bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4340: Increased cytokine and chemokine expression in U87MG glioblastoma cells after large clinically relevant single doses of ionizing radiation
Authors: Mcdonald J. Tyson , Lee Jawon , Rietman Edward , Lamont Clare , Enderling Heiko , Peluso Michael , Hlatky Lynn 
Published: August 2012

Abstract
BACKGROUND: Stereotactic radiosurgery is an established treatment option that uses high, single fraction doses of radiation to target tumors. Despite the best clinical strategies to eliminate brain tumors using this technique or others (surgery, chemotherapy and/or other radiotherapy techniques), post-therapy recurrence of brain tumors remains a major challenge in patients. To better understand the radiation response, we investigated how such high doses modulate the molecular signaling within glioblastoma cell populations from several days to months after irradiation. METHODS: The glioblastoma cell line, U87MG, was treated with single doses of ionizing radiation between 0 to 16Gy in vitro followed by: examination of cell proliferation; clonogenic survival; extraction of RNA; and subcutaneous injection into nude mice to monitor tumor growth 24 hours after cell irradiation. Genome-wide expression profiling was run on the Illumina HT-12 bead array platform and analysis for significant expressed genes was performed along with network analysis using Ingenuity Pathway Analysis and GenePattern platforms. RESULTS: As expected, high doses of radiation stunted growth of the U87MG cells from 0 to 14 days. Long term, single cell clonogenic survival of the irradiated cells was approximately 3% and 0.01% following 8Gy or 16Gy, respectively. Genome-wide gene expression at 1, 4 and 6 days after irradiation of 8 or 16Gy has revealed a dose-dependent increase in inflammatory cytokines and chemokines. Increased cytokine expression for IL-6 and IL-8 was validated in vitro using qRT-PCR. In vivo, 100% of the untreated U87MG cells formed tumors, whereas less than half of all irradiated treatment groups failed to form tumors. In those samples that did grow despite irradiation, the average time to tumor formation (volume = 300mm3) was 13, 32, 58 and 88 days for 0, 8, 12, and 16Gy respectively while the exponential fits to tumor growth rate was shown to be accelerated after 8Gy but diminished after 12 and 16Gy. IL-6 gene expression was found to be elevated in tumors formed from irradiated cells versus control. CONCLUSION: The data presented here provides novel insight into the cellular and molecular modulation of glioblastoma cell populations by large, clinically relevant, single doses of ionizing radiation. A salient finding is the expression of inflammatory cytokines as a major player in the radiation response at periods long after the irradiation insult. This study was supported by NIH ICBP 1U54CA149233
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4340. doi:1538-7445.AM2012-4340
Abstract 4357: The role of lysyl oxidase on proangiogenic phenotypes of tumor endothelial cells
Authors: Osawa Takahiro , Ohga Noritaka , Hida Yasuhiro , Kitayama Kazuko , Yamamoto Kazuyuki , Kawamoto Taisuke , Maishi Nako , Kondo Miyako , Akiyama Kosuke , Onodera Yuichiro , Shinohara Nobuo , Nonomura Katsuya , Shindoh Masanobu , Hida Kyoko 
Published: August 2012

Abstract
Introduction and Objectives: The molecules which are highly expressed in tumor endothelial cell (TEC) are important to target TEC more specifically. We found LOX gene was upregulated in TEC compared to normal endothelial cell (NEC) by DNA microarray analysis in three different types of human tumor xenografts in nude mouse including renal cell carcinoma (RCC). LOX is an enzyme which is reported to play a critical role in the metastatic potential of tumor, possibly promoting tumor cell trafficking into the premetastatic niche in various types of malignancies. However, the effect of LOX on TEC has not been reported. To investigate whether LOX might be a TEC-specific target in cancer therapy, we analyzed its expression in clinical sample and examined the function of LOX on TEC. Methods: We successfully purified human TEC (hTEC) and NEC (hNEC) from surgically resected RCC and normal parenchyma from six patients, respectively. Using cultured hTEC and hNEC, competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed. LOX expression level was investigated using immunohistochemistry (IHC). To explore the role of LOX in TEC, mouse TEC (mTEC) and NEC (mNEC) were isolated from human tumor xenografts in nude mouse and the normal counterparts, respectively. To investigate the function of LOX, LOX was knock-downed using siRNA and TEC phenotypic changes were analyzed by migration assay and vascular tube formation assay. In addition, we investigated the effect of α-aminopropionitrile (BAPN), an irreversible inhibitor of LOX, on tumor angiogenesis and metastatic colonization in vivo. Results: LOX expression levels were higher in isolated TEC than NEC both in human (Tissues: clear cell carcinoma 6; Stage T1, 3; T3, 3; Grade 1, 1; Grade 2, 2; Grade 3, 3) and mouse by RT-PCR. In IHC, LOX was detected in blood vessels in human RCC, not in normal tissue. Cell migration and tube formation of mTEC were suppressed by LOX knock-down using siRNA with decrease in phosphorylation of focal adhesion kinase (Tyr397). Furthermore, BAPN specifically inhibited tumor angiogenesis and micrometastasis in vivo, via inhibition of LOX activity of TEC. Conclusions: Our findings suggest that LOX upregulated in TEC contributes in their proangiogenic phenotype and plays key roles in tumor metastasis. LOX might be a TEC-specific target and be useful for cancer therapeutic purposes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4357. doi:1538-7445.AM2012-4357
Abstract 4359: Use of high resolution Doppler imaging for non-invasive, quantitative evaluation of hypoxia-driven neovascularization following surgical ligation of the femoral artery
Authors: Duesbery Nick , Boguslawski Elissa , Merrifield Brittany , Chang Anthony , Chambers Christopher 
Published: August 2012

Abstract
A tumor's growth is inextricably linked with its vascularization. Rapidly growing tumors outstrip their blood supply, creating hypoxia. To compensate, tumor cells release angioproliferative factors that stimulate endothelial cell proliferation. Proliferating endothelial cells contribute to the formation of new blood vessels that promote tumor perfusion and stimulate further tumor growth. The close link between tumor growth and neovascularization makes it difficult to study either process in the absence of the other. To address this we have adapted a mouse model used in the study of peripheral arterial disease. Ischemia was induced by surgical ligation and excision a 3-5mm portion of the femoral artery, vein, and all nearby arterial branches in the right hindlimb of 10-12 week old athymic nude mice. Limb perfusion was measured prior to surgery and 1, 7, 14, 21, and 28 days post-surgery. A 7mm portion of hindlimb perfusion was quantified using Power Doppler mode on the VisualSonics Vevo 770 High Resolution micro Ultrasound system. Morphological changes were observed by histology and immunohistochemistry using antibodies against CD31 and F4/80. Based on quantified Doppler ultrasound data, limb perfusion was reduced as much as 80% within 24 hrs of ligation. Blood flow was restored over the course of the next 7 days. However, re-perfused limbs showed a diffuse pattern of blood flow in comparison to control limbs. Loss of perfusion was accompanied by muscle atrophy and the accumulation of intra-fasicular fat deposits. IHC revealed a marked increase of F4/80 and CD31 staining in ligated limbs. Similar changes were not observed in contralateral limbs that were not operated on or in sham-ligated hind limbs. Our data is consistent with the interpretation that femoral artery ligation causes acute loss of perfusion that is compensated for by macrophage recruitment and disseminated neovascularization. This model provides a novel opportunity to study neovascularization in the absence of tumor growth that will complement ongoing studies using tumor-based models of angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4359. doi:1538-7445.AM2012-4359
Abstract 436: Resistance to fluid shear stress is a conserved novel biophysical property of malignant cells
Authors: Nauseef Jones T. , Barnes J. Matthew , Henry Michael D. 
Published: August 2012

Abstract
During metastasis, cancer cells access distant tissues via the circulation but how this fluid microenvironment influences cancer cell biology is poorly understood. It has been suggested that physical destruction of carcinoma cells due to exposure to hemodynamic forces during circulation is a barrier to metastasis. Here we report that transformed cells are remarkably resistant to fluid shear stress (FSS) in a novel microfluidic protocol. When subjected to a series of millisecond pulses of high FSS, transformed cells exhibit a biphasic decrease in viability. Significantly, human red and white blood cells survived the forces in this protocol. In stark contrast, non-transformed epithelial cells are markedly more susceptible to death under FSS. Accordingly, we show that FSS resistance is a property conferred by oncogenes. We reveal FSS resistance to be a transient and adaptive response triggered by plasma membrane damage and mediated by both extracellular calcium influx and dynamic reorganization of the actin cytoskeleton. This property of malignant cancer cells may facilitate hematogenous metastasis and indicates, contrary to expectations, that cancer cells are quite resistant to FSS. Thus, destruction of circulating cancer cells by hemodynamic shear is not likely to limit metastasis. Our data suggest that FSS resistance is a biophysical biomarker which may be used to rapidly discriminate between malignant and benign cells and, by virtue of representing phenotypic integration of oncogenic transformation, may be more tractable than conventional molecular biomarkers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 436. doi:1538-7445.AM2012-436
Abstract 4362: Identification and isolation of host factors in response to therapy: an approach to identify new targets for cancer therapy
Authors: Gingis-Velitski Svetlana , Voloshin Tali , Fremder Ella , Shaked Yuval 
Published: August 2012

Abstract
Chemotherapy remains one of the most common treatment modalities for cancer, and while initial tumor regression is usually observed, tumor re-growth and metastatic spread sometimes occur. Several preclinical studies have shown that, under certain circumstances, chemotherapy may induce angiogenesis and metastases. Several mechanisms were suggested for explaining tumor recurrence following therapy, and they are mostly related to the acquired resistance of tumor cells to a specific therapy. A recent body of evidence suggests that host derived molecular and cellular mechanisms may also account for the pro-tumorigenic and pro-metastatic effects of tumor cells following chemotherapy, yet there is still ample necessity for further investigation and isolation of such host factors. In order to solely study the host-driven pro-tumorigenic effects of chemotherapy on tumor cells, we used non-tumor bearing mice which were treated with paclitaxel chemotherapy. Subsequently, when the cytotoxic drug was cleared from the circulation, plasma was collected and used in various screening technologies in order to isolate and identify possible factors which may alter the tumor microenvironment for the tumor's advantage. We found that factors promoting bone marrow derived cell mobilization and angiogenesis, e.g., stromal-derived factor 1-α (SDF-1α) and granulocyte colony-stimulating factor (G-CSF) are substantially upregulated in the plasma of paclitaxel treated mice. In addition, increased activity of metalloproteinase 2 (MMP2) and MMP9 were also observed in plasma and bone marrow derived cells collected from mice primed with paclitaxel chemotherapy. The inductions of such host factors contributed to tumor re-growth due, in part, to their role in angiogenesis mediated by bone marrow derived cells, and to their impact on tumor cell migration and invasion activity which can lead to metastases. The pharmacologic or genetic blockade of each of these factors in conjunction with paclitaxel chemotherapy increased the treatment outcome. Additional factors are currently being evaluated and validated with respect to their impact on tumor re-growth following therapy, and will be presented in the upcoming meeting. Collectively, the evaluation of upregulated host factors in response to chemotherapy may raise potential new targets for cancer therapy, and may therefore contribute to the development of new treatment approaches for prolonging the efficacy of conventional cancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4362. doi:1538-7445.AM2012-4362
Abstract 4698: Inhibition of histone deacetylase (HDAC) 3 induces hyperacetylation and inhibition of nuclear heat shock protein (hsp) 90 leading to depletion of ATR and CHK1 with sensitization to DNA damage in breast and cervical cancer cells
Authors: Ha Kyungsoo , Fiskus Warren , Balusu Ramesh , Rao Rekha , Venkannagari Sreedhar , Bhalla Kapil N. 
Published: August 2012

Abstract
We have recently reported that in addition to checkpoint kinase 1 (CHK1), ataxia-telangiectasia mutated and Rad3- related (ATR) is chaperoned by hsp90. Treatment of breast and cervical cancer cells with hsp90 inhibitor induces proteasomal degradation and depletion of ATR and CHK1. This results in impairment of the DNA damage response (DDR) and causes sensitization to α-irradiation and replication stress due to hydroxyurea (Mol Cancer Ther 10:1194, 3011). In the present studies, we determined that treatment with pan-histone deacetylase (HDAC) inhibitor panobinostat (20 to 50 nM) or vorinostat (0.5 to 2 μM) induced polyubiquitylation and depletion of ATR and CHK1. Co-treatment with bortezomib, a proteasome inhibitor, restored PS-mediated depletion of ATR and CHK1. Notably, treatment with panobinostat induced hyperacetylation of both nuclear and cytoplasmic hsp90. This inhibited the chaperone association of nuclear hsp90 with ATR and CHK1, thereby promoting their degradation. PS treatment induced γ-H2AX levels, which were inhibited by co-treatment with N-acetylcysteine, suggesting that PS-induced ROS is involved in DNA damage. Moreover, PS treatment further increased α-irradiation induced DNA damage and its repair, characterized by the increase in α-irradiation-induced comet tail moment and the lack of DNA repair-mediated attenuation of the comet tail moment. To determine which class I HDAC is involved in deacetylation of nuclear hsp90, we individually knocked down (KD) HDAC 1, 2 and 3, by utilizing specific shRNA, and determined the effect on nuclear hsp90 hyperacetylation and the levels of ATR and CHK1. Our findings show that HDAC3 binds to hsp90 and KD of HDAC3, but not of HDAC1 or 2, caused hyperacetylation of nuclear hsp90 and depletion of ATR and CHK1. This was also observed in HDAC3 null mouse embryonic fibroblasts (MEFs). Ectopic overexpression of HDAC3 inhibited nuclear hsp90 acetylation in transformed cells. These findings demonstrate that HDAC3 is the nuclear hsp90 lysine deacetylase. They also demonstrate that genetic KD of HDAC3, or its inhibition by pan-HDAC inhibitors, induces hyperacetylation of hsp90, mediates loss of hsp90 chaperone association and depletion of ATR and CHK1, abrogates α-irradiation-induced DDR, and results in sensitization of transformed cells to DNA damage due to α-irradiation or replication stress.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4698. doi:1538-7445.AM2012-4698
Abstract 4700: A novel selective EZH2 inhibitor exhibits anti-tumor activity in lymphoma with EZH2 activating mutations
Authors: Creasy Caretha L. , McCabe Michael T. , Korenchuk Susan , Diaz Elsie , Ott Heidi , Thompson Christine S. , Ganji Gopi , Gorman Shelby A. , LaFrance Louis V. , Brandt Martin , McHugh Charles , Verma Sharad K. , Tummino Peter J. 
Published: August 2012

Abstract
EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) responsible for methylating histone H3 on lysine 27 (H3K27) and repressing transcription of target genes. Dysregulation of H3K27 methylation is implicated in tumorigenesis in both solid and hematopoietic tumors and occurs through multiple mechanisms including elevation of EZH2 due to loss of regulating miRNAs; inactivating mutations in UTX, an H3K27 demethylase which acts in opposition to EZH2; and somatic mutations in EZH2. Point mutations identified in EZH2 in both follicular lymphoma (FL) and GCB diffuse large B cell lymphoma (DLBCL) exhibit increased H3K27 tri-methylation due to an altered histone substrate preference. This suggests that inhibitors of EZH2 activity may be effective in treating lymphomas carrying activating mutations in EZH2. We have identified first-in-class inhibitors of EZH2 which are highly-potent, reversible, SAM competitive, selective and equipotent against both WT and mutant EZH2. Cellular mechanistic studies demonstrate that inhibition of EZH2 decreases global H3K27me3 in both WT and EZH2 mutant cell lines; however, the cell proliferation response is quite different. Overall, DLBCL cell lines harboring activating mutations in EZH2 are highly sensitive to EZH2 inhibition, while DLBCL cell lines with WT EZH2 are moderately sensitive or resistant. Transcriptional and ChIP-seq studies reveal differences in the transcriptional response of EZH2 target genes and methylation patterns among cell lines providing insight into the mechanism of sensitivity. In a mouse model bearing EZH2 mutant DLBCL tumor xenografts, inhibition of EZH2 methyltransferase activity reduces global H3K27me3, increases expression of EZH2 target genes and inhibits the growth of tumors in a dose dependent manner. Together, these data demonstrate for the first time that direct inhibition of EZH2 methyltransferase activity is effective at inhibiting tumor growth and suggests a promising path forward in the clinic for the treatment of EZH2 mutant lymphoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4700. doi:1538-7445.AM2012-4700
Abstract 4721: Adaptation to histone deacetylase inhibitors attenuates cancer cell growth
Authors: Lin Hsin-Ching , Liu Catherine , Aranake Amrita , Rabson Arnold B. 
Published: August 2012

Abstract
Histone deacetylase (HDAC) inhibitors, such as SAHA (suberoylanilude hydroxamic acid) inhibit the growth of multiple cancer cell lines in vitro, and human tumor xenografts in vivo. SAHA has recently been approved for the treatment of human T cell lymphomas and is in clinical trials for a number of other different malignancies. HDAC inhibitors lead to increased acetylation of multiple cellular proteins, including histones, and lead to major changes in cellular gene expression, however the precise mechanisms of their therapeutic effects are not known. HDAC inhibitors have been reported to have multiple effects on different cancer cell lines, ranging from induction of differentiation to induction of apoptosis, DNA damage, senescence, and autophagy. We hypothesized that chronic treatment of malignant cells with HDAC inhibitors, through changes in the program of cancer cell gene expression, would induce differentiation and senescence, and attenuate the malignant phenotype. We have treated a subclone of the SW480 colon cancer cells (S3 cells) with step-wise increasing amounts of SAHA. Chronic treatment with SAHA resulted in adaptation of S3 cells to SAHA, associated with marked decrease in cell growth and tumorigenicity in nude mice. In addition to slow growth, SAHA-adapted SW480 cells (designated SH80), exhibit features of differentiation including gland formation and increased intestinal alkaline phosphatase production (IAP), and increased cell size, associated with multiple nuclei and polyploidy. Interestingly, decreased growth rate and increased expression of alkaline phosphatase were seen even following drug withdrawal, suggesting that drug-adaptation resulted in a relatively stable phenotype. Frequent expression of senescence-associated β-galactosidase was observed in SH80 cells, particularly in giant cells and cell clusters, suggesting on-going senescence. Increased expression of p21 RNA and protein, previously suggested to contribute to the growth inhibition effect of HDAC inhibitors, was observed in the SH80 cells. SH80 cells also exhibited changes in the expression of several microRNAs previously implicated in oncogenesis, suggesting that altered expression of these miRs might contribute to the attenuated malignant phenotype in SH80 cells. These data suggest adaptation of colon cancer cells to HDAC inhibitor therapy may attenuate key aspects of the malignant phenotype, and offer a new therapeutic approach to the long-term control of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4721. doi:1538-7445.AM2012-4721