bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1588: Transformation of primary human fallopian tube secretory epithelial cells: A cell of origin for high-grade serous ovarian carcinoma
Authors: Karst Alison M. , Levanon Keren , Drapkin Ronny 
Published: June 2012

Abstract
High-grade serous ovarian carcinoma (HGSOC) is a lethal disease for which improved screening and treatment strategies are urgently required. Progress in these areas has been impeded by our poor understanding of HGSOC pathogenesis. The vast majority of ovarian cancer research is been based on the hypothesis that HGSOC develops from ovarian surface epithelial cells. However, recent studies suggest that &gt; 50% of high-grade serous carcinomas involving the ovary likely arose from secretory cells of the fallopian tube epithelium. Consequently, current ovarian-based experimental models of HGSOC are inadequate in representing the full spectrum of the disease. The aim of our study was to develop the first experimental model of fallopian tube secretory epithelial cell (FTSEC) transformation and to use this model to answer three basic questions: 1) Can FTSECs be transformed in vitro?, 2) What genetic alterations are capable of transforming FTSECs?, and 3) Do transformed FTSECs give rise to high-grade serous carcinomas? To this end, we isolated primary human FTSECs from fresh samples of normal fallopian tube fimbriae and immortalized them via transduction with hTERT and SV40 TAg. Immortal FTSECs were transformed by either H-RasV12 or c-Myc expression, resulting in accelerated proliferation, enhanced clonogenicity, anchorage-independent growth, and tumor formation in immunodeficient mice. When SV40 TAg was replaced with equivalent non-viral genetic alterations (sh-p53, CDK4R24C, and sh-PP2A-B56γ), FTSECs remained susceptible to c-Myc-induced transformation and tumorigenesis. These results indicate that hTERT expression plus combined dysfunction of the p53, Rb, and PP2A tumor suppressor pathways is sufficient to support c-Myc-mediated transformation. Importantly, all of the transformed FTSECs in our study produced high-grade serous tumors with Müllerian and epithelial characteristics. Moreover, these tumors were grossly, histologically, and immunophenotypically consistent with human HGSOC. The genetic elements employed by our model represent the most common genomic alterations in human HGSOC – namely, TP53 mutation, RB1 dysfunction, and c-MYC amplification – and are therefore appropriate for modeling this disease. In summary, we have presented the first proof-of-principle evidence that FTSECs can be transformed into high-grade serous carcinomas resembling HGSOC. Our FTSEC transformation model provides a novel framework for assessing the transformative effects of specific genetic alterations on primary FTSECs and thus determining what role they may play in the pathogenesis of HGSOC.
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 1588. doi:10.1158/1538-7445.AM2011-1588
Abstract 1597: A novel preclinical model of prostate cancer bone metastasis derived from a human primary tumor
Authors: Ainakouzi Nader , Bawa Olivia , Opolon Paule , Lerondel Stephanie , Lepape Alain , Gaudin Catherine , Massard Christophe , Loriot Yohann , Fizazi Karim , Chauchereau Anne 
Published: June 2012

Abstract
Background: Prostate cancer is frequently associated with bone metastases which are the main cause of morbidity and mortality for this tumor. Animal models are important tools to investigate the pathogenesis and develop treatment strategies for bone metastases in humans. However there are few animal models that recapitulate spontaneous clinical bone metastases. We recently obtained the new prostate cell line IGR-CaP1 derived from primary epithelial prostate cancer that has been characterize in vitro.
Methods: The IGR-CaP1 cell line was stably transduced with a luciferase expressing viral vector to monitor tumor growth by bioluminescence imaging (BLI) in male nude mice. Bone lesions were observed after direct intratibial injections of 5×105 luciferase-expressing IGR-CaP1 cells and after injection of 106 cells into the left cardiac ventricle of mice. Bone metastases were detected by bioluminescence imaging and were evaluated by both Computerized Tomography (CT) and micro Single-Photon Emission Computed Tomography (SPECT) measuring the bone fixation of 99Tc methylenediphosphonate (m99Tc-MDP).
Results: In contrast with the widely used PC3 preclinical model showing only osteolytic activity after bone injection, high resolution CT scan showed both lytic lesions in the cortical bone and osteoblastic lesions in the trabecular bone in the IGR-CaP1-injected mice 5 weeks after injection. The mixed nature of the lesions and the intensive bone remodeling were confirmed by bone scintigraphy with a ∼5 fold increase in m99Tc-MDP fixation in injected tibia versus control tibia. Intracardiac injection led to bone metastasis mainly localized in the spinal column, fore and hind limbs and in the mandible. Immunohistochemistry confirmed the presence of these bone metastases and showed high expression of vimentin in metastatic tumor cells. In this model, we are currently analyzing by RT-PCR, the expression of a 25-gene signature that corresponds to genes highly expressed in human bone metastases.
Conclusion: IGR-CaP1 is a unique model issued from a primary tumor able to reconstitute human prostate adenocarcinoma in animals and provide bone metastases. This model provides a novel means for identifying and understanding mechanisms that contribute to bone metastasis and allows for preclinical testing of new anticancer therapies, specifically bone-targeting therapies.
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 1597. doi:10.1158/1538-7445.AM2011-1597
Abstract 16: Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells
Authors: Gabellini Chiara , Trisciuoglio Daniela , desideri Marianna , Ragazzoni Ylenia , De Luca Teresa , Del Bufalo Donatella 
Published: June 2012

Abstract
In addition to act as an antiapoptotic protein, bcl-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia inducible factor 1 (HIF-1) -mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogates the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1α protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1α protein half-life impairing HIF-1α protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.
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 16. doi:10.1158/1538-7445.AM2011-16
Abstract 1600: A xenograft model of spontaneous metastases in NOD SCID mice of human non-small cell lung cancer
Authors: Harris James E. , Shin James , Lee Beverly , Pelosky Kristen , Zahnow Cynthia , Brayton Cory , Yang Stephen , Baylin Stephen , Brock Malcolm V. 
Published: June 2012

Abstract
Introduction: Xenograft models of human non small cell lung cancer cell lines have been unreliable in studying distal organ metastases. Although the flank, as a primary xenograft site, is typically used for the convenience of measurement, rarely do even the most aggressive cell lines develop metastases.
Methods: Using 15 anesthetized NOD.CB17-Prkdcscid/NcrCrl (NOD/SCID) mice, we xenografted 10,000 A549 cells into the liver under direct visualization and allowed the tumors to grow for 7 weeks. The mice were then euthanized, perfused with formalin, and grossly dissected. The liver, lung and spleen were processed, embedded in paraffin, sectioned and stained. A second group of 7 NOD/SCID mice were subsequently xenografted in the liver with A549, and a mouse each week was euthanized for 7 weeks and evaluated.
Results: At 7 weeks, all 15 mice had gross primary tumor in the liver as well as grossly evident splenic (10/15) and mediastinal metastases (5/15). There were no gross pulmonary metastases observed (0/15). Histologic review, however, confirmed multiple microscopic foci of metastatic disease in all mice (15/15) throughout the lungs bilaterally, the mediastinal lymph nodes and spleen. Serially euthanized mice revealed histological evidence of a gradual spontaneous metastatic model system. Histologically evident primary tumor was apparent by week 1 with gross primary tumor development in the liver by week 2. Weeks 3 and 4 showed gross and histologic progression of primary tumor size with no apparent evidence of microscopic distal metastases. By week 5, the first histological findings of micrometastases appeared in the lungs which became wide spread in all the pulmonary parenchyma by week 7. Splenic and mediastinal lymph node involvement were observed histologically by week 6.
Conclusions: Liver xenografting of A549 into NOD/SCID mice is a reliable way of developing widespread micrometastases to the lungs, mediastinal lymph nodes, and spleen. This model is clinically relevant since, unlike tail vein injection, it allows the study of the biology and treatment of a gradually developing primary lung tumor with subsequent metastatic spread.
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 1600. doi:10.1158/1538-7445.AM2011-1600
Abstract 1601: Hsp90 inhibition results in a significant delay in tumor progression in a model of emerging EGFR TKI resistance in non-small cell lung cancer
Authors: Slocum Kelly L. , Sheikh Hana , West Kip , Normant Emmanuel , Robison Keith , MacDougall John , Fritz Christian 
Published: June 2012

Abstract
Heat shock protein 90 (Hsp90) plays a role in regulating the stability of key cancer-causing proteins through its role as a protein chaperone. Proteins chaperoned by Hsp90, known as client proteins, include cancer-causing forms of ALK, BCR-ABL, EGFR, FLT3 and HER2. Infinity is developing two drug candidates in its Hsp90 chaperone inhibitor program: IPI-504 (retaspimycin hydrochloride), an intravenously-administered small molecule, and IPI-493, which is administered orally.
EGFR tyrosine kinase inhibitors (TKIs) are an effective treatment for lung cancer patients with activating mutations in EGFR. After a dramatic initial response, however, most patients become resistant to drug treatment and progress. In about half of these cases, resistance is due to a second point mutation in EGFR (T790M). It is believed that in at least some of these cases, the TKI resistance mutations are pre-existing and that treatment with TKIs selects for the resistant cells.
In an effort to model the emergence of resistance to TKIs from pre-existing mutations, we developed a novel in vivo model, where gefitinib treatment initially leads to tumor regression followed by rebound of tumor growth and outgrowth of drug resistant clones containing the T790M mutation. We show that in this model, treatment with IPI-493 alone and IPI-493 following gefitinib resulted in tumor growth inhibition of 61 and 77%, respectively, when compared with gefitinib treatment alone. Treatment with IPI-493 alone also resulted in a significant delay in time to tumor progression with ∼40% of animals still on study 45 days following tumor implant; all animals treated with either vehicle or gefitinib had been removed due to tumor progression. Interestingly, treatment with IPI-493 following gefitinib resulted in an even more impressive delay in time to progression, with &gt;50% of animals still on study on day 65 post-implant.
These results suggest that further studies with Hsp90 inhibitors in EGFR mutant NSCLC patients who have been pre-treated with a TKI may be warranted.
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 1601. doi:10.1158/1538-7445.AM2011-1601
Abstract 1603: Primary breast cancer xenografts maintain the molecular profiles of corresponding patients’ tumors and recapitulate a part of stroma microenvironment
Authors: Reyal Fabien , Guyader Charlotte , Decraene Charles , Lucchesi Carlo , Auger Nathalie , Assayag Franck , De Plater Ludmilla , Gentien David , Poupon Marie-France , Cottu Paul , De Cremoux Patricia , Vincent-Salomon Anne , Roman-Roman Sergio , Delattre Olivier , Decaudin Didier , Marangoni Elisabetta 
Published: June 2012

Abstract
Identifying new therapeutic agents for breast cancer (BC) treatment requires preclinical models that recapitulate the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and expression profiles of human BC xenografts and their corresponding patient's tumors. Eighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. The molecular characterization of patient's and xenograft's tumors (early and late in vivo passages) was performed by DNA copy number analysis (aCGH) and gene expression analysis using Affymetrix Microarrays. Comparison of genomic profiles of BC xenografts with those of respective patient's tumors, showed a correlation coefficient higher than 0.50 in 14/18 paired tumors. Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together further indicating the striking similarity between pairs. At the level of gene expression profile few variations were found between patient's tumor and their respective xenografts, i.e. 371 genes that were differentially expressed in more than 84% of paired tumors and that largely represent human stromal compartment related genes. Furthermore, analysis of gene expression by murine stroma revealed a partial but significant recapitulation of the primitive human stroma.
Finally, we found that sequential mouse to mouse tumor passages did not affect neither genomic rearrangements nor gene expression profiles, suggesting a striking genetic stability of these models across the time. In conclusions, this panel of human BC xenografts accurately maintains the genomic and the expression profiles of their corresponding patient's tumors and are stable across sequential in vivo passages. Consequently, these xenografts represent a validated model for preclinical investigation of new therapeutic agents.
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 1603. doi:10.1158/1538-7445.AM2011-1603
Abstract 1609: In vivo and ex vivo comparison of two human AML bone marrow engraftment mouse models using fire fly luciferase expressing MOLM-13 and MV4-11 cells
Authors: Lingnau Andreas , Feger Daniel , Hoffmann Steffen , Umber Sarah , Kubbutat Michael HG 
Published: June 2012

Abstract
Acute myeloid leukemia (AML) is the most common leukemia affecting adults. In 70-90% of all AML patients FLT3, a receptor tyrosine kinase which plays an important role in normal hematopoiesis, is highly expressed. Furthermore, in about 30% of all AML patients activating internal tandem duplications (ITDs) or point mutations within the FLT3 gene have been identified. FLT3, therefore, is one of the most promising drug targets for the treatment of AML.
Most often novel FLT3 protein kinase inhibitors are tested in subcutaneous xenograft mouse models using various human AML cell lines. To generate more relevant, orthotopic AML in vivo models, we stably transduced the human AML cell lines MOLM-13 and MV4-11 with fire fly luciferase (MOLM-13-Luci and MV4-11-Luci) suitable for in vivo bioluminescence imaging. MOLM-13 carries a heterozygous and MV4-11 a homozygous FLT3 internal tandem duplication (ITD) mutation. In vivo growth of MOLM-13-Luci and MV4-11-Luci cells after subcutaneous implantation in NMRI nude mice proofed that stable expression of luciferase did not alter growth characteristics of these cells.
To initiate orthotopic growth, both AML cell lines were implanted intravenously via the tail vein into NOD SCID mice after Cyclophosphamide treatment. Cyclophosphamide facilitates engraftment of the human cells by reducing the endogenous bone marrow cell population.
Approximately two (MOLM-13-Luci), or three (MV4-11-Luci) weeks after implantation, luciferase activity was detectable in the pelvic region of the mice indicating growth of both tumor cell lines. Within the next weeks luciferase activity was also seen in additional parts of the mouse at different levels.
After necropsy a set of different organs and tissues was analysed ex vivo for luciferase activity. The pattern of metastasising tumor cells was compared in both models. Furthermore, detection of human Ki-67 protein using appropriate human specific antibodies allowed verification of growth of MOLM-13-Luci and MV4-11-Luci cells in different tissues.
Sutent, a small-molecule kinase inhibitor, totally abolished tumor growth of both orthotopically growing tumors, indicating that both in vivo models are highly suitable for the characterisation of novel drugs directed against AML.
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 1609. doi:10.1158/1538-7445.AM2011-1609
Abstract 161: Plasma-based biomarkers for breast cancer diagnosis
Authors: Hu Zhibin , Shen Hongbing , Dong Jing , Ma Hongxia , Dai Juncheng , Wei Qingyi , Wang Li-E 
Published: June 2012

Abstract
Introduction It has been demonstrated that there are abundant, stable microRNAs (miRNAs) in plasma/serum, which can be detected and is potentially disease-specific. In this study, we aimed to assess whether serum/plasma miRNAs may be used as potential biomarkers for breast cancer diagnosis.
Methods We used systematically Solexa sequencing as well as TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to screen plasma miRNAs in 48 breast cancer patients and 48 age-matched controls of Chinese origin for the discovery stage and validated in an internal validation set (50 patients and 50 controls in Chinese) and in an external validation set (24 patients and 24 controls in Caucasians).
Results Four miRNAs (miR-16, miR-25, miR-222 and miR-324-3p) were differentially expressed between breast cancer cases and controls and subsequently validated in the internal and external validation stage samples. Taken together, Chinese patients with high plasma miRNA expression levels had a significantly increased risk of breast cancer for all the four miRNAs. The Area Under the Receiver Operating Characteristic Curve was 0.917 for the four-miRNA signature in the discovery stage (sensitivity=0.917 and specificity=0.917), 0.930 in the internal validation stage (sensitivity=0.920 and specificity=0.940).
Conclusions The four-miRNA signature from plasma may serve as a noninvasive diagnostic biomarker for breast 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 161. doi:10.1158/1538-7445.AM2011-161
Abstract 1612: Investigating NF-κB pathway as a novel therapeutic target in preclinical lung cancer mouse models
Authors: Xue Wen , Meylan Etienne , Oliver Trudy , Jacks Tyler 
Published: June 2012

Abstract
Lung cancer represents the most frequent cancer type and the leading cause of cancer death (1.3 million worldwide). Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases. NSCLC development is associated with frequent mutations in well-defined oncogenes and tumor suppressor genes such as Kras (30%) and p53 (50-70%). We recently demonstrated that hyper-activated NF-kB pathway in NSCLC is required for the initiation and maintenance of lung cancer, indicating this pathway as a promising therapeutic target. In this study, we tested therapeutic delivery of proteasome inhibitor Bortezomib (Velcade) to inhibit NF-κB pathway in NSCLC mouse models. In mouse lung cancer cell lines harboring KrasG12D and p53 loss (KP cells), Bortezomib efficiently reduced nuclear p65, repressed NF-kB target genes such as Bcl2 and rapidly induced apoptosis. The cell lines with high NF-kB activity are especially sensitive to Bortezomib. Using autochothonous mouse models and microCT imaging, we showed that Bortezomib treatment at a well-tolerated dose leads to lung tumor regression in mice and prolonged survival. Our results demonstrated using preclinical mouse models to study cancer treatment response and supported NF-kB pathway as an effective therapeutic target in lung 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 1612. doi:10.1158/1538-7445.AM2011-1612