bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3379: Iron-deficient anemia promotes breast cancer growth and lung metastasis
Authors: Jian Jinlong , Yang Qing , Huang Xi 
Published: June 2012

Abstract
Young breast cancer patients &lt;45 years old are at a higher risk of dying from the disease than older patients. Specific risk factors contributing to this high mortality rate have not been identified. Iron deficient anemia (IDA) is a common ailment in young pre-menopausal women both in developed and developing countries. In the present study, we hypothesize that IDA promotes breast cancer growth and metastasis. To test this hypothesis, Balb/c mice were fed three levels of iron diets, 3.5 ppm Fe as iron deficient, 35 ppm as normal low, and 350 ppm as normal high for 12 wks. Consistent with previous literature reports, iron levels in diets ranging from 35 to 350 ppm, which were considered normal, did not lead to significant differences in serum iron and transferrin saturation rates. However, an iron level at 3.5 ppm in the diet caused an IDA in mice. After subcutaneously inoculating 4T1 mammary cancer cells into the flanks of mice fed different iron diets, mice with IDA condition have significant higher tumor volumes as compared to those with normal iron status (2922 + 161 mm3 in 3.5 ppm Fe group vs 1636 + 86 mm3 in 35 ppm Fe group and 1453 + 90 mm3 in 350 ppm Fe group). Lung metastasis was also higher in IDA mice with 22.8 + 0.9 nodules per lung lobule in 3.5 ppm vs 13.8 + 0.8 in 35 ppm and 13.6 + 0.9 in 350 ppm Fe. To elucidate molecular mechanisms of IDA in tumor growth and metastasis, levels of epithelial mesenchymal transition (EMT) markers, such as snail, slug and zeb1, were found to be significantly higher in tumor tissues isolated from IDA mice. When investigating signal pathways regulating EMT, it was found that Notch pathway, including Notch 2, 3, 4, and Notch ligands such as Jagged1, 2, were all induced by IDA. In contrast to Notch, transforming growth factor (TGF)-β and wingless-int (WNT) signal pathways, known to stimulate EMT, were not affected, suggesting that IDA-induced EMT is Notch pathway-specific. Since anemia causes hypoxia, the expression of HIF-1α, a key transcription factor controlling hypoxic responses, was also induced by IDA. Similarly, Notch signal pathway and EMT markers were higher after transfecting HIF-1α cDNA into 4T1 cells. These data show that IDA-mediated breast cancer growth and lung metastasis is through HIF-1α accumulation and activation of Notch and EMT. Our study suggests that identification of IDA as a poor prognostic factor and its clinical improvement as a potential cancer therapy could be significant to the high mortality rate of young breast cancer patients. This work is supported by R21 CA132684.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3379. doi:10.1158/1538-7445.AM2011-3379
Abstract 3408: Ovarian cancer stem cell cytokine microenvironment
Authors: Levina Vera V. , Marrangoni Adele , Gorelik Elieser , Edwards Robert , Lokshin Anna 
Published: June 2012

Abstract
Objectives: Epithelial ovarian cancer (EOC) is an extremely aggressive disease associated with a lack of early symptoms, rapid progression to peritoneal metastases, and poor prognosis for patients. Currently available treatments are not effective in preventing or slowing metastatic spread, and the therapeutic resistance of EOC remains a major unresolved clinical and scientific problem.
Cancer stem cells (CSCs) represent the most aggressive part of the tumor. CSCs are drug resistant and are thought to be responsible for the failure of chemotherapy. Earlier, we demonstrated that chemotherapy can lead to selection of CSCs. We hypothesized that malignancy of CSCs was associated with an efficient cytokine network.
Methods: Ovarian CSCs and primary adherent epithelial cultures were established from ascites from ovarian cancer patient with stage III EOC. Ovarian CSCs were isolated using magnetic beads separation columns and human CD133 and CD44 Microbead kits from Miltenyl Biotec and were grown as tumor spheres. The High Content Screening (HCS) and High Content Analysis (HCA) platform from Thermo Scientific Cellomics was applied to study the CSC markers, embryonic markers, transcription factors, epithelial mesenchimal transition markers, cytokines, chemokines, growth and angiogenetic factor receptor expression and intracellular cytokine accumulation. Multiplex xMAP technology was used for the analysis of human cytokines and growth factors in cell culture medium. An in vivo SCID mouse model was used for the analysis of tumorigenity of bulk EOC cells and CSCs.
Results: We established primary EOC cell lines and CSCs from ascites of 3 EOC patients. We confirmed that cells growing in tumor spheres demonstrate all the properties of CSCs: they express high levels of CSCs markers and low levels of differentiated markers, they have capacity to self-renew and differentiate, and they are highly tumorigenic in SCID mice. The EMT and CSC phenotypes were both exhibited in ovarian CSCs. We found that ovarian CSCs have a specific cytokine microenvironment involving the up-regulation of multiple cytokine-receptor axes.
Conclusions: Our findings provide new knowledge regarding ovarian CSC biology. They elucidate the important role of the specific cytokine-receptor signaling axis for the self-renewal and proliferation of ovarian CSCs. We concluded that an optimal antitumor efficacy will be achieved by inhibiting both tumor cell populations: CSCs and bulk EOC cells. We suggest that combining two treatment modalities, e.g. RTK inhibitor that targets CSCs, and cisplatin that eradicates bulk tumor cells will represent a novel paradigm in EOC therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3408. doi:10.1158/1538-7445.AM2011-3408
Abstract 341: Overexpression of FGFR2 gene is associated with advanced stage squamous cell carcinoma of the lung
Authors: Kikuchi Ryutaro , Huang Cheng-long , Miyahara Ryo , Sonobe Makoto , Menju Toshi , Kobayashi Masashi , Ishikawa Masashi , Kitamura Jiro , Date Hiroshi 
Published: June 2012

Abstract
Introduction: Molecular oncology has revealed various types of genetic abnormality are involved in tumorigenesis of lung carcinomas. For example, mutations of epidermal growth factor receptor (EGFR) are associated with non-smoker patients with lung adenocarcinomas, and mutations of K-ras are associated with smoker patients with lung adenocarcinomas. However, few genetic abnormalities were reported in squamous cell carcinomas of the lung. In order to identify the specific genetic abnormality in squamous cell carcinoma of the lung, we performed a clinical study on the fibroblast growth factor receptor (FGFR) gene in patients with non-small cell lung cancers (NSCLCs). Method: One hundred and thirty eight NSCLC patients were studied. Quantitative real-time PCR was performed to evaluate gene expressions of all four members of human FGFR, including FGFR1, FGFR2, FGFR3, and FGFR4. In addition, gene status of EGFR (exon 19-22), K-ras (exon 1), and p53 (exon 5-8) was also investigated using PCR-SSCP confirmed by direct sequencing. Results: FGFR2 gene expression was significantly higher in smoker patients than in non-smoker patients (P=0.008). Regarding the tumor histology, FGFR2 gene expression was significantly higher in squamous cell carcinomas than in adenocarcinomas (P&lt;0.001). Furthermore, among squamous cell carcinomas, FGFR2 gene expression was significantly higher in advanced stage tumors than in early stage tumors (P=0.034). Among squamous cell carcinomas, FGFR1 gene expression was also significantly higher in advanced stage tumors than in early stage tumors (P=0.031). In contrast, there was no these relationships in FGFR3 gene expression or FGFR4 gene expression. Regarding other gene status, FGFR2 gene expression was significantly higher in tumors with wild-type of EGFR than in tumors with mutant EGFR (P=0.004), and was likely to be higher in tumors with wild-type of K-ras than in tumors with mutant K-ras. Furthermore, FGFR1 gene expression was likely to be higher in tumors with wild-type of K-ras than in tumors with mutant K-ras (P=0.064). However, there was no difference in FGFR3 gene expression or FGFR4 gene expression according to EGFR gene status and K-ras gene status. In addition, there was no difference in gene expression of FGFR1, FGFR2, FGFR3, or FGFR4 according to p53 gene status. Conclusions: Overexpression of FGFR2 gene expression is associated with lung carcinomas with wild-type of EGFR and wild-type of K-ras, especially in advanced stage of squamous cell carcinomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 341. doi:10.1158/1538-7445.AM2011-341
Abstract 3417: Class III HDAC induces epithelial-to-mesenchymal transition in prostate cancer cells
Authors: Byles Vanessa , Zhu Lijia , Chmilewski Laura K. , Lovaas Jenna D. , Faller Douglas V. , Dai Yan 
Published: June 2012

Abstract
The epithelial-to-mesenchymal transition (EMT) is a crucial program for initiating invasion and metastasis in many epithelial tumors. EMT is characterized by loss of cell adhesion and increased cell mobility; however, the mechanism underlying this transition is not fully understood. Here we identified SIRT1, a class III histone deacetylase, as a critical regulator of EMT. We show that forced expression of SIRT1 disrupts the epithelial morphology in non-transformed prostate epithelial cells, concomitant with a decrease of epithelial marker E-cadherin, and an increase of mesenchymal protein N-cadherin, and fibronection expression, indicating EMT. In contrast, silencing SIRT1 expression in metastatic prostate tumor cells restores cell to cell adhesion and induces changes in morphology characteristic of epithelial cells, concomitant with an increase of E-cadherin and a decrease of N-cadherin and fibronection expressions. In addition, we show that SIRT1 represses the activity of the E-cadherin proximal promoter with an E-box dependent mechanism, indicating a connection between SIRT1 and the zinc-finger EMT transcription factor, which needs the E-box to suppress E-cadherin transcription. Moreover, we performed ChIP assays to show that SIRT1 and ZEB1 bind to the same DNA fragment on the E-cadherin promoter, and SIRT1 occupancy in the E-cadherin promoter requires ZEB1. In addition, we show that acetylated H3K9 levels were inversely related to occupancy of SIRT1 and ZEB1. Finally, our results show that SIRT1 knockdown reduces prostate cancer cell migration and invasion. Thus, in this study we identified SIRT1 as an important regulator of EMT and demonstrated a new transcriptional mechanism regulating E-cadherin expression by the cooperation of SIRT1 with ZEB1. These findings suggest that overexpressed SIRT1 in prostate cancer cells may be targeted to reverse EMT, and SIRT1 could be a potential target in the treatment of prostate cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3417. doi:10.1158/1538-7445.AM2011-3417
Abstract 3421: Twist1 and clusterin regulate epithelial-mesenchymal transition
Authors: Shiota Masaki , Zoubeidi Amina , Kumano Masafumi , Naito Seiji , Nelson Colleen C. , Gleave Martin E. 
Published: June 2012

Abstract
INTRODUCTION AND OBJECTIVE: Clusterin (CLU) is a stress-activated, cytoprotective molecular chaperone, and is highly expressed in cells surviving apoptotic stimuli and in advanced and treatment-resistant cancers. In addition, CLU has recently been reported to be implicated in epithelial-mesenchymal transition (EMT). Similarly, oncogenic transcription factor Twist1 which binds to E-box (core sequence, 5’-CANNTG-3’) is known to be a master regulator of EMT. Although CLU is known to be transcriptionally activated by heat-shock factor 1, the mechanism CLU expression in EMT is not fully elucidated. This study begins to define mechanism of CLU expression and relevance in EMT of prostate cancer.
METHODS: Human prostate cancer PC-3 and LNCaP cells were used to examine whether the manipulation of Twist1 expression affected CLU expression using quantitative real-time PCR, Western blotting and luciferase reporter assay using CLU promoter region. Chromatin-immunoprecipitation (ChIP) assays were used to determine whether Twist1 binds to CLU promoter region. We also examined markers of EMT after treatment with TGF-β1 and manipulation of Twist1/CLU expression.
RESULTS: Twist1 overexpression was shown to upregulate CLU expression whereas Twist1 knockdown reduced CLU expression. ChIP assay and luciferase reporter assay revealed that Twist1 was bound to CLU promoter region and regulated CLU transcription. Treatment with TGF-β1, which is known to be an EMT-inducing cytokine, upregulated Twist1 expression followed by CLU expression. Furthermore, CLU knockdown ameliorated EMT induced by TGF-β1 and Twist1.
CONCLUSIONS: This study indicates that CLU regulates EMT induced by TGF-β1 and Twist1 in prostate cancer cells. Modulation of CLU expression may be a useful strategy for developing novel therapeutics regulating EMT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3421. doi:10.1158/1538-7445.AM2011-3421
Abstract 3448: Subtypes of medulloblastoma have distinct developmental origins
Authors: Gibson Paul , Tong Yiai , Robinson Giles , Poppleton Helen , Thompson Margaret C. , Currle David S. , Eden Christopher , Hogg Twala L. , Finkelstein David , Pounds Stanley , Patay Zoltan , Scoggins Matthew , Pei Yanxin , Ogg Robert , Lee Youngsoo , Zindy Frederique , Lindsey Janet C. , Boop Frederic A. , Gajjar Amar , Clifford Steven C. , Roussel Martine F. , McKinnon Peter J. , Ellison David W. , Wechsler-Reya Robert , Gutmann David H. , Gilbertson Richard J. 
Published: June 2012

Abstract
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the lower rhombic lip (LRL). We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the LRL and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused an aberrant accumulation of proliferating precursor cells within the LRL. These lesions persisted in the dorsal brainstem of all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that modeled faithfully the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3448. doi:10.1158/1538-7445.AM2011-3448
Abstract 3450: Growth-inhibitory effect of neurotrophin-3-secreting adipose tissue-derived mesenchymal stem cells on the D283-MED human medulloblastoma cell line
Authors: Kim Young-Hoon , Kim Chae-Yong , Cho Byung-Kyu , Wang Kyu-Chang , Kim Seung-Ki , Phi Ji Hoon , Cho Seung Hee , Lee Soo Jung , Choi Seung Ah , Kim Jin Wook , Park Chul-Kee 
Published: June 2012

Abstract
Medulloblastoma (MBL), the most common malignant pediatric brain tumor, is incurable in about one-third of patients and can lead to long-term disabilities despite current multimodal treatments. We evaluate the in vitro, growth-inhibitory effect of neurotrophin-3 (NT-3)-secreting stem cells on an MBL cell line and propose that this cell therapy may have therapeutic effects for MBL. NT-3-secreting stem cells were produced by nucleofecting pIRES2.EGFP-NT3 into human adipose tissue-derived mesenchymal stem cells (hAT-MSCs). Double-layered co-culture experiments with the NT-3-secreting hAT-MSCs and D283-MED MBL cells were performed, and NT-3-induced apoptosis was studied by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) test. The growth-inhibitory effects of these stem cells on human MBL in vitro were confirmed by 3-(4, 5-dimethylathiazol-2-yl)-2, 5-dephenyl-tetrazolium bromide (MTT) assay. We confirmed by western blotting that D283-MED cells express tyrosine kinase C, a specific receptor for NT-3, and we showed by fluorescence microscopy and RT-PCR that transfected hAT-MSCs express NT-3. The double-layered co-culture of D283-MED with NT-3-secreting hAT-MSCs induced a concentration-dependent increase in apoptosis in the tumor cell line. Consequently, the high concentrations of NT-3-secreting hAT-MSCs significantly (P &lt; 0.001) increased the death of D283-MED cells in vitro. The present studies demonstrate the potential of NT-3-secreting hAT-MSCs as an effective therapeutic cell therapy for human MBL in vitro, but in vivo experiments and clinical studies will be required in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3450. doi:10.1158/1538-7445.AM2011-3450
Abstract 3459: Expression of oncogene-induced senescence markers in pilocytic astrocytomaIs associated with younger age and longer survival
Authors: Lim Kah Suan , Bar Eli E. , Raabe Eric H. , Jain Deepali , Eberhart Charles G. 
Published: June 2012

Abstract
Pilocytic astrocytomas are the most common pediatric brain tumor. They are low grade neoplasms, and in some cases can spontaneously stop growing or regress. The recent discovery of constitutive BRAF activation in the majority of pilocytic astrocytomas, due either to gene duplication/fusion or point mutation, suggests a possible molecular basis for this relatively benign pathobiology. Oncogenic BRAF-induced senescence has previously been identified in benign melanocytic nevi and colonic polyps, but whether it also occurs in pilocytic astrocytomas is not clear. To investigate this, we examined the senescence marker acidic beta-galactosidase in low passage pilocytic astrocytoma cultures established from freshly resected tumors. Two of these cultures, tested at passages 2 to 3, were derived from tumors that contained KIAA1549:BRAF fusions, and both expressed the senescence marker in over half of the cells. Another culture tested at passage 3 was also strongly positive for acidic beta-galactosidase, but the genetic status of its parent tumor is not known. A final culture came from a pilocytic astrocytoma lacking the KIAA1549:BRAF fusion, or an activating V600E BRAF point mutation, and was negative for the senescence marker, but was tested at passage 10. To help confirm these effects in vivo, we immunostained a tissue microarray containing 78 pilocytic astrocytoma for p16 and p53, both of which have been implicated in oncogene-induced senescence in other tumor types. The majority of pilocytic astrocytoma expressed p16, but the 13% of tumors lacking this senescence marker were associated with significantly shorter overall survival (p = 0.0002). Patients whose pilocytic astrocytomas lacked p16 were also older (mean age 25 years) as compared to those with intermediate (mean age 12 years) or high expressing tumors (mean age 7 years). Immunohistochemical analysis of p53 revealed much weaker staining, and only 18 tumors were positive, but expression correlated positively with that of p16 (Spearman r = 0.45, p = 0.0001). Our data suggest that the low-grade phenotype of pilocytic astrocytomas may be due to oncogene-induced senescence driven by KIAA1549:BRAF fusions or BRAF V600E point mutations, and that expression of senescence markers in vivo is associated with younger age at presentation and better clinical outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3459. doi:10.1158/1538-7445.AM2011-3459