bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5234: Sequential multi-modality imaging to detect metabolic changes during tumor growth
Authors: Serganova Inna , Moroz Maxim , Rizwan Asif , Ni Xiaohui , Moroz Ekaterina , Koutcher Jason , Blasberg Ronald 
Published: February 2011

Abstract
The expression and activity of lactate dehydrogenase A (LDH-A) in malignant tissue is considered a prognostic marker of poor outcome in many tumors. A limitation of tissue LDH-A measurements is the requirement of tissue for assay. The development of new non-invasive methods is highly demanded for clinical evaluation. One mechanistic link between tumor cell metabolism and the activity of lactate dehydrogenase A (LDH-A) is based on the HIF-1 transcription factor and its upregulation in tumors. HIF-1 binds to the LDH-A promoter and increases LDH-A expression; this in turn results in increased lactic acid production. The objective of this study was to detect the metabolic changes during tumor growth using a multi-modality imaging approach. To monitor HIF-1 pathway activity by bioluminescence imaging (BLI), we cloned an external Gaussia luciferase (exGLuc) reporter gene into an -IRES-GFP cassette, and placed the cassette in a self-inactivated retroviral vector under the control of an enhancer, containing multiple copies of the binding sites for the HIF-1 transcription factor. 18F-fluorodeoxyglucose (FDG)/microPET imaging was used for the detection of glucose metabolism in tumors, while lactate production was measured by proton magnetic resonance spectroscopic imaging (MRI/S). To validate this multi-modality imaging approach, human glioblastoma U87MG cells were transduced with the HIF-1 reporter vector and the HIF-1 reporter response was validated in vitro by exposure cells to hypoxia (1% O2) and to CoCl2 or DFO (deferoxamine mesylate). Despite a high basal level of HIF-1 transcriptional activity in the U87MG reporter cells, a strong correlation between oxygen deprivation and the level of exGLuc/GFP expression (indicating HIF-1 transcriptional activation) was detected, and this increase corresponded with a significant increase in LDH-A expression, assessed by immunoblotting. In vivo experiments using U87 reporter-xenografts also demonstrated a correspondence between the levels of HIF-1 expression and lactate production assessed by MRI/S. The measurement of lactate production using MRI/S with consecutive BLI imaging of HIF-1 activity and 18F fluorodeoxyglucose (FDG)/microPET confirmed the feasibility of a multi-modality imaging approach to study the link between the HIF-1 activity and a lactate production, as well as the level of glucose (FDG) uptake in growing xenografts. This multi-modal imaging paradigm can provide new and relevant information, and the opportunity to initiate and monitor more effective treatment strategies to arrest tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5234.
Abstract 5239: Relationship between metabolite content on magnetic resonance spectroscopy and contrast enhancing fraction on MRI in patients with astrocytoma
Authors: McLean Mary , Sun Amy , Bradstreet Thomas , Schaeffer Andrea K. , Liu Haiying , Blenman-Abage Rose-Ann , Herman Gary , Price Stephen , Griffiths John 
Published: February 2011

Abstract
Background: Both magnetic resonance spectroscopy (MRS) and contrast-enhanced MRI are useful diagnostic tools for astrocytoma, but two important MRS peaks - lactate and lipid - are usually not resolvable. We investigated the relationship in astrocytoma between metabolite content measured in vivo using an MRS method that separated lactate from lipid, and tumor aggressiveness as reflected by contrast enhancing fraction (CEF) on MRI.
Method: Nine patients with astrocytoma (7 Grade IV, 2 Grade III) had both MRS and contrast-enhanced MRI. For MRS, spectra were edited to obtain separate estimates of lactate and lipid1 as well as N-acetyl aspartate (NAA), creatine, and choline from one 8 cm3 volume of interest (VOI) prescribed within the tumor boundary, avoiding areas of visible necrosis or cysts, and one matching VOI in the contralateral hemisphere. The CEF within the VOI was determined by thresholding T1-weighted images following Gadobutrol administration.
Results: Consistent with previous reports2, metabolite content differed markedly in tumor compared to contralateral tissue. Tumors contained higher levels of lactate and lipids and lower NAA and creatine. Choline did not differ significantly between tumor and contralateral tissue. The average CEF was 0.27, with a range from 0.0 in a Grade III tumor to 0.53 in a Grade IV tumor (that is, 53% of the pixels within the Grade IV VOI showed bright signal due to contrast uptake). The small size of the study precluded a formal subgroup analysis by histological grade, but qualitative observation suggests that the CEF, lipid, and lactate were all higher in tumors of Grade IV than III, consistent with expectations. The level of lipid showed a significant positive correlation with CEF (r=0.67, 95% CI 0.01, 0.92), while the numbers were too small to confirm any significant trends for the other metabolites.
Conclusion: In this first study to discriminate lactate from lipid and also compare MRS patterns with contrast enhancement in the same tissue volume, we found a positive correlation between lipid signal and CEF. Lipids, lactate, and CEF all appeared higher in higher-grade tumors on qualitative assessment and all merit further investigation as potential biomarkers of tumor aggressiveness.
References: 1Star-Lack J et al, J. Magn. Reson. 1998; 133:243-254. 2Howe FA et al, Magn. Reson. Med. 2003; 49:223-232.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5239.
Abstract 524: Interaction of metastatic breast cancer cells with osteoblasts and osteoclasts in a 3D in-vitro model
Authors: Krishnan Venkatesh , Vogler Erwin A. , Mastro Andrea M. 
Published: February 2011

Abstract
Breast cancer frequently metastasizes to bone where it causes osteolytic lesions. Although, the bone osteoclasts, not the cancer cells themselves, appear to be responsible for the bone resorbtion, we have evidence from 3D in vitro cell culture studies (bioreactor) that in the presence of breast cancer cells or their medium, the osteoblasts no longer make the proteins required for bone repair. Furthermore, they produce inflammatory cytokines, which in turn can stimulate osteoclasts.
We have developed a bioreactor system that permits continuous growth of bone-accreting osteoblasts (MC3T3-E1) for &gt; 10 months without subculture or perfusion. This results in a mineralizing, multiple-cell-layer tissue that strongly resembles normal bone. We have also shown that, by challenging this osteoblast tissue with human metastatic breast cancer cells (MDA-MB-231GFP), important hallmarks of cancer metastasis including single cell filing of cancer cells, cancer-cell penetration of tissue and colonization can be observed. We hypothesize that addition of osteoclast to this 3D mineralizing osteoblast in the bioreactor would be a relevant in vitro bone surrogate for studying stages of breast-cancer metastasis. In standard tissue culture and in the bioreactor, we have been able to differentiate osteoclasts from hematopoietic progenitor cells isolated from murine bone marrow. The osteoclasts formed by exposure to RANKL and M-CSF were multi-nucleated, TRAP positive cells. The pre-osteoclast cells when introduced onto the osteoblast grown in the bioreactor, differentiated to form multinucleated resorbing osteoclast, also positive for TRAP and actin ring staining. To further improve the bone remodeling aspect, pre-osteoblasts will be re-infused into the system and allowed to ‘re-mineralize’ the matrix resorbed by osteoclasts. Once the system is established, breast cancer cells will be added to examine the three way cell interactions. This 3D in-vitro cell culture system containing both osteoblast and osteoclast will help to further understand the cellular and molecular events that lead to successful breast cancer colonization of bone. Positive outcomes of the work will help clarify the etiology of metastasis but also create a much-needed in vitro tool for study of cancer therapeutics.
This work was supported by US Army Medical and Materiel Command Breast Cancer Idea Program (W81XWH-06-1-0432).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 524.
Abstract 5245: Regional analysis of DCE MR images to unravel tumor growth and response heterogeneity in SW-620 human colon adenocarcinoma xenografts
Authors: Kaimal Vinod , Meade MaryAnne , Woolliscroft Michael , McConville Patrick 
Published: February 2011

Abstract
Introduction: Dynamic Contrast-Enhanced (DCE) MRI, a clinically relevant technique used to assess response to anti-angiogenic therapies, relies on imaging of a T1 modifying contrast agent to characterize vascular response by the dynamics of tracer exchange between the vessels and the interstitial space. The parameter Ktrans is a measure of the tumor vascular permeability, vascular surface area and blood flow, and is normally assessed as mean over the entire tumor volume. Generally, decreasing tumor mean Ktrans occurs after effective vascular targeting. However, localized tumor growth based necrosis/under-perfusion can also lower Ktrans, leading to uncoupling of the endpoint from the effect. Techniques that can overcome confounding effects of heterogeneity may improve Ktrans sensitivity and correlation with outcome. We applied a thresholding technique to Ktrans data to analyze regional Ktrans variations in subcutaneous SW-620 tumors treated with the vascular targeted agent, bevacizumab or vehicle. Materials and Methods: Female nu/nu mice were implanted with SW-620 tumor fragments on Day 0. On Day 14, mice were distributed into groups with matching tumor burden. DCE-MRI images were acquired 24 hours before treatment (vehicle or bevacizumab; IP; 5mg/kg; Q3Dx4), and one week after treatment. The data were fitted to a Tofts-Kermode kinetic model to generate Ktrans over the entire tumor volume. Thresholds we determined by pooling all the Ktransvalues from the pre-treatment DCE MRI scans. The Ktrans values for each image were distributed into low, mid and high Ktrans fractions and the percentage of voxels in each fraction was calculated. Results: Bevacusimab resulted in moderate tumor growth inhibition (T/C = 43% on Day 22). Tumor mean Ktrans one week post-treatment start did not correlate with this effect, with Ktrans (T/C) = 131%. Analysis of location of voxels in the low, mid and high Ktrans fractions in the pre-treatment images showed that lower Ktrans values were generally confined to the tumor core, while higher Ktrans values were generally confined to the tumor periphery. These regions presumably related to under-perfused (core) and well perfused (periphery) tissue. A comparison of the high Ktrans volume fractions one week post-treatment (treated vs control) showed a correlation with the growth based treatment effect (high Ktrans volume fraction (T/C) = 44%). Ktrans thresholding may therefore provide a means to increasing sensitivity to treatment-based vascular inhibition.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5245.
Abstract 5248: Neuroblastoma tumors with different ALK mutations are sensitive to Perifosine
Authors: Li Zhijie , Thiele Carol J. 
Published: February 2011

Abstract
Background: Neuroblastoma (NB) is the most common extracranial solid tumor of children. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase predominantly expressed in the developing nervous system. Recently, mutated ALK has been identified in association with familial and sporadic neuroblastoma (NB). Patients whose tumors contain amplification, mutation or express increased levels of activated ALK have a poor prognosis. Downstream targets of ALK include the STAT and Akt pathways. Perifoisine is an Akt inhibitor that has been reported to inhibit tumor growth in adult pre-clinical models. The aim of this study was to assess whether ALK mutations affect the response of NB cells to perifosine.
Methods: We selected 4 NB cell lines with different ALK mutation status (SY5Y-ALK F1174L mutation; KCNR-ALK R1275Q mutation, AS and NGP with wild-type (wt) ALK. The effect of perifosine on Akt phosphorylation and cell survival was evaluated in these cell lines. In vivo studies were also performed in nude mice by subcutaneous injection of NB cells with or without ALK mutation. The tumor growth and phosphorylated Akt levels in tumor tissues were studied.
Results: In vitro, treatment with perifosine induced decreases in Akt phosphorylation in all the 4 cell lines. SY5Y-ALK F1174L which is reported to be sensitive to ALK inhibitor TAE684, and KCNR-ALK R1275Q, AS-ALK wt and NGP-ALK wt which are reported to be resistant to ALK inhibitor TAE684, all responded to perifosine treatment. In vivo, perifosine treatment delayed or inhibited growth of tumors containing mutant or wild-type ALK. The phosphorylated Akt levels were lower in tumors treated with perifosine compared to tumors treated with control reagent.
Conclusions: These data indicate that Perifosine is able to control NB tumor cell growth despite the mutational status of ALK. Perifosine may be a candidate treatment for NB tumors not only for those with wt ALK but especially for those that carry mutations that are resistant to ALK inhibitor treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5248.
Abstract 525: ADAM-9 expression in gastric cancer and its association with invasiveness
Authors: Kim Jeong Min , Yu Eun Jeong , Jung Jae Joon , Kim Tae Soo , Rha Sun Young , Ahn Joong Bae , Ahn Jung Ryun , Kim Chan , Chung Hyun Cheol , Roh Jae Kyung , Jeung Hei-Cheul 
Published: February 2011

Abstract
The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. Accumulating evidence associates an increased expression of individual ADAM family members with various types of cancer including prostate, breast, skin and lung cancers. However, little is known about its role in gastric cancer. Herein, we investigated the expression of ADAM-9 in gastric cancer, and its implication as a potential therapeutic target for anti-metastaasis therapy.
First, we evaluated the expression of ADAM-9 on protein by immunoblotting and transcript level in 24 gastric cancer cell lines by RT-PCR. ADAM-9 protease activity was also measured using ADAM-9 fluorogenic substrate (R&D systems, Minneapolis, MN, USA). We then conducted invasion assay using transwell coated with matrigel in the presence or absence of ADAM-9-specific inhibiting antibody (kindly supplied from Raven Biotechnologies, Inc., South San Francisco, CA). The mRNA expression of ADAM-9 was observed in all the gastric cancer cell lines while the protein expressions of pro- and active-form and protease activities were variable. We selected the cell lines of high baseline ADAM-9 expression (SNU-638, MKN-28 and AGS) and of low baseline expression (SNU-216, MKN-1 and HS-746T) to continue further experiment. Baseline level of ADAM-9 is little correlated with invasion activity though matrigel. Treatment of anti-ADAM-9 antibody does not influence the cytotoxicity. However, it reduced its protease activity and invasiveness, which was dependent on baseline ADAM-9 activity. Actually, protease activity reduced 64.5±0.3% when the specific antibody to ADAM-9 was treated to high expressed cell lines, but 9.6±0.4% were decreased in low expressed cell lines at the 20ug/ml of the antibody. Anti-ADAM-9 antibody inhibited the invasion activity dose dependently, and its effect was more prominent in high ADAM-9-expressing cell lines (67.7±1.9% vs 5.9±4.3% at the 20 ug/ml antibody). Anti-ADAM-9 treatment did not influence on the cell-matrix adhesion, which implies this anti-invasive effect is through its inhibition of protease function. In the hypoxic condition (1% oxygen), invasion was increased along with elevation of both active form of ADAM-9 and its protease activity, suggesting that increased ADAM-9 could have a role of enhancing invasiveness of gastric cancer. To conclude, we presented that ADAM-9 has a role in invasiveness of gastric cancer and would be one of the putative targets for anti-metastasis therapy.
This work was supported by the Brain Korea 21 Project for Medical Science, Yonsei University.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 525.
Abstract 5273: The cyclin dependent kinase inhibitor p27KIP1 inhibits neuroblastoma cell migration and invasion
Authors: Koomoa-Lange Dana-Lynn T. , Bachhmann Andre S. 
Published: February 2011

Abstract
Neuroblastoma (NB) is the most common extra-cranial pediatric tumor. Over 70% of NB patients are diagnosed with metastasis, and the survival probability of these patients is significantly lower than patients without metastasis. While the role of p27KIP1 in cell cycle regulation is well documented and conserved in all cell types, there are contradictory reports regarding its function in regulating cell migration and invasion. The purpose of the present study was to elucidate the role of p27KIP1 in regulating migration and invasion of NB cells with MYCN over-expression. Western blot analysis, migration and invasion assays were performed on NB cells with and without over-expression of MYCN. The expression of p27KIP1 was down-regulated using siRNA, and the migration rate was determined on NB cells with MYCN over-expression. Also, the cytoplasmic localization of p27KIP1 in NB cells with and without MYCN over-expression was determined. The results from the current study show that MYCN over-expression increases migration and invasion of NB cells, compared to cells without MYCN over-expression via a process that involves p27KIP1. In addition to its role as a cell cycle regulator, p27KIP1 also regulates NB migration and invasion. This dual role of p27KIP1 as a tumor repressor suggests that it may be an attractive therapeutic target for NB.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5273.
Abstract 5274: Role of Bcl-XL and STAT3 in γ-irradiation-induced invasion of lung cancer cells
Authors: Ho Jin-Nyoung , Kang Ga Young , Um Hong Duck 
Published: February 2011

Abstract
Previous reports suggest that, besides its therapeutic effects, ionizing radiation (IR) may increase the invasiveness of surviving cancer cells. Here, we show that this activity of IR in lung cancer cells is mediated by a signaling pathway that involves p38 kinase, phosphoinositide 3-kinase, Akt, and MMP-2. The invasion-promoting doses of IR also increased and reduced the levels of vimentin and E-cadherin, respectively, both of which are markers for the epithelial-mesenchymal transition (EMT). Interestingly, all these actions of IR were mimicked by the overexpression of Bcl-XL in lung cancer cells. Moreover, both RNA and protein levels of Bcl-XL were elevated upon irradiation of the cells, and the prevention of this event using small interfering RNAs of Bcl-XL reduced the ability of IR to promote invasion signals and EMT-associated events. This suggests that Bcl-XL functions as a signaling mediator of the malignant effects of IR. It was also demonstrated that IR enhances levels of STAT3 phosphorylation, and the reduction of STAT3 levels by RNA interference prevented IR-induced Bcl-XL accumulation, and thus all the tested Bcl-XL-dependent events. Overall, the data suggest that IR induces Bcl-XL accumulation via STAT3, which then promotes cancer cell invasion and EMT-associated markers. Our findings demonstrate a novel function of Bcl-XL in cancer, and also advance our understanding of the malignant actions of IR significantly.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5274.
Abstract 5280: Exchange protein activated by cAMP (Epac) accelerates melanoma cell migration through Ca 2+-dependent actin assembly
Authors: Baljinnyam Erdene , Nowycky Martha , Iwatsubo Kousaku 
Published: February 2011

Abstract
Background: We previously reported that Epac, a guanine nucleotide exchange factor directly activated by cAMP, increases melanoma cell migration through Ca2+ elevation. Both Epac-induced cell migration and Ca2+ elevation were reduced by pharmacological inhibition of phospholipase C (PLC) and inositol triphosphate (IP3) receptor. Accordingly, we studied the involvement of PLC/IP3 receptor in Epac-induced Ca2+ elevation by knockdown of these molecules. However, the mechanism how Epac-induced Ca2+ elevation mediates melanoma cell migration is unknown. Here, we investigate the effect of Epac induced-Ca2+ elevation on actin assembly, which plays a major role in cell migration.
Methods: SK-Mel-2, a cell line from human metastatic melanoma, was used in this study. Intracellular Ca2+ was measured with Fura-2AM fluorescent dye. Cell migration was examined with the Boyden chambers. IP3 production was examined by IP3 radioimmunoassay. Actin assembly was examined by immunocytochemistry. In some experiments, ablation of a target protein with lentivirus-based shRNA induction system was performed.
Results: 8-pMeOPT-2′-O-Me-cAMP (8-pMeOPT), an Epac-specific agonist, increased Ca2+ and cell migration in SK-Mel-2. Such Ca2+ elevation and cell migration was negated by ablation of PLCε or IP3 receptor 1. In addition, Epac-induced IP3 production was inhibited by U73122, a PLC inhibitor, and ablation of PLCε. These data suggest that Epac increases Ca2+, and thus cell migration, via the PLCε/IP3 receptor 1 signaling pathway. Cytochalasin D, an actin assembly inhibitor, reduced 8-pMeOPT-induced cell migration. In addition, immunocytochemistry showed that 8-pMeOPT increases actin assembly. When U73122 or Xestopongin C, an IP3 receptor inhibitor, was used, Epac-induced actin assembly was decreased. These data suggest that Epac-induced Ca2+ elevation mediates actin assembly. Further, immunoprecipitation showed that 8-pMeOPT increased physical interaction of myosin heavy chain IIA (MHCIIA), which enhances actin assembly, with S100A4, a Ca2+-binding protein which activates MHCIIA. These data suggest that Epac-induced Ca2+ elevation mediates actin assembly via the S100A4/MHCIIA signaling pathway.
Conclusion: Epac increases Ca2+ via the PLCε/IP3 receptor 1 pathway. Also, Epac-induced Ca2+ elevation mediates melanoma cell migration via actin assembly. These data suggested that Epac could be a target for treating patients with melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5280.