bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA-20: EMT in tumor invasion and metastasis
Authors: Brabletz Thomas 
Published: May 2012

Abstract
Most colorectal adenocarcinomas (CRC) have mutations in the APC gene leading to overexpression of the Wnt-pathway effector β-catenin. By acting as a transcriptional activator, nuclear β-catenin is involved in two fundamental processes in embryonic development: epithelial to mesenchymal transition (EMT) and generation of stem cells.
We have previously shown, that in particular tumor cells at the invasive front of CRCs accumulate nuclear β-catenin, undergo an EMT and aberrantly express EMT-associated transcriptional repressors, like ZEB1. The amount of such cells strongly correlates with clinical outcome and metastasis formation.
We further showed that ZEB1 represses target genes involved in basement membrane formation and epithelial cell polarity. Moreover we report that ZEB1 directly suppresses transcription of members of the miRNA-200 family, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT-activators TGFβ2 and ZEB1 itself are predominant targets downregulated by these miRNAs. These results indicate that ZEB1 triggers a microRNA-mediated positive feedbackloop, which stabilizes EMT and promotes invasion of cancer cells. In contrast tumor cells in central tumor areas are differentiated and often show membranous, E-cadherin-bound β-catenin.
Strikingly, metastases show again a differentiated phenotype and lack nuclear beta-catenin, indicating a mesenchymo-epithelial re-transition (MET) and a regulatory role of the tumor environment during malignant tumor progression.
Based on the developmental functions of beta-catenin and our data we propose, that the EMT-associated tumor cells at the invasive front act as “migrating cancer stem cells” which can re-differentiate and, depending on the range of dissemination, give raise to the primary carcinoma and metastases. We suggest that both primary tumors and metastases are derived from a pool of EMT-associated “migrating cancer stem cells” at the tumor host interface. They are defined by strong nuclear beta-catenin accumulation and EMT-phenotype, which gives these epithelial tumor cells a feature driving malignant tumor progression including metastasis: the unusual combination of a migratory and stem cell phenotype.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-20.
Abstract IA-4: Studying tumor evolution in mouse models of cancer
Authors: Jacks Tyler 
Published: May 2012

Abstract
Like other solid tumors, lung adenocarcinoma progresses through multiple stages including tumor initiation, expansion in the lung, and metastasis of the primary tumor to distant organs. Dissection of this process requires quantitative and tractable models that recapitulate the human disease at the genetic and histological level. We have employed autochthonous mouse models of lung adenocarcinoma that recapitulate tumor initiation, progression and metastasis in the human disease both genetically, and pathologically. We have established oncogenic Kras as the initiating event in lung adenoma and amplification of the oncogenic signaling is associated with progression to adenocarcinoma. The p53 tumor suppressor limits tumor progression in this model. Restoration of the Trp53 locus has pinpointed the adenoma-adenocarcinoma transition as the stage in which p53 function is critical for tumor suppression. Expression of oncogenic Kras in the absence of p53 leads to the development of distant metastases after long latency. This suggests that unknown cooperating genetic events are required for metastatic spread and we are utilizing multiple tools to identify these changes. Use of lentiviral vectors that drive stable GFP expression in tumors allows for identification and purification of tumor cells. Additionally, identification of the lentiviral integration site in each tumor allows the clonal relationship between metastases and the primary tumors to be unequivocally established. Gene expression and DNA copy number analyses of metastasis-derived cell lines and primary lung tumors have uncovered a metastasis associated gene expression signature and recurrent genomic alterations. Integration of these datasets, other genome-wide analyses and human tumor data are providing insights into the molecular mechanism and biology of lung cancer progression and metastasis.
Citation Information: Cancer Res 2009;69(23 Suppl):IA-4.
Expression of Cocaine- and Amphetamine-Regulated Transcript Is Associated with Worse Survival in Small Bowel Carcinoid Tumors
Authors: Landerholm Kalle , Shcherbina Liliya , Falkmer Sture E. , Järhult Johannes , Wierup Nils 
Published: May 2012

Abstract
Purpose: Cocaine- and amphetamine-regulated transcript (CART) peptide exerts several regulatory functions acting both as neurotransmitter and hormone. We recently showed that CART is expressed in various neuroendocrine tumors, including small bowel carcinoids. The main objective of the present study was to examine whether CART expression is associated with survival in patients with small bowel carcinoid. Secondary aims were to assess whether CART expression is associated with other tumor characteristics or clinical symptoms.
Experimental Design: Specimens from 97 patients with small bowel carcinoids were examined for CART expression using immunohistochemistry. A CART score was introduced on the basis of the proportion of CART immunoreactive cells. On inclusion, specimens were examined by routine histopathologic methods and detailed clinical patient data were retrieved. The effect of CART on cell viability was assessed in vitro using two intestinal tumor cell lines.
Results: Expression of CART (P = 0.011) and increasing CART score (P = 0.033) were associated with worse disease-specific survival. Adjusting for age, disease stage, and tumor grade in multivariable analysis, CART expression was still associated with worse survival [Low CART HR, 5.47; 95% confidence interval (CI), 0.71–42.46; and High CART HR, 9.44; 95% CI, 1.14–78.14]. CART expression was not associated with patient age, disease stage, tumor grade, or any presenting symptom. Supporting our clinical data, we found that CART promoted tumor cell viability in vitro in two different tumor cell lines.
Conclusion: Expression of CART in small bowel carcinoid tumors is associated with worse survival. Clin Cancer Res; 18(13); 3668–76. ©2012 AACR.
BEAMing Up Personalized Medicine: Mutation Detection in Blood
Authors: Richardson Andrea L. , Iglehart J. Dirk 
Published: May 2012

Abstract
BEAMing is a feasible, accurate, and sensitive method for detection of PIK3CA mutations in circulating tumor DNA in blood. Mutation status of PIK3CA may change between primary tumor and recurrence. The results suggest a new approach for noninvasive determination of current mutation status in patients with metastatic disease. Clin Cancer Res; 18(12); 3209–11. ©2012 AACR.
Smoothened Antagonists Reverse Taxane Resistance in Ovarian Cancer
Authors: Steg Adam D. , Katre Ashwini A. , Bevis Kerri S. , Ziebarth Angela , Dobbin Zachary C. , Shah Monjri M. , Alvarez Ronald D. , Landen Charles N. 
Published: May 2012

Abstract
The hedgehog pathway has been implicated in the formation and maintenance of a variety of malignancies, including ovarian cancer; however, it is unknown whether hedgehog signaling is involved in ovarian cancer chemoresistance. The goal of this study was to determine the effects of antagonizing the hedgehog receptor, Smoothened (Smo), on chemotherapy response in ovarian cancer. Expression of hedgehog pathway members was assessed in three pairs of parental and chemotherapy-resistant ovarian cancer cell lines (A2780ip2/A2780cp20, SKOV3ip1/SKOV3TRip2, HeyA8/HeyA8MDR) using quantitative PCR and Western blot analysis. Cell lines were exposed to increasing concentrations of two different Smo antagonists (cyclopamine, LDE225) alone and in combination with carboplatin or paclitaxel. Selective knockdown of Smo, Gli1, or Gli2 was achieved using siRNA constructs. Cell viability was assessed by MTT assay. A2780cp20 and SKOV3TRip2 orthotopic xenografts were treated with vehicle, LDE225, paclitaxel, or combination therapy. Chemoresistant cell lines showed higher expression (&gt;2-fold, P &lt; 0.05) of hedgehog signaling components compared with their respective parental lines. Smo antagonists sensitized chemotherapy-resistant cell lines to paclitaxel, but not to carboplatin. LDE225 treatment also increased sensitivity of ALDH-positive cells to paclitaxel. A2780cp20 and SKOV3TRip2 xenografts treated with combined LDE225 and paclitaxel had significantly less tumor burden than those treated with vehicle or either agent alone. Increased taxane sensitivity seems to be mediated by a decrease in P-glycoprotein (MDR1) expression. Selective knockdown of Smo, Gli1, or Gli2 all increased taxane sensitivity. Smo antagonists reverse taxane resistance in chemoresistant ovarian cancer models, suggesting combined anti-hedgehog and chemotherapies could provide a useful therapeutic strategy for ovarian cancer. Mol Cancer Ther; 11(7); 1587–97. ©2012 AACR.
Betulinic Acid Targets YY1 and ErbB2 through Cannabinoid Receptor-Dependent Disruption of MicroRNA-27a:ZBTB10 in Breast Cancer
Authors: Liu Xinyi , Jutooru Indira , Lei Ping , Kim KyoungHyun , Lee Syng-ook , Brents Lisa K. , Prather Paul L. , Safe Stephen 
Published: May 2012

Abstract
Treatment of ErbB2-overexpressing BT474 and MDA-MB-453 breast cancer cells with 1 to 10 μmol/L betulinic acid inhibited cell growth, induced apoptosis, downregulated specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and decreased expression of ErbB2. Individual or combined knockdown of Sp1, Sp3, Sp4 by RNA interference also decreased expression of ErbB2 and this response was because of repression of YY1, an Sp-regulated gene. Betulinic acid–dependent repression of Sp1, Sp3, Sp4, and Sp-regulated genes was due, in part, to induction of the Sp repressor ZBTB10 and downregulation of microRNA-27a (miR-27a), which constitutively inhibits ZBTB10 expression, and we show for the first time that the effects of betulinic acid on the miR-27a:ZBTB10-Sp transcription factor axis were cannabinoid 1 (CB1) and CB2 receptor–dependent, thus identifying a new cellular target for this anticancer agent. Mol Cancer Ther; 11(7); 1421–31. ©2012 AACR.
IEX-1 Deficiency Protects against Colonic Cancer
Authors: Ustyugova Irina V. , Zhi Liang , Abramowitz Joel , Birnbaumer Lutz , Wu Mei X. 
Published: May 2012

Abstract
The immediate early response gene X-1 (IEX-1) is involved in regulation of various cellular processes including proliferation, apoptosis in part by controlling homeostasis of reactive oxygen species (ROS) at mitochondria. The present study shows reduced inflammatory responses and colorectal cancer in IEX-1 knockout (KO) mice treated with azoxymethane/dextran sulfate sodium (DSS). However, DSS induced worse colitis in RAG−/−IEX-1−/− double KO mice than in RAG and IEX-1 single KO mice, underscoring an importance of T cells in IEX-1 deficiency-induced protection against colon inflammation. Lack of IEX-1 promoted the differentiation of interleukin (IL)-17–producing T cells, concomitant with upregulation of Gαi2 expression, a gene that is well-documented for its role in the control of inflammation in the colon. In accordance with this, T-helper 17 (TH17) cell differentiation was compromised in the absence of Gαi2, and deletion of Gαi2 in T cells alone aggravated colon inflammation and colorectal cancer development after azoxymethane/DSS treatment. Null mutation of IEX-1 also enhanced both proliferation and apoptosis of intestinal epithelial cells (IEC) after injury. A potential impact of this altered IEC turnover on colon inflammation and cancer development is discussed. These observations provide a linkage of IEX-1 and Gαi2 expression in the regulation of TH17 cell differentiation and suggest a previously unappreciated role for IEX-1 in the control of colon epithelial homeostasis. Mol Cancer Res; 10(6); 760–7. ©2012 AACR.
Abstract A100: Histological classification of primary lung cancer in relation to age, gender, and types of tobacco smoking.
Authors: Bukhari Mulazim , Hussain Muhammad , Naeem Samina 
Published: May 2012

Abstract
A100

Background
According to available data the lung cancer remains the leading malignancy amongst males showing a strongest association with smoking. The study was conducted to analyze the histological classification of primary lung cancer in relation to age, gender and types of Tobacco Smoking

Methods
The study was conducted on randomly selected 300 patients of 10-90 years age from Ghulab Devi Chest Hospital Lahore. Light microscopy was used for histopathological classification on the sections stained with haematoxylin and eosin. Special (PAS and Alcian blue) stains were used for subclassication. Literature for WHO classification was reviewed.

Results
The primary malignancy of lung was more common in males (male to female ratio was 5.7:1) and in old ages with mean age was 54.17±3.46 years.. Significantly large numbers of patients (70%) were smokers. The trend of smoking is changing in Pakistan from old traditional hukka to cigarette. A strong association of smoking was found between small cell carcinoma (SCC), and squamous cell carcinoma (SQCC), and Large cell carcinoma (LCC), (P&lt;0.02, P&lt; 0.001 and p&lt;0.02 respectively). No significant difference was seen between smokers and non smokers harboring adenocarcinoma (ADC;P&gt;0.05). According to the WHO classification, SQCC (43%) was found to be the commonest histological variant and SCC (22%) was second in the frequency. The frequency of ADC, LCC and others variants was 18%, 11%and 5% respectively.

Conclusion
WHO criteria are the better ways to classify the lung carcinoma with light microscopy and provide a potential widespread and worldwide application of this classification system. A strong association of lung cancer was found with age, sex, and all types of smoking and histological variants.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A100.
Abstract A102: Men with low serum cholesterol have a lower risk of high-grade prostate cancer in the Prostate Cancer Prevention Trial
Authors: Platz Elizabeth , Till Cathee , Goodman Phyllis , Parnes Howard , Figgs William , Albanes Demetrius , Kristal Alan 
Published: May 2012

Abstract
A102

Objectives
Several prospective studies suggest that use of cholesterol-lowering statin drugs is inversely associated with advanced and possibly high-grade prostate cancer. A nested case-control study investigating low circulating cholesterol as a possible mechanism underlying these findings reported that men with a lower cholesterol concentration had a lower risk of high-grade and possibly advanced prostate cancer (Int J Cancer 2008;123:1693-8). Given these findings, we investigated the association of low serum cholesterol with prostate cancer overall and by histologic grade in the Prostate Cancer Prevention Trial (PCPT). Unlike standard cohort studies, men in the PCPT underwent PSA screening annually, cases were biopsy detected, diagnoses and Gleason sum determinations were confirmed centrally, and controls were men who were biopsied at the end of the trial per trial protocol irrespective of indication.

Methods
We conducted a prospective cohort study of 5,616 men aged 55+ years old randomized to the placebo arm of the PCPT between 1993 and 1996 and who had serum cholesterol measured at entry. By the end of follow-up, 1,251 cases were confirmed. Serum cholesterol concentration was measured enzymatically. We used logistic regression to calculate the multivariable odds ratio (OR) of total, organ-confined, and Gleason sum ≥ 8 (n=59), 7 (n=199), and &lt; 7 (n=993) prostate cancer comparing low (normal: &lt; 200 mg/dL) to high (borderline and elevated cholesterol: ≥ 200 mg/dL) serum cholesterol.

Results
Men with low cholesterol had a lower risk of Gleason sum ≥ 8 prostate cancer (OR=0.41, 95% confidence interval (CI) 0.22-0.77; p-trend across quintiles of cholesterol = 0.01) compared with men with high cholesterol; this association was stronger after restricting to organ-confined disease (OR=0.32, 95% CI 0.15-0.66, p-trend &lt; 0.001). No association was present for prostate cancer overall (OR=0.97, 95% CI 0.85-1.11, p-trend=0.43), or Gleason &lt; 7 (OR=1.03, 95% CI 0.89-1.18, p-trend=0.94) or 7 (OR=0.93, 95% CI 0.69-1.24, p-trend=0.49) disease.

Conclusion
These prospective findings from the PCPT, in which the opportunity for detection of high-grade prostate cancer was similar because all men underwent biopsy, suggest that low cholesterol may protect against the development of high-grade prostate cancer. The contemporary body of literature on statins, cholesterol, and prostate cancer suggests that cholesterol metabolism should be investigated further in the etiology of prostate cancer that has a worse prognosis.
Funding: NCI/NIH P01 CA108964 (Biology of the PCPT). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A102.
Abstract A107: Polymorphisms in nucleotide excision repair pathway and acute myeloid leukemia outcome
Authors: Strom Sara , Gokhale Sameer , Estey Elihu 
Published: May 2012

Abstract
A107
Acute myeloid leukemia (AML), the most common leukemia in adults is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, AML patients are classified into favorable, intermediate and poor subgroups. Cytogenetics are good predictors of treatment outcome for the favorable and poor subgroups. However, for patients with intermediate cytogenetics, optimal treatment is uncertain. For these patients incorporating genetic markers to the existing prognostic factors might be helpful to identify subgroups of patients. Variants in genes within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity which could eventually influence AML outcome. We studied the role of 5 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, and CCNH Val270Ala) within this pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid karyotypes (n = 117) and non-diploid karyotypes (n = 53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. After a median follow-up of 16 months, 56% of diploid patients died compared to 71% among the non-diploid group (Log Rank p= 0.03). Among patients with diploid karyotypes, after adjusting for clinical and socio-demographic characteristics (age, sex, ethnicity, WBC, performance status, and smoking), XPD Lys751Gln and XPC Ala499Val were found to be independently associated with overall survival. Patients with the XPD Lys751Gln/Gln751Gln genotype were twice more likely to have died than those with the wild genotype (HR: 1.97; 95% CI: 1.09 - 3.55). XPC Ala499Val/Val499Val patients had a 75% increased mortality compared to those with the wild genotype (HR: 1.75; 95% CI: 1.02 - 2.98). Patients carrying both (XPD Lys751Gln/Gln751Gln and XPC Ala499Val/Val499Val) had significantly shorter survival compared to those with the wild genotype (HR: 3.49; 95% CI: 1.58 - 7.68). 21% of the AML patients with diploid cytogenetics carried both risk variants. No significant associations were observed for disease-free survival in AML patients. Our results suggest that polymorphic variants in NER repair enzymes may modulate AML outcome in patients with diploid cytogenetics. Patients with the high risk genotype combination could have diminished DNA repair capacity, which in turn, could result in greater susceptibility to genotoxic effects of treatment decreasing overall survival. These findings could in the future be used in selecting treatment strategies for patients with normal cytogenetics.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A107.
Abstract A118: Tea drinking habits and esophageal cancer in a high risk area in Northern Iran
Authors: Islami Farhad , Kamangar Farin , Pourshams Akram , Nasrollahzadeh Dariush , Fahimi Saman , Abnet Christian , Moller Henrik , Dawsey Sanford , Malekzadeh Reza , Boffetta Paolo 
Published: May 2012

Abstract
A118
Golestan Province in northern Iran is a high incidence area for oesophageal squamous cell carcinoma (ESCC). We investigated the association between tea drinking habits and risk of ESCC in a population-based case-control study conducted between 2003 and 2007 in Golestan, with 300 histologically-proven ESCC cases and 571 matched neighborhood controls. In addition, we measured tea temperature and tea drinking patterns among 48582 healthy participants in a cohort study in the same region. Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume of over one liter/day, and over 60% drank their tea at temperatures over 60°C. The results of the case-control study showed that compared to drinking lukewarm or warm tea, the OR (95% CI) for drinking hot tea was 2.07 (1.28-3.35) and for drinking very hot tea was 8.16 (3.93-16.9). Likewise, compared to drinking tea four or more minutes after pouring it, the ORs (95% CIs) for drinking tea 2-3 minutes and less than 2 minutes after pouring were 2.49 (1.62 - 3.83) and 5.41 (2.63 - 11.1), respectively. There was a strong agreement between responses to questions on temperature of tea drinking and time interval from pouring tea to drinking it (weighted kappa = 0.68). In conclusion, drinking hot tea, a habit commonly seen in Golestan Province, was strongly associated with higher risk of ESCC.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A118.
Abstract A134: Honokiol targets STAT3 in head and neck squamous cell carcinoma
Authors: Leeman Neill Rebecca , Cai Quan , Arbiser Jack , Grandis Jennifer 
Published: May 2012

Abstract
A134
Head and neck squamous cell carcinoma (HNSCC) is a commonly occurring malignancy associated with severe morbidity, persistently high mortality rates, frequent recurrence, and the appearance of second primary tumors. Honokiol, a naturally occurring compound that is derived from the plant, Magnolia officinalis, which has been used in traditional Chinese medicine, has been shown to have anticancer activity in various models and to inhibit nuclear factor kappa B (NFκB), an oncogenic transcription factor. Crosstalk between NFκB and another transcription factor, signal transducer and activator of transcription (STAT)-3, has been demonstrated in HNSCC. Furthermore, NFκB and STAT3 have been found to directly interact in certain cell lines and to have various target genes, including proteins that regulate apoptosis, the cell cycle, and tumor angiogenesis, in common. Therefore, we hypothesized that honokiol might be useful in targeting STAT3, a protein that is known to promote growth, invasion, metastasis, and tumor angiogenesis in HNSCC and that shows promise as an important therapeutic target in the treatment of HNSCC. In the current study, 72-hour honokiol treatments inhibited the growth of HNSCC cell lines, Cal-33, UM-22b and 1483 with IC50’s ranging from 3.90-7.44 μM, as shown through trypan blue dye exclusion assays. Honokiol treatment also decreased expression levels of phosphotyrosine STAT3 in these same cell lines. The growth inhibitory activity of honokiol is associated with apoptosis, as demonstrated by staining for annexin-V. Because clinical data indicates that currently available HNSCC therapies have been inadequate in improving mortality rates over the last three decades, it is of interest that honokiol enhances the activity of the small-molecule receptor tyrosine kinase inhibitor, erlotinib, in HNSCC cells. Finally, honokiol was found to modestly inhibit the growth of tumors in HNSCC xenograft models. These results suggest that honokiol inhibits HNSCC growth in conjunction with downregulation of phosphotyrosine STAT3 in HNSCC.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):A134.