bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5206: Systems biology identification of processes/pathways facilitating the development of high-grade serous ovarian cancer
Authors: Balch Curt , Jadhav Rohit , Fang Fang , Pilrose Jay , Li Meng , Shen Changyu , Li Lang , Huang Tim H-M , Nephew Kenneth P. 
Published: August 2012

Abstract
Previously, based on well-known stem cell phenotypes (sphere formation, potent tumorigenicity, embryonic gene expression, and chemoresistance), we used patient tumors to isolate high-grade serous (HGS) ovarian cancer-initiating cells (OCICs) that express the cell surface markers CD44 (a hyaluronate receptor) and CD117 (c-kit) (Zhang et al., 2008, Cancer Res 68:4311). Here, to identify biological pathways that underlie HGS ovarian tumorigenesis, including the specific role of OCICs in that process, we performed integrated analyses of global gene expression, DNA copy number, and DNA methylation patterns. To that end, OCICs and “bulk” (i.e., disaggregated but unsorted) tumor cells were compared to primary human normal ovarian surface epithelial (nOSE) cells that, along with fallopian tube epithelial (FTE) cells, represent hypothesized cells-of-origin for HGS pelvic cancers. Principle components analysis and unsupervised hierarchical clustering revealed distinct DNA methylation and gene expression profiles for replicate (n=3) samples of each cell type (i.e., OCIC, bulk tumor, and nOSE). Gene ontology and additional unsupervised analyses of “gene expression signatures” corresponding to the epithelial-to-mesenchymal transition (82 of 159 signature genes), TGF-beta (47 of 86 genes), and Wnt (75 of 151 genes) pathways demonstrated well-defined segregation of the three cell types, with mesenchymal and Wnt signaling hierarchies being nOSE &gt; OCIC &gt; bulk tumor cells. To examine early events in HGS ovarian tumorigenesis, previously published (Tone et al., 2008, Clin Cancer Res 14:4067) gene expression datasets were employed to show that nOSE, OCIC, and bulk ovarian tumor cell transcriptomes distinctly segregate from normal (FTE) and malignant fallopian epithelial transcriptomes. Interestingly, the largest divergence was between the nOSE and FTE gene expression profiles. Finally, DNA methylation and gene expression patterns were integrated, implicating specific networks/circuits in ovarian carcinogenesis. Taken together, these results support a mesenchymal-to-epithelial transition during ovarian tumorigenesis, reveal legitimate therapeutic targets (at the pathway level), and raise uncertainty that surface epithelial cells of the fallopian tube and ovary are reciprocal cells-of-origin for HGS pelvic carcinomas.
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 5206. doi:1538-7445.AM2012-5206
Abstract 5232: Tyrosine kinase inhibitor, gefitinib targets ZAP-70 over expressing chronic lymphocytic leukemia cells
Authors: Gibson Spencer , Xiao WenYan , Yoon Ju Yoon , Noh Edward , Brown Michelle , Johnston James B. 
Published: August 2012

Abstract
Most patients with chronic lymphocytic leukemia (CLL) initially respond to chemotherapy but relapse. There is a subset of CLL patients that have aggressive disease characterized by an over expression of the tyrosine kinase ZAP-70. These ZAP-70+ patients have a poorer survival and are more resistant to chemotherapy. The biological effects of ZAP-70 in CLL are believed to be related to its ability to enhance activation of Syk with subsequent triggering of down-stream modulators, such as ERK and AKT. Normally, Syk is activated by increased phosphorylation by Lyn, which is increased in CLL, or by activation of the B-cell receptor. Gefitinib is a tyrosine kinase inhibitor that is presently used to treat lung cancer. The drug inhibits epidermal growth factor receptor (EGFR) tyrosine kinase activity but has activity against &gt;20 other kinase targets, including members of the Src family of kinases, such as Lyn and Syk. We thus evaluated the cytotoxic activity of gefitinib against primary CLL cells using the MTT assay. Gefitinib was cytotoxic to ZAP-70+ (≥20% cells positive) CLL samples (median IC50, ∼3.0 µM) while ZAP-70- patients failed to respond to gefitinib with a median IC50 of &gt;15.0 µM. Jurkat cells, which are T cells that express high levels of ZAP-70, were more sensitive to gefitinib than B cell lines that did not express ZAP-70 (BJAB and NALM6). Further studies confirmed that gefitinib was inducing cell death through apoptosis. Gefitinib was also effective against ZAP-70+ CLL cells that were resistant to fludarabine and chlorambucil indicating a novel mechanism of action to standard chemotherapy. Enhanced apoptosis was observed in ZAP70+ CLL and Jurkat cells exposed to gefitinib and fludarabine or chlorambucil, but this was not observed in ZAP-70- or the B cell lines. In contrast, another EGFR inhibitor, erlotinib, had no effect against ZAP-70+ CLL cells indicating that gefitinib was inhibiting a kinase unaffected by erlotinib. When Jurakat and ZAP-70+ CLL cells were treated with gefitinib, there was reduced total tyrosine phosphorylation and decreased tyrosine phosphorylation of ZAP-70, and Syk but no difference in Lyn phosphorylation. Furthermore, gefitinib blocked B cell receptor activation and mediated cell survival. Taken together, these results indicate that gefitinib may be useful agent in the treatment of ZAP-70+ CLL, either alone or in combination with fludarabine or chlorambucil. Ongoing studies are determining the precise mechanism of action of gefitinib in ZAP-70+ CLL and assessing its effects on the CLL microenvironment.
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 5232. doi:1538-7445.AM2012-5232
Abstract 5237: Interrogating cell heterogeneity and dormancy in prostate cancer disseminated tumor cells
Authors: Ruppender Nazanin S. , Brown Lisha , Coleman Roger , Lakely Bryce , Coleman Ilsa , Welty Christopher , Gulati Roman , Nelson Peter S. , Lange Paul H. , Corey Eva , Vessella Robert , Morrissey Colm 
Published: August 2012

Abstract
Dissemination of tumor cells to the bone is an early event in prostate cancer (PCa) and is often insufficient by itself for the development of metastases; while PCa cells may be present in bone marrow, not all patients develop tumors in the bone. Therefore, the characterization of disseminated tumor cells (DTC) in bone marrow is important. We hypothesize that profiling gene expression in DTC could identify molecular cues that determine why some DTC are dormant, which dormant cells have the potential to reactivate, and which DTC will remain dormant. Our objectives were: (1) to develop a method to profile the transcriptome of individual PCa cells, (2) use the method to profile tumor cell heterogeneity and markers of dormancy in individual DTC from patients, and (3) use LuCaP xenograft lines to examine tumor cell heterogeneity and dormancy in vitro. We have demonstrated previously that we can obtain 15,441 positive probes from one PCa cell using a high stringency cut off on Agilent 44K oligonucleotide arrays. Furthermore, using the same high stringency cut off, the sensitivity and specificity between 1 and 10 cells was 0.640 and 0.946 respectively, demonstrating a very low false positive rate. Using this methodology, we are comparing the gene expression profile of 10 individual DTC from each of 5 patients with no evidence of disease four years after radical prostatectomy and 10 individual DTC from each of 5 patients with advanced metastatic disease. Additionally, our laboratory has developed 24 LuCaP PCa xenografts that do not proliferate in typical in vitro cell culture conditions. However, we have developed a technique using reactive bone marrow stroma that allows for in vitro culture and proliferation of these xenografts. Thus, we are comparing individual LuCaP cells in three cellular ‘states’ in vitro (1) dormant, (2) activated, and (3) inactivated to interrogate tumor cell heterogeneity and identify markers of tumor cell dormancy. Using this new technique for in vitro culture of xenografts, we show that cell contact, not only to the underlying stroma but also to other tumor cells, is required for proliferation of LuCaP cells in vitro. Furthermore, we show that proliferating, “active” LuCaP cells can be induced to enter a dormant, “inactive” state through lack of cell-cell contact. In conclusion, our studies will address the heterogeneity of single DTC isolated from the bone marrow of patients with PCa, and using both clinical and experimental specimens, identify potential genes associated with dormancy in PCa.
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 5237. doi:1538-7445.AM2012-5237
Abstract 5246: Use of γH2aX and other biomarkers to quantify distribution of drug activity in solid tumors
Authors: Saggar Jasdeep K. , tannock ian F. 
Published: August 2012

Abstract
Background: The disorganized vasculature within solid tumors leads to decreased drug delivery and poor penetration of drugs from blood vessels to the tumor cells. Our laboratory has used quantitative immunohistochemistry (IHC) to show limited intratumoral distribution of the auto-fluorescent drugs doxorubicin and mitoxantrone. Most anti-cancer drugs are not fluorescent and do not have antibodies that recognize them; there is a need for biomarkers that can be used to quantify their distribution and efficacy in different regions of solid tumors. The aim of the present study was to characterize the spatial distribution within solid tumors of biomarkers of drug effect that can be used to test drug efficacy. Methods: Cleaved caspase 3 (a marker of apoptosis), γH2aX (a marker of DNA damage) and Ki67 (a marker of cell proliferation) were quantified in tumor sections in relation to blood vessels (recognized by CD31) using monoclonal antibodies and IHC. To validate the use of these biomarkers we compared their time-dependent distribution with (i) the distribution of auto-fluorescent doxorubicin and (ii) the distribution of a fluorescent monoclonal antibody that detects melphalan-induced DNA adducts. The biomarkers were then used to study the distribution of docetaxel in relation to tumor blood vessels. Results: The distributions of doxorubicin in MCF7 & MDA-MB-231 xenografts and of melphalan-induced DNA adducts in MCF-7 & EMT-6 tumors decreased exponentially with increasing distance from tumor blood vessels; they were similar to the distribution of γH2aX at 10 minutes after injection of these drugs. The distributions of cleaved caspase 3 and of change in Ki-67 at 24 hours following treatment also mirrored the distribution of the drugs. The distribution of these biomarkers following injection of docetaxel also showed a sharp decrease in drug activity with increasing distance from tumor blood vessels in solid tumors (MCF-7, PC-3 & A431). Conclusions: Activation of γH2aX occurs within 10 minutes after injection of several drugs and is the preferred biomarker for studying distribution of drug activity in tumors. There is heterogeneity of activity of many anticancer drugs in solid tumors, with rapid decrease in activity with increasing distance from tumor blood vessels. Poor distribution of drugs to cells within tumors is an important cause of drug resistance. Supported by a research grant from the Canadian Institutes of Health Research
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 5246. doi:1538-7445.AM2012-5246
Abstract 5318: DPC4 loss results in the activation of alternative oncogenic pathways in pancreatic cancer
Authors: Brosnan Jacqueline A. , White Catherine M. , Iacobuzio-Donahue Christine A. 
Published: August 2012

Abstract
Introduction: Pancreatic cancer remains one of the most lethal forms of cancer, with a five-year survival rate of less than five percent. Many of these patients succumb to complications from metastasis. We have shown that genetic inactivation of DPC4, a major factor in TGF-β signaling, is significantly correlated with widespread metastasis in pancreatic cancer patients at autopsy. We hypothesize that DPC4 loss may be driving pancreatic cancer metastasis by forcing the TGF-β signal down an alternative pathway. Methods: DPC4 was stably restored into three cell lines that harbor a homozygous deletion of the locus (A2.1, A6L, and BxPC3), forming isogenic pairs of DPC4−/− and DPC4+ cells. Matched DPC4−/− and DPC4+ cells were treated with TGF-β1 for 24 hours prior to protein extraction. Immunoblotting was performed for total and phospho Akt (Pi3K pathway), p44-42 (ERK pathway), and Stat3 (JAK-Stat pathway), as well as nuclear and cytoplasmic p65 (NFκB pathway), as these networks have previously been identified as being activated by TGF-β. Immunohistochemistry was performed on 50 surgically resected pancreatic cancers for pAkt. Results: DPC4 was successfully introduced into DPC4−/− cells, as evidenced by semi-quantitative PCR for DPC4, as well as a TGF-β luciferase assay. DPC4+ cells displayed characteristic differences in cell behavior, such as decreased proliferation, migration, and invasion, compared to DPC4−/− cells. Western blot analysis of Smad-independent TGF-β pathways in three sets of DPC4-complemented pancreatic cancer cell lines revealed patterns of preferential activation of the Pi3K and ERK signaling pathways in cells lacking DPC4. In surgically-resected pancreatic cancers, activation of Pi3K was associated with the presence of lymph node metastases (p=0.03), while concomitant DPC4 loss and Pi3K pathway activity was associated with poor survival in pancreatic cancer patients (p=0.02). Conclusions: Restoration of DPC4 into DPC4−/− cells results in the abrogation of Pi3K and ERK signaling, and simultaneous DPC4 loss and Pi3K activation correlates to a poor prognosis of pancreatic cancer patients at surgery. Further studies will confirm whether genotype-specific activation of the ERK and Pi3K pathways plays a role in pancreatic cancer cell behavior, particularly those processes that directly impact metastasis (i.e. migration and invasion). Nevertheless, it is intriguing to consider the Pi3K and ERK pathways as therapeutic targets in pancreatic cancer patients with loss of DPC4.
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 5318. doi:1538-7445.AM2012-5318
Abstract 5328: Interleukin-4 receptor regulates metastasis of mammary epithelial cancer cells
Authors: Venmar Katherine T. , Hwang Daniel G. , Dozier Ashley , Carter Kathy J. , Gillani Sareena , Fingleton Barbara 
Published: August 2012

Abstract
Interleukin-4 (IL-4), a cytokine produced mainly by immune cells, may promote cancer cell survival by mediating apoptosis resistance in epithelial tumors. The IL-4 Receptor (IL-4R) is overexpressed in a variety of human solid cancer cell lines and primary cell lines, and may be a promising target for anti-tumor therapy. Here, we show that loss of IL-4Rα, a component of the IL-4 receptor, in two murine mammary tumor cell lines (R221A and 4T1), reduces tumor cell survival and results in attenuated metastatic growth in secondary sites. Proliferation and direct cell counting analyses, following knockdown of IL-4Rα with RNA interference, show that R221A clones with reduced IL-4Rα expression proliferate at a comparable rate to control clones, but the number of cells is significantly reduced. This data correlates with the finding that reduced IL-4Rα expression in R221A cells almost completely abolishes tumor take after orthotopic mammary injection in vivo. Furthermore, reduced IL-4Rα expression in R221A and 4T1 cell lines results in a decrease [2.4 fold] in lung metastatic growth in vivo. Reduced expression of IL-4Rα in 4T1 cells results in a similar decrease of liver metastasis. In support of this data, proliferation assays following serum starvation and a modified clonogenic survival assay show that both 4T1 and R221A knockdown clones have a decrease [2 fold] in survival ability in comparison to control clones. Taken together, our results indicate that the IL-4 receptor promotes survival of breast cancer cells at metastatic sites, and suggests that drugs targeting this pathway, currently in clinical trials for respiratory ailments, may have potential for limiting 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 5328. doi:1538-7445.AM2012-5328
Abstract 533: Dendritic cells are professional educators of Natural Killer cells
Authors: Wiernik Andres , Miller Jeffrey S. 
Published: August 2012

Abstract
Dendritic cells (DCs) and Natural Killer (NK) cells are important components of innate immunity. NK cells are the principal effectors of the innate immune system and play an important role in tumor surveillance and anti-viral immunity. It has been commonly accepted that CD56bright NK cells are the main source of cytokine production while CD56dim are mostly responsible for cytolytic activity and target cell killing. CD56dim NK cells acquire KIR (Killer cell Immunoglobulin-like Receptors or KIR) receptors by a process called NK cell education or licensing. NK cell education has been defined as the mechanism by which NK cell acquire inhibitory KIR and how signaling by specific cognate ligands leads to gain of NK cell function. DCs are antigen presenting cells which act as sentinels for the immune system by engulfing pathogens, processing and presenting them to CD4 and CD8 T cells. Interactions between dendritic cells and natural killer cells have been extensively studied but the role that DCs might play in NK cell education remains elusive and poorly understood. We evaluated the in-vitro interaction between adult monocyte-derived dendritic cells and natural killers cells from healthy donors. Mature monocyte-derived dendritic cells (mdDCs) were co-cultured with KIR negative and KIR positive NK cells in addition to different concentrations of IL-15. After 5 days of co-culture; the KIR negative population (0.8% KIR positive after 5 days of co-cultured) acquired up to 3.8% KIR expression when co-cultured with mdDCs (1:1 ratio) and 0.5 ng/mL of IL-15. In addition, a population of NK cells which expressed 28% KIR after 5 days of culture expressed up to 38% KIR when mdDCs and 0.5 ng/mL of IL-15 were added to the culture. Of note, enhanced KIR expression (as a marker of maturation) required both IL-15 and mdDcs as no effect was seen when mdDcs or IL-15 were added alone. Aside from the differences noted in KIR expression, a population of CD56dim NK cells became CD56bright when both KIR negative (8.44% to 23.6%) and KIR positive (0.8% to 24.9%) NK cells were co-cultured with mdDCs and IL-15. In conclusion, our studies suggest that dendritic cells have the ability to educate NK cells and that this process is dependent on IL-15, which can be trans-presented through IL-15Rα on DCs. Dendritic cells in addition to IL-15 may also revert a population of mature CD56dim NK cells to a CD56bright NK cells, which are considered less differentiated, suggesting that NK maturation can be bidirectional and may exhibit more plasticity than previously recognized.
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 533. doi:1538-7445.AM2012-533
Abstract 5344: Subtyping of glioblastoma stem-like cancer cells with neural lineage markers predicts invasiveness and correlates with survival
Authors: Zorniak Michael , Clark Paul A. , Leeper Heather E. , Tipping Matthew D. , Francis David M. , Kozak Kevin R. , Salamat M. Shahriar , Kuo John S. 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. GBM gene expression and microRNA profiling recently revealed developmental subtypes that potentially correlates with prognosis and treatment response. However, the clinically significant subset of glioblastoma stem-like cells (GSC) still lacks detailed molecular characterization and correlation to patient survival. We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also demonstrate significant correlation to survival in both the mouse model and human patients. Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. After orthotopic injection into immunodeficient mice, Ki-67 proliferative index independent xenograft infiltration was observed: class I GSCs (OPC and NPC positive) created focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, cyclic nucleotide phosphodiesterase (CNP), exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression significantly correlated with mouse model survival, and CNP assay of a large clinically annotated human GBM tissue microarray also showed differential patient survival. Therefore, GSC molecular characterization with neural lineage markers revealed a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC subtyping.
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 5344. doi:1538-7445.AM2012-5344