bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-92: Isoflurane increases the metastatic potential of renal cell carcinoma cells via the hypoxia inducible factor pathway- an in vitro study
Authors: Benzonana Laura L. , Perry Nicholas J. , Watts Helena R. , Ma Daqing 
Published: July 2012

Abstract
Background: Patients with solid tumours are likely to have to undergo surgery during the course of their disease. Surgery and anaesthesia may influence the tumour's metastatic potential. Isoflurane is known to up-regulate hypoxia inducible factors (HIFs). HIFs are heavily implicated in tumorigenesis and may play an important role in tumour cell proliferation, migration, invasion and angiogenesis (VEGF signaling). Our aim was to investigate the potential impact of isoflurane on tumour cell progression in vitro.
Methods: Human Renal Cell Carcinoma (RCC4) cells were exposed to 2% isoflurane for 2 hours at 37°C. HIF-1α, HIF-2α, p-Akt, and VEGFA protein levels were measured by Western Blotting at different time points (0, 2, 4, 8 and 24 hours) following isoflurane exposure. HIF-1α was also measured by fluorescent immunocytochemistry after cell fixation. Cell proliferation was measured by MTT and trypan blue exclusion assays. Cell migration was measured using an Oris cell migration assay.
Results: Isoflurane up-regulated HIF-1α in a time-dependent manner, with the highest levels being detected at 8 hours post gas exposure (p&lt;0.001). These results were confirmed by immunofluorescence, showing a significant accumulation of HIF-1 α in the nucleus at 8 hours. Isoflurane also up-regulated HIF-2α, maximal levels were detected at 24 hours (p&lt;0.01). Isoflurane activated the PI3K pathway, as indicated by significantly raised levels of p-Akt from 4 to 24 hours, with highest levels at 8 hours (p&lt;0.001). An increase in VEGFA accumulation was seen at 24 hours (p&lt;0.01). MTT assays performed 8 hours following gas exposure demonstrated that isoflurane increased the rate of cell proliferation (p&lt;0.01), as confirmed by immunofluorescence findings at this time point. Cell migration assays showed an increased migration of Isoflurane treated cells 8 hours post exposure (p&lt;0.01), as confirmed by immunofluorescence, where an increased number of cells showing filipodia (cells migrating) was observed.
Conclusion: Isoflurane at clinically relevant concentrations up-regulates HIF-1α and HIF-2α, which may be due to upstream PI3K pathway activation. Isoflurane up-regulates the major pro-angiogenic factor VEGFA and increases the rate of proliferation and migration in RCC4 cells in vitro. These findings may have major clinical implications for patients undergoing cancer surgery under general isoflurane anaesthesia.
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 LB-92. doi:10.1158/1538-7445.AM2011-LB-92
Abstract PL03-02: Microenvironment survival signals for disseminated cancer cells
Authors: Massagué Joan 
Published: July 2012

Abstract
To form metastases, circulating cancer cells that egress into a distant parenchyma must be able to survive in the newly invaded microenvironment. Identifying these survival mechanisms may provide therapeutic strategies for the eradication of disseminated disease and the prevention of metastasis. In breast cancer, where relapse develops in an organ-specific manner, we have identified metastasis progression genes that prime cancer cells for extravasation into specific organs, as well as genes that mediate overt metastatic colonization. However, the survival of newly extravasated cells depends on a distinct set of genes and pathways. SRC primes breast cancer cells for survival in the bone marrow by potentiating AKT activation by CXCL12 and IGF1, cytokines that are abundant in the marrow. Recent work revealed how bone metastatic seeds may be preselected in the primary tumor. In the lungs, VCAM1- and tenascin-C support the survival of micrometastatic cancer cells. The mechanisms involve interactions with tumor-infiltrating leukocytes and an extracellular matrix niche. Inhibition of SRC, VCAM1 and tenascin-C suppresses experimental micrometastases and the growth of aggressive lesions.
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 PL03-02. doi:10.1158/1538-7445.AM2011-PL03-02
Abstract PL04-03: Targeting the hedgehog pathway in meduloblastoma and basal cell carcinoma
Authors: de Sauvage Frederic J. 
Published: July 2012

Abstract
The hedgehog (Hh) pathway is an ancient signaling cascade that directs patterning in most animals and is crucial for proper development. While Hh signaling is very active during embryogenesis, it remains relatively quiet in adult life. However, aberrant reactivation of the pathway in adult tissues can lead to the development of cancer. Hh pathway activation in tumors such as basal cell carcinoma (BCC) and medulloblastoma is the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. Targeting the Hh pathway with small molecule antagonists therefore provides a new therapeutic opportunity for the treatment of these tumor types. GDC-0449, an oral Hedgehog (Hh) pathway inhibitor, was tested in a first-in-human, first-in-class, phase I study in BCC patients. Strong antitumor activity was observed in patients with locally advanced and metastatic BCC, thereby highlighting the potential benefit of inhibiting aberrant Hh signaling in tumors where the pathway is mutated. While most BCC tumors display Hh pathway activity, only a subset of medulloblastoma tumors are caused by mutations in the Hh pathway. Early evidence of clinical benefit of GDC-0449 in a medulloblastoma patient selected for Hh pathway activity was demonstrated. However, as is the case for most targeted therapies used in cancer, mechanisms of resistance to Hedgehog pathway inhibitors have started to emerge in man and mouse models, highlighting the importance of this pathway for these tumors. Characterization of various resistance mechanisms such as SMO mutations or amplification of downstream pathway components suggests potential for therapeutic strategies for the treatment of HPI resistant tumors.
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 PL04-03. doi:10.1158/1538-7445.AM2011-PL04-03
Abstract SY01-04: Tackling breast cancer: from genetic screens to new therapeutic strategies
Authors: Westbrook Thomas F. 
Published: July 2012

Abstract
Breast cancer is a collection of diseases with distinct clinical behaviors and underlying genetic causes. Triple-negative breast cancer (TNBC) is a common subtype of breast cancer that confers a particularly poor prognosis and is refractory to current targeted therapies. Unfortunately, the molecular determinants driving this aggressive malignancy are poorly understood. Using an unbiased genetic screen, we have identified a novel tumor suppressor network that governs proliferation and transformation of TNBCs in vitro and in vivo. We define PTPN12 as a core component in this network and a commonly inactivated tumor suppressor in TNBC. PTPN12 is a potent suppressor of human mammary epithelial cell proliferation and transformation. PTPN12 function is frequently compromised in human TNBCs by inactivating mutations, deletion, or loss of protein expression. Mechanistically, PTPN12 is a tyrosine phosphatase that suppresses cellular transformation by interacting with and inhibiting several oncogenic receptor tyrosine kinases including HER2, EGFR, and PDGFR. Notably, the tumorigenic and metastatic potential of PTPN12-deficient TNBCs is severely impaired by restoring PTPN12 function or by inhibiting kinase targets of PTPN12, suggesting that TNBCs are dependent on the proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor and provide a rationale for combinatorially targeting tyrosine kinases in TNBC and other cancers based on their profile of tyrosine phosphatase activity.
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 SY01-04. doi:10.1158/1538-7445.AM2011-SY01-04
Abstract SY02-02: Interaction of MMPs with oncogenic signaling: Disruption of dynamic reciprocity and tissue polarity
Authors: Beliveau Alain , Mott Joni , Lo Alvin , Chen Emily , Muschler John , Spencer Virginia , Bissell Mina J. 
Published: July 2012

Abstract
Whether or not epithelial cells organize into three-dimensional structures defines their normal or invasive and malignant status. In a model of human breast morphogenesis, we have shown that inhibiting key signaling pathways in breast cancer cells leads to phenotypic reversion of the malignant cells. Using intact architecture or invasive behavior as an endpoint, we report that in all cases, signaling through Raf/MEK/ERK disrupts tissue polarity via MMP9 activity. Induction of Raf or activation of an engineered functionally inducible MMP9 in nonmalignant cells leads to loss of tissue polarity and reinitiates proliferation. Conversely, inhibition of Raf or MMP9 with small molecule inhibitors or shRNAs restores the ability of cancer cells to form polarized quiescent structures. Silencing MMP9 expression reduces tumor growth dramatically in a murine xenograft model. LC-MS/MS analysis comparing secreted proteins from nonmalignant cells – with or without active MMP9 – reveals laminin 111 (LN1) as a prominent target of MMP9. LN1 is shown to be necessary for acinar morphogenesis; thus its degradation by MMP9 provides the molecular mechanism by which tissue polarity is lost and growth and invasion reinitiated. These findings underscore the essential dynamic reciprocity between ECM integrity, tissue polarity, and suppression of Raf/MEK/ERK and MMP9 activities: the correct balance is essential to homeostasis, whereas imbalance leads to malignant 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 SY02-02. doi:10.1158/1538-7445.AM2011-SY02-02
Abstract SY03-02: Tumor metabolic phenotyping and treatment stratification by positron emission tomography
Authors: Radu Caius , Lee Jason T. , Campbell Dean O. , Czernin Johannes 
Published: July 2012

Abstract
The ability to noninvasively measure key metabolic pathways in living subjects may assist the development of new, more efficacious therapies against cancer. Here we show that two new positron emission tomography (PET) probes, 1-(2′-deoxy-2′-18F-fluoro-β-D-arabinofuranosyl)cytosine (18F-FAC) and 1-(2′-deoxy-2′-18F-fluoro-β-L-arabinofuranosyl)-5-methylcytosine (L-18F-FMAC), detect distinct phenotypic signatures of tumor nucleoside metabolism. 18F-FAC and L-18F-FMAC accumulation in tumors measured in vivo by PET is indicative of the activities of deoxycytidine kinase (dCK) and cytidine deaminase (CDA), two key enzymes in nucleic acid metabolism. Metabolic subtypes detected by 18F-FAC and L-18F-FMAC were shown to correspond to the differential utilization by cancer cells of the nucleoside salvage pathway to generate and maintain deoxyribonucleotide pools required to sustain tumor growth. We also show that the metabolic subtypes defined by 18F-FAC and L-18F-FMAC PET measurements correlate with markedly distinct sensitivities to therapeutic interventions. These findings support the utility of PET-based phenotyping of tumor nucleoside metabolism for treatment stratification in 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 SY03-02. doi:10.1158/1538-7445.AM2011-SY03-02
Abstract SY06-03: Exploiting the dependency of cancer cells on molecular chaperone systems
Authors: Workman Paul 
Published: July 2012

Abstract
Please see attachment link below for the complete presentation.
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 SY06-03. doi:10.1158/1538-7445.AM2011-SY06-03
Abstract SY09-01: Control of class III PI 3-kinase in autophagy and cancers
Authors: Lipinski Marta , Furuya Tsuyoshi , Kim Minsu , Hoffman Greg , Ng Aylwin , Blenis John , Xavior Ramnik , Yuan Junying 
Published: July 2012

Abstract
Autophagy, a lysosome-dependent catabolic process involved in the turnover of cellular components, mediates normal homeostasis during development and protects multicellular eukaryotes from neurodegeneration, cancer and other diseases. However, the mechanisms regulating autophagy under normal nutritional conditions most frequently encountered by cells in organisms under physiological conditions remain unknown. Our recent studies highlight an important role of class III PI 3-kinase in regulating autophagy. First, we show that phosphorylation of Vps34 by Cdk1 and Cdk5 negatively regulate type III PI 3-kinase and production of PI3P in mitotic cells and in neurodegeneration. Second, we show that multiple growth factors negatively regulate the activity of type III PI 3-kinase. In an image-based genome-wide human siRNA screen, we show that upregulation of autophagy by only 14 (6.4%) of the identified hit genes was accompanied by downregulation of activity of mTORC1, an essential regulator of starvation-induced autophagy. On the other hand, we found that 110 (50.2%) of the hit genes, including a group of growth factors and cytokines, regulate autophagy by targeting the type III PI 3-kinase. These cytokines inhibit the type III PI 3-kinase through multiple pathways. Third, we show that ROS may have a general signaling function in autophagy. We uncovered a large group of genes (117, or 54% of all genes tested) whose knockdown led to vesicular translocation of LC3-GFP in the absence but not the presence of antioxidant, suggesting that ROS are required for the induction of autophagy. Finally, using a small-molecule inhibitor that promotes the degradation of class III PI 3-kinase, we show that successful targeting this pathway can lead to selective cancer cell death. Our study suggests that the type III PI 3-kinase integrates diverse signals to regulate cellular levels of autophagy. Thus, autophagy and cell proliferation may represent two alternative cell fates that are regulated in a mutually exclusive manner, implicating autophagy as a common tumor suppression mechanism downstream of multiple signaling pathways.
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 SY09-01. doi:10.1158/1538-7445.AM2011-SY09-01
Abstract SY09-02: A new C. elegans cell death pathway: Implications for neurodegeneration and cancer
Authors: Shaham Shai 
Published: July 2012

Abstract
Programmed cell death is an essential process during metazoan development. During development of the nematode C. elegans nearly all cells slated to die activate caspases and undergo stereotypical morphological changes, including chromatin compaction and cell shrinkage. The male-specific linker cell, however, is an exception. The linker cell leads the migration of the developing gonad and once migration is complete the cell dies. Strikingly, mutations in the genes ced-3/caspase, ced-4/Apaf-1, egl-1/BH3-only, or ced-9/BCL2, the main regulators of apoptosis in C. elegans, do not affect linker cell death. Linker cell death must, therefore, be controlled by a novel program. Electron micrographs of dying linker cells reveal nonapoptotic features, including nuclear membrane invaginations, absence of chromatin condensation, and swelling of mitochondria and the endoplasmic reticulum. Similar features are seen in dying vertebrate neurons during development and in neurons that die from polyglutamine-induced toxicity as occurs in Huntington's disease and other spinocerebellar ataxias.
To understand the molecular basis of linker cell death we sought genes that regulate the process. We have identified over 15 genes controlling linker cell demise and have begun to place these in genetic pathways. Our results demonstrate that linker cell death is initiated by a cell-autonomous transcriptional program that induces the expression of genes required to promote linker cell death. One transcriptional target, the gene pqn-41, has been studied in detail. pqn-41 encodes a 2100 amino-acid protein with a C-terminal domain in which 151 of 427 amino acids are glutamine. pqn-41 expression is induced in the linker cell just prior to onset of death, and the protein partitions to both nucleus and cytoplasm, accumulating in cytoplasmic puncta. Importantly, an endogenous transcript encoding only the polyglutamine domain of pqn-41 is sufficient to rescue pqn-41 mutants. pqn-41 functions together with a MAPK pathway and a pathway regulated by the microRNA let-7, whose expression is often disrupted in human lung cancer.
Our results demonstrate the existence of a new metazoan cell death pathway and raise the possibility that neurodegenerative diseases resulting from polyglutamine expansions may inappropriately activate this program to cause neuronal loss.
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 SY09-02. doi:10.1158/1538-7445.AM2011-SY09-02
Abstract SY10-01: Whole genome sequencing and analysis in a clinical trial setting: Aromatase inhibitor therapy in breast cancer
Authors: Mardis Elaine 
Published: July 2012

Abstract
We have applied the use of next-generation sequencing of whole genomes in fifty matched pretreatment tumor core biopsy specimens and blood normals resulting from a clinical trial of aromatase inhibitor therapy, from the American College of Surgeons Oncology Group (ACOSOG) Z1031 study. We also have studied the whole genomes of the post-treatment samples obtained from surgical resection, for additional comparison. We used additional accrued samples from this clinical trial to extend our findings. I will present our analysis of these data, including significantly mutated genes and pathways, the impact of aromatase inhibitor therapy on genomic heterogeneity, and integrated analyses to reveal a genomic signature predictive of aromatase inhibitor response.
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 SY10-01. doi:10.1158/1538-7445.AM2011-SY10-01
Abstract SY11-02: The role of the histone deacetylase SIRT6 in glucose homeostasis and cancer
Authors: Mostoslavsky Raul , Sebastian Carlos , Zhong Lei , Giacosa Sofia , Toiber Deborah 
Published: July 2012

Abstract
Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP production. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration. This switch is critical to maintain cells during periods of starvation or hypoxia; furthermore, recent studies indicate that modulating this switch proved beneficial under chronic glucose imbalance, such as in patients with type II diabetes, and it also plays a critical role in cancer metabolism, as defined by Otto Warburg decades ago. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism and DNA repair. In mice, SIRT6-deficiency provokes a profound and lethal hypoglycemia which culminates in accelerated death. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic genes. In this context, SIRT6 functions at chromatin to attenuate a Hif1α transcriptional nutrient response. SIRT6 co-represses Hif1α, acting as a histone H3 lysine9 (H3K9) deacetylase to inhibit expression of Hif1α-target gene promoters (Zhong et al, 2010). In the absence of SIRT6, H3K9 acetylation is enhanced in these promoters, triggering a Hif1α-dependent glycolytic switch, a response that appears critical in order to maintain cells under conditions of nutrient stress. In this context, our new studies indicate that this “glycolytic switch” observed in the absence of SIRT6 provides a growth advantage in the context of tumorigenesis. Potential mechanistic implications will be further discussed.
Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R.E., Vadysirisack, D.D., Guimaraes, A., Marinelli, B., Wikstrom, J.D., Nir, T., Clish, C.B., Vaitheesvaran, Iliopoulos, O., B., Kurland, I., Dor, Y., Weissleder, R., Shirihai, O.S., Ellisen, L., Espinosa, J.M., and Mostoslavsky, R. (2010). The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1a. Cell, 140, 280-293.
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 SY11-02. doi:10.1158/1538-7445.AM2011-SY11-02