be effective in B-RAF V600E mutant melanoma including patients with acquired resistance to B-RAF kinase inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-196. doi:1538-7445.AM2012-LB-196
Abstract LB-306: Multiplex RT-qPCR study on the expression of stem cell markers CD24, CD44, and ALDH1 in circulating tumor cells of breast cancer patients
Authors: Strati Areti D. , Georgoulias Vassilis , Lianidou Evi S. 
Published: August 2012

Abstract
Background: Molecular characterization of Circulating Tumor Cells (CTC) can give important information on their suspected connection to cancer stem cells. In breast cancer, putative cancer stem cells have been identified to have a CD44+CD24-/low and ALDH1+ cell phenotype. Patients and methods: We developed a tetraplex quantitative RT-qPCR assay for CD24, CD44, ALDH1 and HPRT based on the in-silico design of primers and probes with different fluorescence emission spectra. Specificity and sensitivity experiments were performed using the SKBR-3 cancer cell line. We isolated CTC from peripheral blood according to our previously described methodology (Strati et al, BMC cancer 2011) from 40 patients with early breast cancer before the administration of adjuvant chemotherapy, 23 patients with verified metastasis and 18 female healthy volunteers. We evaluated all our data with respect to CD24, CD44, ALDH1 expression of healthy volunteers using the 2βΔΔCt method. Results: In 23 patients with verified metastasis 9.0% were found to have CD44+CD24-/low phenotype and 13% ALDH1high/CD24-/low phenotype. In 40 operable breast cancer patients 8 patients (20.0%) were found to have CD44+CD24-/low phenotype and 12 patients (30.0%) were found to have ALDH1high/CD24-/low phenotype. CK-19, MAGE-A3, HER-2, TWIST1, hTERT α+β+, and mammaglobin gene transcripts were also quantified in the same samples. Discussion: Molecular characterization of CTC has shown that in breast cancer patients CTCs are partly characterized by a putative stem cell phenotype. The clinical significance of these findings in early breast cancer remains to be elucidated when the clinical outcome of these patients is known.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-306. doi:1538-7445.AM2012-LB-306
Abstract LB-322: Cruciferous vegetable intake after diagnosis of breast cancer and survival: a report from the shanghai breast cancer survival study
Authors: Nechuta Sarah J. , Lu Wei , Cai Hui , Zheng Ying , Bao Ping-Ping , Zheng Wei , SHu Xiao Ou 
Published: August 2012

Abstract
BACKGROUND: Cruciferous vegetables are a major source of glucosinolate-derived bioactive compounds, such as isothiocyanates and indoles, which have been shown in animal studies and in vitro to inhibit cancer growth and progression. However, little is known regarding the role of cruciferous vegetables in breast cancer prognosis. Using resources from the Shanghai Breast Cancer Survival, a large population-based prospective cohort study of Chinese breast cancer survivors, we evaluated the association of cruciferous vegetable consumption after cancer diagnosis and breast cancer outcomes with repeated dietary assessments after diagnosis. METHODS: Women with incident breast cancer aged 20-75 years were recruited within 6-months of diagnosis during 2002-2006. In-person baseline interviews collected detailed data on clinic characteristics, socio-demographics, and lifestyle factors. Medical records were used to verify clinical data. The cohort has been followed-up by a combination of in-person follow-up surveys and record linkage to the Shanghai Vital Statistics Registry. Cruciferous vegetable intake (g/day) was reassessed at 18- and 36-months. Cox regression models were used to derive hazard ratios (HR) and 95% confidence intervals (CIs) for the associations of cruciferous vegetables and breast cancer outcomes. Analyses include 4,886 women with stage I-IV breast cancer. RESULTS: After a median follow-up of 5.2 years, 587 deaths (496 breast cancer deaths) and 615 recurrences occurred. Cruciferous vegetable intake increased after diagnosis (mean (SD)=62.5 (44.5) at 6-months and 133.8 (93.3) at 36-months). After adjustment for socio-demographics, clinical characteristics including treatment and tumor characteristics, and lifestyle factors, cruciferous vegetable intake was associated with improved breast cancer survival in a dose-response pattern (P for trend &lt; 0.01). The multivariable hazard ratios (95% confidence intervals) across increasing quartiles (vs. Q1) were 0.73 (0.60-0.90), 0.51 (0.41-0.64), and 0.38 (0.29-0.49) for total mortality; 0.78 (0.62-0.97), 0.53 (0.41-0.68), and 0.38 (0.29-0.51) for breast cancer-specific mortality; 0.79 (0.63-0.98), 0.71 (0.57-0.88), and 0.65 (0.52-0.81) for recurrence. These associations persisted after excluding the first year of observation, although the association for recurrence was no longer statistically significant. CONCLUSION: Cruciferous vegetable intake after breast cancer diagnosis was associated with improved prognosis among Chinese women.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-322. doi:1538-7445.AM2012-LB-322
Abstract LB-324: The cancer risks and life shortening effect of low and very low cholesterol among Asians
Authors: Wen Chi-Pang , Wu Xifeng , Yang Yi Chen , Tsai Min Kuang , Hsu Chung Yi 
Published: August 2012

Abstract
Background: Attention has been focused on the increased risk of high cholesterol, but the effect of low cholesterol remains unclear and receives little attention. Method: The study cohort, 537,430 adults in Taiwan who went through a medical screening program between 1996 and 2008, was followed up for an average of 8.5 years for mortality and cancer incidence, with 18,745 deaths and 17,714 cancer cases identified. Low and very low cholesterol or LDL were defined as &lt; 180 and &lt;160, or &lt;110 and &lt;90 mg/dL, respectively. Cox proportionate model was used for hazard ratio (HR) calculation, by controlling for all relevant risk factors (Age, gender, BMI, smoking, drinking, blood pressure, blood sugar, physical activity and anemia) Results: One out of four (24.6%) had low cholesterol and 7.5% had very low cholesterol, in contrast to 10.4% with high cholesterol. Increases in all cancer mortality were found for those with low cholesterol (HR:1.41, with 95% 1.3-1.5) and very low cholesterol (HR: 1.58 with 95% 1.4-1.7), with 180-239 mg/dL as reference. Similar results were seen for cancer incidence. The increase came prominently from liver cancer (HR:2.86), and the increases remained after all deaths or all cancer incidences within the first 3 years were excluded (HR: 1.31), or after HBV carriers were excluded (HR: 1.33). All cancer mortality increased by 1% for every unit decrease of cholesterol across all levels. With 60% increase in all-cause mortality, the life span of very low cholesterol was shortened by 5-6 years. Conclusion: Found in 1/4 of adult Asians, subjects with low cholesterol (&lt;180 mg/dL), a level commonly reached by those taking statins or on vegetarian diet, had approximately 50% increase in cancer risks. The inverse relationship existed across all levels of cholesterol, with 10% increase for every 10-unit decrease. Those with very low cholesterol had their life span shortened by 5-6 years. While reverse causation with pre-clinical cancer cases could be responsible, the fact that the cancer risks remained after excluding first three years of cancer implied low cholesterol is an independent risk factor or risk marker for all cancer. In this Asian community, low cholesterol should receive as much attention as high cholesterol.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-324. doi:1538-7445.AM2012-LB-324