bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A74: TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma
Authors: Natsuizaka Mitsuteru , Kagawa Shingo , Whelan Kelly , Ohashi Shinya , Ohnishi Shunsuke , Suda Goki , Sakamoto Naoya , Rustgi Anil K. , Nakagawa Hiroshi
Published: May 2015

There exists a highly tumorigenic subset of esophageal squamous cell carcinoma (ESCC) cells defined by high expression of CD44 (CD44H). CD44H cells have cancer stem-like characteristics and as few as ten CD44H cells can form tumors in an athymic nude mouse. Epithelial-mesenchymal transition (EMT) has a critical role to maintain CD44H cells in ESCC. Notch1-mediated signaling may facilitate either EMT or squamous-cell differentiation in a context-dependent manner. However, detailed mechanism how Notch signaling promotes either EMT or differentiation remains unclear. We investigated how TGF-β in tumor microenvironment might influence Notch signaling to maintain CD44H cells via EMT in ESCC. TGF-β promoted EMT and enriched CD44H cells by activating Notch1 and ZEB1 and suppressing Notch3, while in absence of TGF-β, Notch1 rather activated Notch3, one of pivotal transcription factors in keratinocyte differentiation, led to keratinocyte differentiation. Highly conserved binding sites of ZEB1 exist in the 2nd intron of Notch3. ZEB1 induced by TGF-β bound to the 2nd intron of Notch3 and sharply suppressed the Notch3 transcription, confirmed by CHIP and luciferase assay. Thus TGF-β and Notch1 cooperatively promote EMT and maintain tumor initiating cells. TGF-β signaling influences the tumor initiating capacity of ESCC by modulating novel opposing activities of Notch1 and Notch3 in EMT, and may have translational implications.

Citation Format: Mitsuteru Natsuizaka, Shingo Kagawa, Kelly Whelan, Shinya Ohashi, Shunsuke Ohnishi, Goki Suda, Naoya Sakamoto, Anil K. Rustgi, Hiroshi Nakagawa. TGF-β in tumor microenvironment changes a switch of Notch1-mediated signaling to maintain cancer stem-like cells in esophageal squamous cell carcinoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A74. doi:10.1158/1538-7445.CHTME14-A74
Abstract A77: Hematopoietic stem cell-derived adipocytes promote tumor progression
Authors: Xiong Ying , Laws Dayvia A. , LaRue Amanda C.
Published: May 2015

The risk of developing a variety of tumors is increased under the condition of obesity or excess adiposity. Adipose tissue, apart from its critical role as the energy storage depot, contributes to the composition of tumor microenvironment that influences tumor behavior. It has generally been believed that bone marrow cells giving rise to adipocytes are mesenchymal stem cells (MSCs). Our previous study based on a single hematopoietic stem cell (HSC) transplantation model has identified a novel source of adipocytes from HSCs via progenitors for monocytes/macrophages. When cultured under adipogenic conditions, bone marrow-derived monocyte progenitors differentiated into adipocytes that are positive for Oil Red O staining, and secrete various adipokines including adiponectin, HGF, IGF-1 and MCP-1. These HSC-derived adipocytes underwent further maturation when embedded in matrigel and injected subcutaneously into syngeneic C57Bl/6 mice. To better understand the role of HSC-derived adipocytes in tumor progression, we tested the proliferative and migratory capacities of murine melanoma cells (B16F1) and breast cancer cells (EO771) under the influence of HSC-derived adipocytes. Conditioned medium from HSC-derived adipocyte culture (Ad-CM) supported cell proliferation and enhanced cell migration for both tumor types. We found IGF-1 plays a more important role in EO771 cell proliferation and HGF is indispensible for B16F1 cell migration, which correlate with the observations that B16F1 and EO771 cells express significantly more cMet and IGF-1R, respectively. When co-injected with B16F1 or EO771 cells into C57Bl/6 mice, HSC-derived adipocytes accelerated both melanoma and breast tumor growth, with HSC-derived adipocytes being more effective for B16F1 tumor growth than EO771 tumor growth. Taken together, we conclude that HSC-derived adipocytes regulate melanoma and breast tumor progression with different mechanisms. The ongoing work is directed to further delineate the function, mechanism and regulation of HSC-derived adipocytes in different tumor microenvironments.

Citation Format: Ying Xiong, Dayvia A. Laws, Amanda C. LaRue. Hematopoietic stem cell-derived adipocytes promote tumor progression. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A77. doi:10.1158/1538-7445.CHTME14-A77
Abstract B18: Blocking α4β1 integrin interaction with matrix metalloproteinase-9 overcomes stroma-induced resistance of chronic lymphocytic leukemia cells to fludarabine and arsenic trioxide
Authors: Amigo-Jiménez Irene , Bailón Elvira , Ugarte-Berzal Estefanía , García-Marco José Antonio , Garcia-Pardo Angeles
Published: May 2015

Chronic lymphocytic leukemia (CLL) progression is determined by CLL cell accumulation in lymphoid organs, where they receive survival signals that impair therapeutic treatments. MMP-9 is a microenvironment component and we have shown that induces a signalling pathway that leads to CLL cell survival. We have now studied whether MMP-9 is involved in the response to cytotoxic agents such as fludarabine and arsenic trioxide (ATO). Both agents upregulated MMP-9 (mRNA and protein) and enhanced its binding to CLL cells. Cell-associated MMP-9 was restricted to early apoptotic cells and totally dependent on apoptosis onset, suggesting a role in the response to these drugs. Indeed, anti-MMP-9 antibodies accelerated apoptosis. Moreover, MEC-1 cells (CLL-derived) stably transfected with MMP-9 were more resistant to drug-induced apoptosis than Mock-transfected cells. Western blot analyses revealed that MMP-9 prevented down regulation of anti-apoptotic Bcl-2 family members. Therefore, MMP-9 likely represents a compensatory survival response that contributes to drug resistance. Additionally, culturing CLL cells with bone marrow stromal cells (BMSC) prevented the apoptotic effect of ATO and this was nearly completely reverted with anti-MMP-9 antibodies. Blocking α4β1 integrin (MMP-9 receptor) and/or αLβ2 integrin (ICAM-1 receptor) also overcame stroma-induced survival. This was also partially achieved by culturing CLL cells with BMSC-conditioned medium, indicating that both cell adhesion and soluble factors contributed to the observed drug resistance. To determine the mechanisms involved, the effect of blocking several signalling pathways was studied. Inhibiting the PI3K/Akt or focal adhesion pathways with specific inhibitors significantly restored the sensitivity of CLL cells to ATO. Therefore, our results highlight the role of MMP-9 in CLL drug resistance and indicate that concomitant targeting of MMP-9 may improve the CLL response to treatment. Supported by grants SAF2012-31613 and RD12/0036/0061 (AGP) from the Ministry of Economy and Innovation, Spain; S2010/BMD-2314 (AGP) from the Comunidad de Madrid/European Union, and by a grant from the Fundación Puerta de Hierro, Madrid (JAGM).

Citation Format: Irene Amigo-Jiménez, Elvira Bailón, Estefanía Ugarte-Berzal, José Antonio García-Marco, Angeles Garcia-Pardo. Blocking α4β1 integrin interaction with matrix metalloproteinase-9 overcomes stroma-induced resistance of chronic lymphocytic leukemia cells to fludarabine and arsenic trioxide. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B18. doi:10.1158/1538-7445.CHTME14-B18
Abstract B29: GILZ mediates glucocorticoid action and inhibits hypoxia-induced COX-2 expression in A549 cells
Authors: Lim WonChung , Lee YoungJoo
Published: May 2015

The COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. Glucocorticoid receptor (GR) strongly suppresses COX-2 expression induced by inflammatory stimuli. However, the role of GR pathway on COX-2 induction by hypoxia and the mechanisms involved are not known. We examined whether the hypoxia induction of COX-2 was under the influence of glucocorticoid; we found that COX-2 promoter activity and mRNA and protein levels were depressed by dexamethasone and antagonized by the glucocorticoid receptor (GR) antagonist RU486. Overexpression of glucocorticoid-induced leucine zipper (GILZ) inhibited hypoxia-induced COX-2 promoter activity, and knockdown of GILZ by shRNA reduced glucocorticoid inhibition of hypoxia-induced COX-2 expression. Finally, we show that dexamethasone and GILZ inhibits cell invasion by hypoxia in A549 cells. Our results suggest that GR inhibits the hypoxic induction of COX-2 expression via GILZ and regulates cell invasion under hypoxia in A549 cells.

Citation Format: WonChung Lim, YoungJoo Lee. GILZ mediates glucocorticoid action and inhibits hypoxia-induced COX-2 expression in A549 cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B29. doi:10.1158/1538-7445.CHTME14-B29
Abstract B37: Phenotypic analysis of single cells dissociated from solid tumors
Authors: Ruitenberg Joyce J. , Middlebrook Aaron , Suni Maria , Hahn Friedrich , Snowden Eileen , Porter Warren , Ferguson Mitchell , Blaesius Rainer , Ghanekar Smita A.
Published: May 2015

Current methods for solid tumor analysis may be inadequate for addressing both the heterogeneity of tumor cells and the components of the tumor microenvironment. Comprehensive analysis requires the ability to analyze tumor biopsy specimens at the single-cell level. A better understanding of how the tumors are behaving at a cellular level, in relation to the other cells within the tumor microenvironment, could lead to more accurate and specific treatment, and better patient prognosis. Evaluation of tumor derived single cells by flow cytometry could provide unique information that is not readily obtained from current methods.

Here we demonstrate the single-cell analysis of solid tumors from breast and colorectal cancers. Since single-cell analysis of solid tumors may not occur at the collection site, it is important that tumors be preserved in order to retain their characteristics during transport. Using tumors from PDX mouse models, and human samples, different preservatives were evaluated for their effects on cellular viability and surface marker expression. Following shipment of the tumor samples in preservation solutions, the solid tumors were dissociated into single-cell suspensions using enzyme cocktails containing collagenase. Phenotypic evaluation was performed using flow cytometry after staining the single cells with monoclonal antibody panels specific for either tumor or immune cells.

The results indicate that the dissociation method did not seem to adversely impact the expression of surface proteins. We demonstrate that it is feasible to analyze dissociated tumor cell populations with relevant surface markers. Analysis of the data revealed distinct phenotype patterns for single cells dissociated from breast and colorectal cancers. Further extensive evaluation of heterogeneity in these tumor types could reveal phenotypic signatures that may be clinically relevant.

Citation Format: Joyce J. Ruitenberg, Aaron Middlebrook, Maria Suni, Friedrich Hahn, Eileen Snowden, Warren Porter, Mitchell Ferguson, Rainer Blaesius, Smita A. Ghanekar. Phenotypic analysis of single cells dissociated from solid tumors. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B37. doi:10.1158/1538-7445.CHTME14-B37
Abstract B48: Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling
Authors: Achyut B.R , Bader David , Robles Ana , Darawarlee Wanga , Harris Curtis , Ried Thomas , Yang Li
Published: May 2015

Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelial homoeostasis. However, the underlying mechanisms remain to be elucidated. Here we report that deletion of the gene encoding TGF-ß receptor 2 (Tgfbr2) in the stromal fibroblasts (Tgfbr2fspKO) induces inflammation and significant DNA damage in the neighboring epithelia of the forestomach. This results in loss or down-regulation of cyclin-dependent kinase inhibitors p15, p16, and p21, which contribute to the development of invasive squamous cell carcinoma (SCC). Anti-inflammation treatment restored p21 expression, delayed tumorigenesis, and increased survival of Tgfbr2fspKO mice. Our data demonstrate for the first time that inflammation is a critical player in the epigenetic silencing of p21 in tumor progression. Examination of human esophageal SCC showed a down-regulation of TGFß receptor 2 (TßRII) in the stromal fibroblasts, as well as increased inflammation, DNA damage, and loss or decreased p15/p16 expression. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TßRII in the stroma.

Citation Format: B.R Achyut, David Bader, Ana Robles, Wanga Darawarlee, Curtis Harris, Thomas Ried, Li Yang. Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-β signaling. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B48. doi:10.1158/1538-7445.CHTME14-B48
Abstract B68: miR-218 opposes an important RTK–HIF signaling pathway in Glioblastoma
Authors: Mathew Lijoy K. , Skuli Nicolas , Mucaj Vera , Lee Samuel S. , Venneti Sriram , Lal Priti , Lathia Justin D. , Rich Jeremy N. , Keith Brian , Minn Andy J. , Simon M Celeste
Published: May 2015

Glioblastoma multiforme (GBM) are highly malignant primary brain tumors, and the Mesenchymal GBM subtype in particular, frequently exhibit regions of severe hypoxia and necrosis. As these features correlate with poor prognosis, we investigated miRNAs whose expression might regulate ischemic cell survival and growth. We found that miR-218 expression is significantly repressed in highly necrotic and chemoresistant Mesenchymal GBMs, compared to the Proneural subtype. Furthermore, restoring miR-218 expression in glioblastoma stem like cells (GSCs) significantly sensitizes orthotopic xenograft tumors to chemotherapeutic treatment, suggesting that low miR-218 confers GBM chemoresistance. Moreover, reduced miR-218 levels correlate with poor survival and rapid recurrence in human Mesenchymal GBM patients treated with radio- and chemotherapy (in contrast, no survival differences were observed in other GBM subtypes). Importantly, miR-218 targets multiple components of the receptor tyrosine kinase (RTK) signaling pathways, and reduced miR-218 expression increases their abundance and activity, thereby overcoming RTK inhibitory homeostatic mechanisms that normally modulate active signaling. We further demonstrate that HIFs, specifically HIF2α, function as downstream effectors of the low miR-218-RTK activation cascade in GSC cells. In strong support of our experimental findings, we observed a significant correlation between elevated HIF activity and low miR-218 expression in Mesenchymal GBM patient samples; in contrast, no correlation was observed in Proneural tumors. Altogether, our data reveal a novel functional association between miR-218 expression and HIF2α activity, and delineate RTK activation as the mechanistic link between the two in highly necrotic GBMs. Moreover, as tumor hypoxia is associated with chemoresistance and poor prognosis, our results uncover a new mechanism whereby miR-218 repression enhances HIF activity, and contributes to the chemoresistant phenotype predominantly seen in Mesenchymal GBM.

Citation Format: Lijoy K. Mathew, Nicolas Skuli, Vera Mucaj, Samuel S. Lee, Sriram Venneti, Priti Lal, Justin D. Lathia, Jeremy N. Rich, Brian Keith, Andy J. Minn, M Celeste Simon. miR-218 opposes an important RTK–HIF signaling pathway in Glioblastoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B68. doi:10.1158/1538-7445.CHTME14-B68
Abstract B77: The role of fibroblasts in invasive lobular breast carcinoma
Authors: Boelens Mirjam C. , Wientjens Ellen , Schut Eva , Klarenbeek Sjoerd , Visser Karin E. de , Jonkers Jos
Published: May 2015

Cancer-associated fibroblasts (CAFs) can promote breast cancer growth and metastasis, but the underlying mechanisms are still largely unknown. In order to study the role of CAFs in breast cancer development in an in vivo setting, we make use of a spontaneous mammary tumor mouse model for invasive lobular carcinoma (ILC). ILC is the second most common type of breast cancer, and is characterized by loss of E-cadherin, a rich stromal compartment, infiltrative growth, and treatment resistance. Often, the PI3K pathway is observed activated in the ILC subtype. Based on these characteristics, we have generated mouse models with mammary epithelial-specific conditional knockout of E-cadherin and PTEN that develop classical ILCs with a strong resemblance to human ILC. Using PDGFRβ as a fibroblast marker, we have observed an abundant presence of stromal fibroblasts in these ILCs, similar to human ILC. Based on a mammary gland transplantation setting using fluorescent labeled recipient mice, we have shown that fibroblasts get recruited from the host during tumor development. In vitro, we have also shown that tumor cells recruit fibroblasts. Inhibition of PDGFRβ in this in vitro model can at least in part inhibit this recruitment. We are currently investigating whether inhibition of PDGFRβ in vivo can prevent the recruitment of fibroblasts and subsequently tumor development or progression. In parallel, we have isolated fibroblasts from primary mouse ILCs and wild-type mammary glands to screen for other important players in the tumor-stroma crosstalk using RNA-seq and cytokine profiling. We will subsequently assess their functional significance during ILC development and progression.

This research is supported by a fellowship of the Dutch Cancer Society

Citation Format: Mirjam C. Boelens, Ellen Wientjens, Eva Schut, Sjoerd Klarenbeek, Karin E. de Visser, Jos Jonkers. The role of fibroblasts in invasive lobular breast carcinoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B77. doi:10.1158/1538-7445.CHTME14-B77
Abstract B87: Prolyl hydroxylase and the regulation of reactive oxygen species (ROS) levels in cancer cells
Authors: Philip Beatrice , Ito Koichi , Moreno-Sanchez Rafael , Ralph Stephen J.
Published: May 2015

Hypoxic microenvironments frequently exist within many solid tumors with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors or HIFs, a family of transcription factors which orchestrate signalling events promoting cancer stem cells, leading to angiogenesis and increased tumorigenesis. Several events conspire together to stabilize HIF-αs to become constitutively expressed in many cancer cell types, regardless of oxygen levels. Prolyl hydroxylases (PHDs) play a crucial role in HIF regulation by hydroxylating HIF proline residues to target these proteins for proteasomal degradation. Hypoxic microenvironments existing within tumors and cytosolic accumulation of mitochondrial metabolites such as succinate or increased ROS production are known to suppress PHD function, resulting in HIF stabilisation and transcriptional activation in the nucleus thereby triggering various pro-oncogenic signalling pathways. Abnormal HIF-αα regulation has gained significant prominence in tumor biology over recent years and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary as a driver promoting greater tumor malignancy. More recently, it has been realized that these hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. We address many of these functions and their relationship to cancer stem cells and their metastastic properties. We also show that overexpressing prolyl hydroxylase reduces HIF expression and malignancy of cancer cells as well as affecting the levels of reactive oxygen species and respiratory chain function in these cells.

Citation Format: Beatrice Philip, Koichi Ito, Rafael Moreno-Sanchez, Stephen J. Ralph. Prolyl hydroxylase and the regulation of reactive oxygen species (ROS) levels in cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B87. doi:10.1158/1538-7445.CHTME14-B87
Abstract IA02: Macrophage entry in hypoxia: Implications for cancer and angiogenesis
Authors: Mazzone Massimiliano
Published: May 2015

Cancer typically has an inflammatory nature. Of all immune cells invading the tumor, the role of macrophages remains controversial because of their functionally distinct differentiation states. Classically activated (M1-like) macrophages and alternatively activated (M2-like) macrophages represent the two extremities of a continuum, in which the former are proinflammatory and tumoricidal, whereas the latter display pro-angiogenic and protumoral activities. This heterogeneity reflects the plasticity and versatility of these cells in response to microenvironmental signals. The tumor environment is constituted of cancer cells and stromal cells that coexist under different oxygen tensions and the influence of soluble factors. A plethora of (hypoxia-induced) cytokines and chemokines can define the macrophage phenotype and their positioning within the tumor. Understanding the signals that lead to macrophage positioning in different tumor niches and how this reflects macrophage phenotypes can open new opportunities for cancer treatment. We have elucidated an elegant mechanism by which macrophages are recruited and retained in avascular hypoxic niches of the tumor, where they exert their immunosuppressive and pro-angiogenic activity. Hypoxia by itself indeed strongly affects macrophage function, as the cells are forced to adapt and alter their metabolism, which is accompanied by a drastic change in their transcriptome and proteome. We have found that the resultant metabolic changes drive macrophages towards a pro-angiogenic phenotype in an attempt to restore oxygenation. Soluble factors derived from the tumor exacerbate this macrophage shift by further enforcing this metabolic adaptation. As a consequence, tumor blood vessels are abnormal and dysfunctional, thus perpetuating hypoxia, which in turn fosters metastasis. By using genetic tools in mice, we show that inhibiting macrophage recruitment in hypoxic niches, or altering their metabolic and energetic state can break this feed-forward loop, resulting in normalized blood vessels and thus, strongly reducing metastatic dissemination.

Citation Format: Massimiliano Mazzone. Macrophage entry in hypoxia: Implications for cancer and angiogenesis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA02. doi:10.1158/1538-7445.CHTME14-IA02
Abstract PR16: Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance
Authors: Mumenthaler Shannon , Foo Jasmine , Choi Nathan , Pao William , Agus David , Michor Franziska , Mallick Parag
Published: May 2015

Tumor growth is a complex evolutionary process driven by dynamic feedback between a heterogeneous cell population and selection pressures from the tumor microenvironment. Spatio-temporal heterogeneity in the microenvironment can create physical niches that facilitate cellular adaptation as seen in regions of hypoxia and acidosis where cells may up-regulate glycolysis and become resistant to acid-meditated toxicity in order to survive. In recent studies, using clinically prevalent subtypes of EGFR-related non-small cell lung cancer (NSCLC), we observe that nutrient and drug gradients resulting from a cells' proximity to vasculature, can produce selective pressures driving tumor evolution. We provide a detailed examination of the microenvironmental impact (i.e. oxygen, glucose, and drug) on growth rates of NSCLC cell lines that are either sensitive or resistant to the EGFR TKI, erlotinib. Often we consider drug resistance to be associated with a fitness cost to the cell in the absence of drug. However, here we demonstrate that the situation is more complex, with the local tumor microenvironment influencing the magnitude and the directionality of the selective effect. In fact, the resistant cells actually gain a selective advantage in nutrient-stressed environments compared to the sensitive cells. The resulting growth dynamics were used to inform a stochastic compartment-based tumor model of pre-existing drug resistance where each compartment represents a specific tumor environmental niche. This integrative modeling framework was then used to predict rebound growth kinetics and tumor composition (i.e. % resistance) and in particular, provide insight into the magnitude by which the microenvironment influences these results. These investigations strongly suggest that ignoring the microenvironment or using laboratory environmental conditions to inform tumor dynamics can lead to inaccurate conclusions. Therefore, knowledge of the selective advantage/disadvantage of different cell populations within different regions of the tumor will better guide model predictions, influence overall tumor dynamics, and impact treatment strategies.

This abstract is also presented as Poster A80.

Citation Format: Shannon Mumenthaler, Jasmine Foo, Nathan Choi, William Pao, David Agus, Franziska Michor, Parag Mallick. Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR16. doi:10.1158/1538-7445.CHTME14-PR16
Abstract A47: Self-renewing cellular compartments in embryonal rhabdomyosarcoma are modulated by hedgehog signaling
Authors: Satheesha Sampoorna , Bovay Amandine , Manzella Gabriele , Bode Peter , Feuchtgruber Simone , Koscielniak Ewa , Belle Reka , Casanova Elisa , Dogan Nurhak , Schäfer Beat W.
Published: May 2015

Rhabdomyosarcoma (RMS) is a heterogeneous group of malignancies with features of impaired skeletal muscle differentiation and represents the majority of soft tissue cancers in the pediatric age group. Current treatment regimens show clinical benefit but this has reached a plateau. Since there is significant risk of adverse side effects and secondary tumors later in life, identifying and targeting sub-populations with higher tumorigenic potential and self renewal capacity would not only decrease tumor burden but also lower the probability of relapse.

Using in vitro self renewal assays we could identify self-renewing cellular compartments within embryonal RMS (eRMS) cell lines. These compartments showed upregulation of several components of the sonic hedgehog pathway. Here, we now show using both genetic loss- and gain-of-function experiments and clinically relevant small molecule modulators that Hedgehog signalling is important for determining the self-renewal, tumor initiation capability both in vitro as well as in vivo. In addition, the hedgehog pathway can also influence chemoresistance of eRMS cells and altered the differentiation status of the cells by directly modulating the expression of various stem cell associated transcription factors. The pathway was found to be heterogeneously activated within eRMS patient samples in a comprehensive tissue microarray analysis. Importantly, the presence of Hedgehog-active cells identified using effector transcription factors could negatively predict patient survival in a retrospective analysis of this patient cohort. This work elucidates both a novel and central role played by the Hedgehog pathway in eRMS and underscores the importance of studying tumor heterogeneity in pediatric cancer.

Citation Format: Sampoorna Satheesha, Amandine Bovay, Gabriele Manzella, Peter Bode, Simone Feuchtgruber, Ewa Koscielniak, Reka Belle, Elisa Casanova, Nurhak Dogan, Beat W. Schäfer. Self-renewing cellular compartments in embryonal rhabdomyosarcoma are modulated by hedgehog signaling. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A47.
Abstract B15: Pediatric glioblastoma cell lines maintain response to developmental growth factors
Authors: Mooney Marie Renee
Published: May 2015

Glioblastoma (GBM) is a highly invasive brain tumor arising from an astrocytic cell lineage. In the United States, nearly 500 children each year develop GBMs. Pediatric GBM has a different mutational, methylation, and gene expression spectra than adult GBM, implicating a strong role for developmental processes in disease pathogenesis. The developmental growth factors that define the astrocytic lineage include epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Expression of these growth factors also distinguishes pediatric versus adult GBM. Here, we use EGF or PDGF as a stimulus for malignant behavior in GBM cell lines isolated from either adult or pediatric patients to understand whether the cell line models parallel growth factor receptor signaling preferences observed clinically. In response to these stimuli, pediatric cell lines demonstrate distinct protein signaling and invasion phenotypes from adult cell lines in vitro, and generate invasive, multifocal lesions in an orthotopic xenograft model. Thus, distinguishing features of adult and pediatric GBM are maintained in the cell line models that will be used to test therapeutic regiments preclinically. Both of the receptors activated by EGF and PDGF are known to interact with a promising therapeutic target in adult glioblastoma: signal transducer and activator 3 (STAT3). STAT3 acts as either an oncogene or tumor suppressor depending on cellular context such as the activating receptor complex and phosphatase and tensin homolog (PTEN) mutational status. Our studies will therefore address the differential implications of STAT3 therapy for pediatric versus adult GBM.

Citation Format: Marie Renee Mooney. Pediatric glioblastoma cell lines maintain response to developmental growth factors. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B15.
Sensoriamento remoto aplicado à análise chuva-vegetação na Amazônia Central
Authors: Seixas Ian Marins , Pinheiro Eduardo Da Silva
Published: April 2015

Estudos indicam que o desmatamento da Amazônia pode influenciar a redução do fornecimento de umidade para atmosfera e, consequentemente, a precipita- ção. Este artigo apresenta os resultados da aplicação de técnicas de sensoriamen- to remoto para verificar o comportamento da precipitação e da temperatura de brilho do topo de nuvens (TBTN) em nove áreas, com cobertura variando entre desmatamento intenso a floresta praticamente inalterada. Os dados de precipita- ção foram obtidos do satélite TRMM 3B43, os de TBTN, do satélite Goes e os dados do desflorestamento, de Inpe (2011). Os resultados indicaram possíveis al- terações nos padrões de chuva e de formação de nuvens de convecção profunda e tendências negativas de precipitação na área desmatada.
Desempenho ocupacional, qualidade de vida e adesão ao tratamento de pacientes com epilepsia
Authors: Gritti Cristiane Carnaval , Paulino Vânia Uemura , Marques Lúcia Helena Neves , Castiglioni Lilian , Bianchin Maysa Alahmar
Published: April 2015

Os objetivos do estudo foram avaliar o desempenho ocupacional, qualidade de vida e adesão ao tratamento medicamentoso de pacientes com epilepsia de difícil controle. Trata-se de um estudo transversal e quantitativo com 30 pacientes em acompanhamento no ambulatório de neurologia em epilepsia de difícil controle da no ambulatório do Hospital de Base de São José do Rio Preto. Os instrumentos utilizados foram: ficha de Identificação, Teste de Morisky, Qualityof Life in Epilepsy Inventory – 31 e Medida Canadense de Desempenho Ocupacional. Os resultados apontaram que: 70% dos participantes obtiveram média adesão ao tratamento medicamentoso; em relação à qualidade de vida os piores resultados foram a preocupação com as crises e os efeitos adversos das drogas antiepilépticas. No Desempenho Ocupacional, as principais dificuldades levantadas constataram prevalência no funcionamento na comunidade, trabalho e socialização. O estudo possibilitou identificar o comportamento do paciente em relação ao uso da medicação, mensurar a qualidade de vida no contexto vivenciado pela doença e identificar as áreas variadas de desempenho ocupacionais prejudicadas.
Atrial Fibrillation and Risk of ST-Segment–Elevation Versus Non–ST-Segment–Elevation Myocardial Infarction
Authors: Soliman Elsayed Z. , Lopez Faye , O’Neal Wesley T. , Chen Lin Y. , Bengtson Lindsay , Zhang Zhu-Ming , Loehr Laura , Cushman Mary , Alonso Alvaro
Published: April 2015

Background—

It has recently been reported that atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with the type of MI (ST-segment–elevation MI [STEMI] versus non–ST-segment–elevation MI [NSTEMI]) might shed light on the potential mechanisms.

Methods and Results—

We examined the association between AF and incident MI in 14 462 participants (mean age, 54 years; 56% women; 26% blacks) from the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary heart disease at baseline (1987–1989) with follow-up through December 31, 2010. AF cases were identified from study visit ECGs and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow-up of 21.6 years, 1374 MI events occurred (829 NSTEMIs, 249 STEMIs, 296 unclassifiable MIs). In a multivariable-adjusted model, AF (n=1545) as a time-varying variable was associated with a 63% increased risk of MI (hazard ratio,1.63; 95% confidence interval, 1.32–2.02). However, AF was associated with NSTEMI (hazard ratio, 1.80; 95% confidence interval, 1.39–2.31) but not STEMI (hazard ratio, 0.49; 95% confidence interval, 0.18–1.34;
P
for hazard ratio comparison=0.004). Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men (
P
for interaction <0.01 for both).

Conclusions—

AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.
Circulating Tissue Factor Levels and Risk of Stroke
Authors: Iacoviello Licia , Di Castelnuovo Augusto , de Curtis Amalia , Agnoli Claudia , Frasca Graziella , Mattiello Amalia , Matullo Giuseppe , Ricceri Fulvio , Sacerdote Carlotta , Grioni Sara , Tumino Rosario , Napoleone Emanuela , Lorenzet Roberto , de Gaetano Giovanni , Panico Salvatore , Donati Maria Benedetta
Published: May 2015

Background and Purpose—

Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort.

Methods—

Using a nested case–cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35–71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method.

Results—

Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratio
IVvsI quartile
, 2.01; 95% confidence interval, 1.25–3.23). The association was independent from several potential confounders (odds ratio
IVvsI quartile
, 1.91; 95% confidence interval, 1.15–3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratio
IVvsI quartile
, 2.13; 95% confidence interval, 1.10–4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratio
IVvsI quartile
, 1.12; 95% confidence interval, 0.49–2.55; fully adjusted model).

Conclusions—

Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes.
Alliance Coercion and Nuclear Restraint: How the United States Thwarted West Germany's Nuclear Ambitions
Authors: Gerzhoy Gene
Published: May 2015

When does a nuclear-armed state's provision of security guarantees to a militarily threatened ally inhibit the ally's nuclear weapons ambitions? Although the established security model of nuclear proliferation posits that clients will prefer to depend on a patron's extended nuclear deterrent, this proposition overlooks how military threats and doubts about the patron's intentions encourage clients to seek nuclear weapons of their own. To resolve this indeterminacy in the security model's explanation of nuclear restraint, it is necessary to account for the patron's use of alliance coercion, a strategy consisting of conditional threats of military abandonment to obtain compliance with the patron's demands. This strategy succeeds when the client is militarily dependent on the patron and when the patron provides assurances that threats of abandonment are conditional on the client's nuclear choices. Historical evidence from West Germany's nuclear decisionmaking provides a test of this logic. Contrary to the common belief among nonproliferation scholars, German leaders persistently doubted the credibility and durability of U.S. security guarantees and sought to acquire an independent nuclear deterrent. Rather than preferring to renounce nuclear armament, Germany was compelled to do so by U.S. threats of military abandonment, contradicting the established logic of the security model and affirming the logic of alliance coercion.
A U.S.-China Grand Bargain? The Hard Choice between Military Competition and Accommodation
Authors: Glaser Charles L.
Published: May 2015

Despite the intense focus on China's rise, the United States has yet to confront the most challenging question posed by this power shift: Should it pursue a strategy of limited geopolitical accommodation to avoid conflict? U.S. policy continues to focus almost entirely on preserving the geopolitical status quo in Northeast Asia. Given the shifting power balance in Asia, however, there are strong theoretical rationales for considering whether significant changes to the status quo could increase U.S. security. A possibility designed to provide the benefits of accommodation while reducing its risks is a grand bargain in which the United States ends its commitment to defend Taiwan and, in turn, China peacefully resolves its maritime disputes in the South China and East China Seas and officially accepts the United States' long-term military security role in East Asia. In broad terms, the United States has three other options—unilateral accommodation, a concert of Asian powers, and the current U.S. rebalance to Asia. Unilateral accommodation and the rebalance have advantages that make the choice a close call, but all things considered, a grand bargain is currently the United States' best bet.
Phaedo 100b3-9
Authors: Sharma Ravi
Published: May 2015

The paper examines a puzzling sequence of verb tenses at Phaedo 100b3-9. It rejects the idea, almost universal among commentators, that the puzzle is to be solved by construing the first verbal expression as if it were equivalent to a future. The paper then offers another solution and explores its implications for understanding the broader philosophical context of the passage. What emerges is that the new solution provides a valuable clue to figuring out what precisely Socrates has in mind when he speaks at 100b4 of the ‘mode of explanation’ with which he is presently engaged. Hence, the tightly focused linguistic discussion at the paper’s outset ultimately takes on a good deal of significance for the interpretation of this difficult but important section of the dialogue.
Rereading Galen and Zeuxis on Ptolemy’s Port
Authors: Nelson Eric D.
Published: May 2015

This article casts doubt on the use of Zeuxis’ testimony (preserved by Galen in his commentary on Epidemics 3) regarding the acquisition of books in Alexandria as an explanation for the anonymity of some texts of the Hippocratic Corpus. Instead, it suggests that Galen’s account needs to be seen, in conjunction with his other musings on the subject, as a projection of his own experience and frustration with the fraudulent trafficking of books, including (and, perhaps, particularly) his own.
Cultural Similarity and Mediation Offers in Interstate Conflicts, 1945–1995
Authors: Bond Kanisha , Ghosn Faten
Published: May 2015

This article seeks to explain the role and salience of culture in interstate conflict management efforts. Past studies of cultural similarity in conflict management involving third parties often focused on two-way cultural relationships: either examining cultural similarity between disputants or similarity between third parties and each of the disputants as individuals. However, we argue that this first wave of research should be augmented by a focus on triads. Our study asks the question: to what extent does cultural similarity among disputants and potential mediators predict the likelihood of a mediation offer? We test our hypotheses using data from the International Conflict Management Dataset between 1945 and 1995 and find that mediation offers are most likely to emerge when the triad is ethnically or religiously similar, while shared political culture is not a reliable predictor of mediation offers to disputing dyads.
Defence, Civil Honour, and Artificial Will
Authors: Jonathan Boyd
Published: May 2015

Three influential interpreters – Michael Oakeshott, Leo Strauss, and Carl Schmitt – note that Hobbes’s sovereign is tasked with containing the natural wills of subjects for the sake of civil peace. Yet Hobbes’s sovereign also has a mandate to govern or use his subjects for collective defence, and each suggest that the political-psychological means to ensure submission preclude and prevent the contribution of subjects towards collective ends, which would render Hobbes’s commonwealth near indefensible. This paper will argue instead that Hobbes does envision a way his sovereign could harness potentia publica: the sovereign must also instil an artificial will through civil honour, an artificial will that is necessary for the defence of the commonwealth.
Gulf-funding of British Universities and the Focus on Human Development
Authors: Draege Jonas Bergan , Lestra Martin
Published: April 2015

We use quantitative content analysis to compare the academic publications and events of Gulf-funded Middle East research institutions in the uk to those that have not received such funding from a Middle Eastern donor. Our results provide some support for hypotheses about funding leading to a bias in the selection of research topics. We show that Gulf-funding of uk Middle East Studies research institutions is associated with less focus on democracy and human rights than non-funded comparable institutions. Moreover, we show that Gulf-funded institutions focus more on their donor countries than do non Gulf-funded institutions, but that they give more attention to issues of education and youth unemployment than issues of democracy, human rights, and gender equality when writing about their donor countries.
Comparative Politics and the Arab Uprisings
Authors: Schwedler Jillian
Published: April 2015

How have scholars working in the political science subfield of comparative politics approached the Arab uprisings in their analyses? Two dominant trends have been to explore the uprisings through the literatures on robust authoritarianism and on social movements. While each of these has produced rich and lively debates, scholars of Middle East politics have mostly drawn comparisons at the national level: for example, explaining variation between those state that experienced uprisings and those that did not, or between those uprisings that turned violent and those that did not. I suggest that adopting “states” and “movements” as objects of analysis can obscure some of the more unique dynamics of the uprisings—dynamics that might be leveraged in contributing new ideas to broader theoretical debates. I illustrate the ways in which research designs that focus on identifying and explaining variation between and across cases tend to assume discrete objects of study (i.e., regimes and movements) in ways that obscure other fascinating processes and practices at both the micro-level and in terms of the complex interconnections across states and regions. This focus has in turn led to a deficit in studies of in-case variation: how mobilization and state repression varied, for example, between Cairo, Alexandria, the Suez, rural regions, and other locations outside of Tahrir Square. Finally, I applaud and encourage the continuation of the lively and open debates within the field about the strengths and weaknesses of our earlier scholarship and the potential of various future research agendas.