bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3322: Adding pericyte inhibition to combined anti-angiogenesis and irradiation slows tumor growth but increases metastasis in mice model
Authors: Deng Lei , He Jiazhuo , Xue Jianxin , Lan Jie , Zhou Lin , Liu Yongmei , Lu You 
Published: August 2015

Abstract
Increased pericyte coverage has been suggested to be one of the resistant mechanisms of anti-angiogenic treatment (AAT), but targeting pericytes disrupts tumor vascular normalization and abolishes the benefit of oxygenation for the combination of irradiation (IR) with AAT. This raises the question of whether pericyte inhibition should be added to the combination of AAT and IR. We and others have shown that Endostar (Endo), a humanized endostatin, induces a normalization window starting from D5, characterized by decreased tumor hypoxia and increased pericyte coverage of vessels. In this study, we tried to utilize the reduced hypoxia in vascular normalization window to radiosensitize tumor and attempted to test whether inhibiting pericytes after the window may result in optimal anti-tumor effect. Subcutaneous Lewis lung carcinoma was used as the tumor model. Pericyte inhibition was achieved by administering CP673451 (CP) at a dose of 20mg/kg, a platelet-derived growth factor receptor (PDGFR) inhibitor. Endo was given daily for 10 days. 12Gy/1f IR was administered on D5 post-endostar initiation. CP was given from D6 to D10 in order not to interfere with the hypoxia alleviation by Endo when IR was given. We found that percentage of pericyte-covered endothelial cells was the lowest in IR+Endo+CP group compared to IR alone and IR+Endo. IR+Endo+CP significantly reduced tumor growth rate compared to the other two groups. However, the local growth retardation was not translated to mice survival benefits, without even any trend could be suggested. We next found that trimodality treatment resulted in significantly more metastasis in mice lungs. This might be due to increased tumor hypoxia in RT+Endo+CP group, which was found to be the highest among the three. Thus, we hereby conclude that adding pericytes inhibition to the combination of IR and AAT even without interfering vascular normalization when IR is administered confers benefit to local tumor control but not to mice survival, due to increased hypoxia and distant metastasis.
Citation Format: Lei Deng, Jiazhuo He, Jianxin Xue, Jie Lan, Lin Zhou, Yongmei Liu, You Lu. Adding pericyte inhibition to combined anti-angiogenesis and irradiation slows tumor growth but increases metastasis in mice model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3322. doi:10.1158/1538-7445.AM2015-3322
Abstract 333: Evaluation of the mixed solution of sodium hyaluronate and hydroxyethylstarch on gynecologic cancer cell line
Authors: Lee Ha-Young , Cho Hyun-Jung , Lee Shin-Wha , Lee Sang-Eun , Kim Dae-Yeon , Kim Jong-Hyeok , Kim Yong-Man , Kim Young-Tak , Nam Joo-Hyun 
Published: August 2015

Abstract
Effect of hyaluronic acid and hydroethyl starch mixture in ovarian cancer cell
Objective: Post-operative tissue adhesion is a very serious problem in patients with ovarian cancer. This study is to investigate the role of hyaluronic acid and hydroethyl starch mixture against the tissue adhesion through in vitro experimentations with ovarian cancer cell lines.
Methods: We used different concentrations of hyaluronic acid and hydroethyl starch (HA/HES) mixture in SKOV3 cell lines. We performed the adhesion and proliferation inhibition assay in different method, mixing and spreading cells. For the migration inhibition assay, we evaluated the effect according to the concentration of HA/HES mixture. The wound-healing assay was performed after artificial injury and physical barrier of 100% HA/HES mixture was evaluated.
Results: In adhesion and proliferation inhibition assay, the viable adherent cells were decreased according to the concentration of HA/HES mixture. The confluence increased over time, except for 100% HA/HES mixture. This result was more obvious in spreading method. The wound recovery was slow in high concentration of HA/HES mixture in the migration inhibition assay and wound-healing assay. The physical barrier of 100% HA/HES mixture inhibited the cell growth until 48 hours.
Conclusion: The proliferation and recovery inhibition of SKOV3 cell lines using HA/HES mixture was confirmed and the inhibitory effect appeared to be in proportion of the concentration of HA/HES mixture. This growth inhibition effect of HA/HES mixture will be useful clinically in patients with ovarian cancer
Citation Format: Ha-Young Lee, Hyun-Jung Cho, Shin-Wha Lee, Sang-Eun Lee, Dae-Yeon Kim, Jong-Hyeok Kim, Yong-Man Kim, Young-Tak Kim, Joo-Hyun Nam. Evaluation of the mixed solution of sodium hyaluronate and hydroxyethylstarch on gynecologic cancer cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 333. doi:10.1158/1538-7445.AM2015-333
Abstract 3333: The expression of FKTN gene in gastric cancer related to radiation exposure: research on atomic bomb survivors
Authors: Pham Trang T.B. 
Published: August 2015

Abstract
While radiation use increases, the Life Span Study (LSS) atomic bomb survivor cohort of Radiation Effects Reserach Foundation (RERF) from 1951-2003 shows a significant cancer risk for most major organs in the body, including stomach. To identify genes associated with gastric cancer, we utilize Escherichia coli ampicillin secretion trap (CAST) method, which is a powerful tool for novel cancer biomarkers. By this method, we found that FKTN (fukutin) was overexpressed in gastric cancer. Fukutin localizes to the Golgi apparatus and normally has low expression, but overexpresses in some cell lines. It is thought to forms a complex with protein POMGnT1, a glycosyltransferase involved in the synthesis of O-mannosyl glycan attached to mucin-like domain of alpha-dystroglycan. The POMGnT1 activity was also downregulated by fukutin mutation and resulted in Fukuyama congenital muscular dystrophy: brain malformation, one of the most common autosomal-recessive disorders in Japan. To elucidate the molecular mechanisms of radiation carcinogenesis, we analyzed FKTN expression from sporadic gastric cancer cohort and LSS cohort by immunohistochemistry. In the sporadic cohort of 695 gastric cancer samples, there was a significant correlation of FKTN expression in differentiated type gastric cancer. For mucin markers, a significant relationship was detected between FKTN and CD10 (p&lt;0.0001). The LSS cohort of 86 gastric cancer samples showed FTKN expression downregulated in high-dose than in low-dose exposed patients (p&lt;0.0001), but with no correlation between FKTN and mucin phenotype expression. This is the first analysis on the expression of fukutin protein in gastric cancers among atomic-bomb survivors and the radiation dose response, using immunohistochemistry. These results suggest that FTKN has a possible relationship with radiation exposure and gastric cancer among atomic bomb survivors.
Citation Format: Trang T.B. Pham. The expression of FKTN gene in gastric cancer related to radiation exposure: research on atomic bomb survivors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3333. doi:10.1158/1538-7445.AM2015-3333
Abstract 3335: Targeting Egr1 selectively radioprotects normal tissues while killing cancer cells
Authors: Zhao Diana Yi , Jacobs Keith M. , Hallahan Dennis E. , Thotala Dinesh 
Published: August 2015

Abstract
Radiotherapy is a common therapeutic modality for a wide range of malignancies. Normal tissue toxicity reduces the therapeutic index of radiotherapy and decreases the quality of life for cancer survivors. Apoptosis is a key element of the radiation response in normal tissues like the hippocampus and small intestine, and results in neurocognitive disorders and intestinal malabsorption. The Early Growth Response 1 (Egr1) transcription factor mediates radiation-induced apoptosis since it activates the transcription of pro-apoptosis genes in response to ionizing radiation (IR). Therefore, we hypothesized that the genetic abrogation of Egr1 and the pharmacological inhibition of its transcriptional activity could attenuate radiation-induced apoptosis in normal tissues. We demonstrated that Egr1 null mice had less apoptosis in the hippocampus and intestine following irradiation as compared to their wild-type littermates. Alternatively, mice treated with Mithramycin A, a drug that prevents binding of Egr1 to target promoters, also displayed reduced apoptosis following irradiation in the intestine as compared to mice treated with vehicle. In cell culture based studies, shRNA-mediated silencing of Egr1 expression dampened apoptosis and enhanced the clonogenic survival of irradiated HT22 hippocampal neuronal cells and IEC6 intestinal epithelial cells. Mechanistically, these events involved an abrogation of p53 induction by IR and an increase in the ratio of Bcl-2/Bax expression. In contrast, targeted silencing of Egr1 in two cancer cell lines (GL261 glioma cells, HCT116 colorectal cancer cells) was not radioprotective, since it reduced their growth while also sensitizing them to radiation-induced death. These results strongly support the potential of targeted silencing of Egr1 in order to improve the therapeutic index of radiotherapy and minimize the normal tissue complications associated with radiation therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Diana Yi Zhao, Keith M. Jacobs, Dennis E. Hallahan, Dinesh Thotala. Targeting Egr1 selectively radioprotects normal tissues while killing cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3335. doi:10.1158/1538-7445.AM2015-3335
Abstract 334: Glucose regulates chemoresistance and stemness via Wnt/β-catenin signaling in ovarian cancer cells
Authors: Gwak HyeRan , Kim Soochi , Jo UnTek , Song Yong Sang 
Published: August 2015

Abstract
Glucose metabolic alteration is one of the hallmarks of ovarian cancer. Here, we first demonstrated the function of glucose as a signature molecule that regulated chemosensitivities in ovarian cancer cells. To verify the role of glucose on the chemoresistance in ovarian cancer cells, we used various concentrations of glucose containing media (0 mM to 20 mM). Glucose reduction inhibited proliferation of various ovarian cancer cell types; irrespective of p53 status and cisplatin (CDDP) sensitivities. Interestingly, CDDP (10 to 20 μM) induced apoptosis were increased and expressions of p-glycoprotein (multidrug resistance protein 1, MDR1) and ABCG2 (ATP-binding cassette sub-family G member 2) were decreased in both mRNA and protein levels by glucose free conditions. Moreover, sphere forming capacities and stemness related gene expressions, SOX2, OCT4, BMI1 and Nanog, were also decreased in ovarian cancer cells in response to glucose starvation. Suppression of CDDP resistance and stemness in ovarian cancer was found to be associated with the activation of GSK3β in response to limitation of glucose availabilities, as confirmed by the function of the GSK3β inhibitors (LiCl and SB SB216763) and also downstream molecules, β-catenin and cyclin D1. In contrast, high glucose (20 mM) environment enhanced CDDP resistance in ovarian cancer cells via elevation of p-glycoprotein and ABCG2 expressions, sphere forming capacities and stemness related gene expressions. Moreover, CDDP (10 to 20 μM) in high concentration of glucose media induced apoptotic cell death were significantly decreased. This study described the novel function of glucose in chemoresistance in ovarian cancer cells by deregulation of multidrug efflux pumps and stemness through Wnt/ β-catenin signaling cascades.
Citation Format: HyeRan Gwak, Soochi Kim, UnTek Jo, Yong Sang Song. Glucose regulates chemoresistance and stemness via Wnt/β-catenin signaling in ovarian cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 334. doi:10.1158/1538-7445.AM2015-334
Abstract 3341: TP508 sensitizes cancer stem cells to radiation and delays brain cancer cell relapse in vitro
Authors: Moya Stephanie M. , Kantara Carla , Sower Laurie , Carney Darrell H. 
Published: August 2015

Abstract
In 2014, approximately 70,000 adults and 4,500 children are expected to be diagnosed with brain cancer in the U.S alone, making this disease the second leading cause of cancer related deaths in children and young adults. Currently available therapies such as radio/chemotherapy are ineffective in completely eradicating the tumor bulk and cancer stem cells within the tumor, thus allowing recurrence of the disease. Therefore, it is important to develop novel therapeutics that sensitize cancer cells to make them more susceptible to radiation therapy and reduce the number of viable cancer stem cells. Preliminary data showed that injection of TP508, a 23 amino acid thrombin derived peptide drug, increased brain tumor shrinkage post-radiation therapy (RT) in mice. To study this phenomenon, we chose to use an in vitro model of tumor relapse that selects for and allows quantification of tumor stem cells in 3D spheroid cultures. Our goal was to determine whether TP508 could specifically sensitize cancer stem cells to the effects of RT and prevent or delay stem cell mediated in vitro tumor relapse. Medulloblastoma (Daoy) cells were grown as 3D spheroids in vitro to select for the growth of stem cells. Primary spheroids were treated on day 5 with either saline or TP508 (0.5mg/mL), and exposed to radiation (10Gy) on day 7 using a Cs137 source. One day post-RT, cells were dissociated and cultured as secondary spheroids to determine the stemness or relapse potential of the cells following RT. Daily images were taken to quantify neurosphere formation. Spheroids were also analyzed for viability, apoptosis, proliferation (PCNA), and for stem cell markers (CD133/LGR5/CD44/DCLK1/Sox-2), using western blots, flow cytometry, and immuno-fluorescent staining. TP508 treatment of Daoy cell spheroids prior to RT significantly delayed the formation of secondary spheroids, decreased cell viability, number of proliferating cells, and the number of cells expressing cancer stem cell markers. Thus, in this in vitro assay, TP508 sensitized cancer stem cells to the effects of RT and delayed relapse of brain tumor stem cells in vitro. These findings suggest that injection of TP508 prior to RT treatment may sensitize cancer stem cells to radiation and help prevent brain tumor relapse. Studies are underway to determine the mechanism by which TP508 sensitizes cancer stem cells to RT and whether TP508 has similar effects on other types of cancer stem cells. This work was supported by NCI Contract # HHSN261201300076C to DC.
Citation Format: Stephanie M. Moya, Carla Kantara, Laurie Sower, Darrell H. Carney. TP508 sensitizes cancer stem cells to radiation and delays brain cancer cell relapse in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3341. doi:10.1158/1538-7445.AM2015-3341
Abstract 3360: Macrophages promote resistance to pegylated arginine deiminase in malignant pleural mesothelioma
Authors: Phillips Melissa M. , Khadeir Ramsay , Tookman Laura , McCarthy Fiona , Steele Jeremy , Bomalaski John , Ghazaly Essam , Szlosarek Peter W. 
Published: August 2015

Abstract
Background
Approximately 50% of all malignant pleural mesotheliomas (MPM) are deficient in argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine biosynthesis, and are therefore sensitive to arginine deprivation. This discovery in MPM has been translated into the clinic using the arginine depletor pegylated arginine deiminase (ADI-PEG20) which showed a halving in the risk of disease progression in a randomized phase II study (Szlosarek et al, ASCO 2014). However, unstudied to date, stromal resistance to ADI-PEG20 may reduce its efficacy. Here, we studied the effect of macrophages, which are abundant in mesothelioma, on the tumor cytotoxicity of ADI-PEG20.
Methods
ASS1 negative MPM cell lines treated with ADI-PEG20 were analysed using the Affymetrix Human Genome U133 Plus 2.0 array, with validation of genes involved in stromal-tumor cell communication. Additional studies involved using tumor-macrophage co-culture experiments, mass spectrometry and an MPM xenograft model.
Results
A distinct pro-inflammatory cytokine gene expression signature involved in macrophage recruitment and activation was identified in the ADI-PEG20-treated ASS1 negative MPM cell lines. Notably, a significant increase in ASS1 negative MPM cell viability was seen upon co-culture with macrophages in the presence of ADI-PEG20. This was accompanied by a significant increase in ASS1 expression in co-cultured macrophages, with a corresponding increase in argininosuccinate lyase (ASL) expression in co-cultured tumor cells and a doubling in levels of the arginine precursor, argininosuccinate, in cell supernatant. The addition of argininosuccinate to tumor cell media rescued ASS1 negative MPM cells from ADI-PEG20 cytotoxicity, while the macrophage-mediated resistance to ADI-PEG20 was abrogated following ASL knockdown in MPM cells. Finally, xenograft studies demonstrated a significant reduction in tumor volume in mice treated with ADI-PEG20 in combination with macrophage depletion, compared with ADI-PEG20 monotherapy.
Conclusion
Collectively, our data indicate that as a result of metabolic ‘cross-talk’ between macrophages and ASS1 negative MPM cells, macrophages mediate MPM resistance to ADI-PEG20 via the provision of argininosuccinate. Our studies provide a rationale for combining ADI-PEG20 with an inhibitor of macrophage recruitment in the treatment of ASS1-deficient mesothelioma.
Citation Format: Melissa M. Phillips, Ramsay Khadeir, Laura Tookman, Fiona McCarthy, Jeremy Steele, John Bomalaski, Essam Ghazaly, Peter W. Szlosarek. Macrophages promote resistance to pegylated arginine deiminase in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3360. doi:10.1158/1538-7445.AM2015-3360
Abstract 3363: RAGE/S100A7/Stat3-axis enhances breast cancer growth and metastasis via modulating tumor microenvironment
Authors: Nasser Mohd W. , Wani Nissar A. , Ravi Janani , Amponsah Grace A. , Ahirwar Dinesh K. , Powell Catherine A. , Elbaz Mohamad , Zhao Helong , Shilo Konstantin , Ganju Ramesh K. 
Published: August 2015

Abstract
The Receptor for Advanced Glycation Endproducts (RAGE), a multifunctional, multi-ligand receptor, has been shown to play an important role in inflammation. However, not much is known about its role in breast cancer growth and metastasis. In this report, we observed that RAGE expression is upregulated in triple negative breast cancer (TNBC) cell lines, primary tumors and lymph-node metastasis samples. RAGE-/- mice show reduced breast cancer growth. Additionally, blocking RAGE with neutralizing-antibody inhibited lung metastasis in an intracardiac mouse model. Further elucidation of RAGE-mediated mechanisms revealed that RAGE binds to S100A7 and mediates S100A7-induced cell migration, Stat3 and NF-ĸB activation. Our results also indicate that S100A7/RAGE axis-modulates invasion/migration through Stat3 dependent MMP9 activation. In addition, RAGE neutralizing antibody and soluble RAGE inhibited breast cancer progression and metastasis in the inducible mS100a7a15 mouse model system. We demonstrated that RAGE/S100A7 enhanced mammary hyperplasia, tumor growth and metastasis through Stat3 activation. Notably, our studies revealed that RAGE/mS100a7a15 modulates the breast tumor microenvironment through recruitment of phospho-Stat3/MMP9-positive tumor-associated macrophages. Our studies suggest that RAGE expression could be used as a novel biomarker for aggressive/invasive breast cancer, especially TNBC. Collectively, these findings suggest that RAGE/S100A7/Stat3-axis has a novel role in linking inflammation to the development of invasive/aggressive breast cancer including TNBC.
Citation Format: Mohd W. Nasser, Nissar A. Wani, Janani Ravi, Grace A. Amponsah, Dinesh K. Ahirwar, Catherine A. Powell, Mohamad Elbaz, Helong Zhao, Konstantin Shilo, Ramesh K. Ganju. RAGE/S100A7/Stat3-axis enhances breast cancer growth and metastasis via modulating tumor microenvironment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2015-3363
Abstract 3375: Can prostate cancer derived neuromodulators regulate intratumoral axonogenesis
Authors: Gutkin Dmitriy W. , Shurin Galina V. , Shurin Michael R. , Keskinov Anton A. 
Published: August 2015

Abstract
Well-developed angiolymphatic network in solid malignant tumors has been proven as an important requirement for tumor growth and progression. However, the level of innervation of the tumor mass is not a well-known factor in tumor development and spreading. Several mechanisms may be responsible for activation and inhibition of neural elements in the tumor microenvironment, including numerous neurotrophic factors (NF) that have axon attractive and axon repellent properties. We have examined 40 cases of human prostate adenocarcinoma by immunohistochemical stains, highlighting neural elements (S-100, PGP9.5, neurofilament) and blood vessels (CD31, CD34). The result revealed that while blood vessels were abundant in the tumor tissue, the neural structures were very scarce compared to benign prostate tissue. Next, in a model system, cell-free supernatants from TRAMP C2 and RM-1murine prostate cancer cell lines were added to the murine neuron cultures, and morphology of the neurons was analyzed by assessing the number of cells with neurites, the number of neuritis per cell, and the lengths of neurites. The data showed that tumor-conditioned media of TRAMP-C2 and RM-1 cells significantly inhibit the neurite growth in mouse neuron cultures. Analysis of gene expression in murine prostatic adenocarcinoma by RT-PCR revealed expression of Semaphorin 4A, Semaphorin 3F, Ephrin A1, Ephrin B2, and Slit2. Finally, the transfection of murine prostate cancer cells with Ephrin 1A and Slit2 siRNAs has prevented their neuron-inhibiting effect. Together, our results suggest that prostate carcinoma cells express NF factors that may inhibit neurite growth and lead to down-regulated innervation of tumor mass. The role of this phenomenon in tumor growth and metastatic potential is under investigation.
Citation Format: Dmitriy W. Gutkin, Galina V. Shurin, Michael R. Shurin, Anton A. Keskinov. Can prostate cancer derived neuromodulators regulate intratumoral axonogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2015-3375