bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5849: Exosomes promote survival and migration in squamous head and neck cancer cells after ionizing radiation: Evidence for a bystander effect
Authors: Mutschelknaus Lisa , Azimzadeh Omid , Heider Theresa , Winkler Klaudia , Vetter Marcus , Tapio Soile , Merl-Pham Juliane , Kell Rosemarie , Huber Stephan , Edalat Lena , Radulovic Vanja , Anastasov Natasa , Peters Carsten , Atkinson Michael John , Moertl Simone 
Published: July 2017

Abstract
Exosomes are important intercellular communicators in the acute radiation stress-response. Here we show that exosomes from head and neck tumor cells confer protective signals to their neighboring cells. This promotes the tumorigenic and radioresistant phenotype of head and neck cancer cells.
Isolation of exosomes was performed by serial ultracentrifugation of conditioned medium collected from irradiated or non-irradiated head and neck cancer cell lines BHY and FaDu. Quantification by NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response, exosomes isolated from non-irradiated and irradiated donor cells were transferred on non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes, when transferred to irradiated recipient cells compared to the transfer to non-irradiated cells.
Functional analyses indicate increased survival of irradiated recipient cells after exosome transfer. These findings mesh with increased DNA double strand break repair that we found after the transfer of exosomes isolated from irradiated cells. Moreover we observed an increased migration and enhanced chemotaxis induced motility after the transfer of exosomes isolated from irradiated cells. To investigate whether differential protein loading into exosomes is responsible for the functional differences we performed proteome analysis of the exosomes. We have identified 679 proteins, of which 39 were up- and 36 were downregulated by irradiation of the donor cells. In a good agreement with our functional assays, the proteome profiling showed that exosomal proteins were mainly involved in wound healing.
Exosomes are functional components of the response of tumor cells to therapeutic radiation exposure. In a clinical context these results suggests that radiotherapy modified exosomes may influence the cancer progression, metastasis and therapeutic success.
Citation Format: Lisa Mutschelknaus, Omid Azimzadeh, Theresa Heider, Klaudia Winkler, Marcus Vetter, Soile Tapio, Juliane Merl-Pham, Rosemarie Kell, Stephan Huber, Lena Edalat, Vanja Radulovic, Natasa Anastasov, Carsten Peters, Michael John Atkinson, Simone Moertl. Exosomes promote survival and migration in squamous head and neck cancer cells after ionizing radiation: Evidence for a bystander effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5849. doi:10.1158/1538-7445.AM2017-5849
Abstract 585: Chromosome 9p24.1 deletions as a determinant of tumor immune surveillance and immune checkpoint blockade therapy in non-small cell lung cancer
Authors: Shen Tao , Wu Jie 
Published: July 2017

Abstract
Anti-PD-1/PD-L1 immune checkpoint blockade therapy requires the presence of PD-L1/PD-L2 and MHC class I antigens on the tumor cell surface. We previously found JAK1 truncating mutations in endometrial cancer cells that impairs JAK1/JAK2-STAT1-IRF1-mediated signaling pathway, which regulates MHC class I antigen presentation. To determine the potential role and genetic defects in the IFN-γ-IRF1 pathway in non-small cell lung cancer (NSCLC), we analyzed the Cancer Genome Atlas (TCGA) data. Expression of IRF1 correlated with cytolytic activity markers GZMA and PRF1. Loss-of-function (LOF) genetic alterations in the IFN-γ-IRF1 pathway genes were found in 64 cases (6.3%) among 1016 patients. These genetic defects occurred prevalently in the JAK2 gene (33 cases) and often through deletions (29 cases) of chromosome 9p24.1. JAK2 gene deletions were frequently associated with deletions of CD274 and PDCD1LG2 genes that encode PD-L1 and PD-L2, respectively, whereas CD274 and PDCD1LG2 deletions were always accompanied by JAK2 deletions. Chromosome 9p is frequently deleted in NSCLC. This has been attributed to CDKN2A/CDKN2B and PTPRD tumor suppressor genes located at the chromosome 9p21.3-9p24.1. Interestingly, JAK2, CD274, and PDCD1LG2 genes are co-localized at chromosome 9p24.1 near the CDKN2A/CDKN2B and PTPRD genes. JAK2, CD274, and PDCD1LG2 deletion often but not always coincided with CDKN2A/CDKN2B and PTPRD deletions. IFN-γ induced IRF1 expression and cell surface HLA-ABC levels in A549 cells that contain wildtype JAK2 but not in H1573 cells that had a truncating JAK2. Deletion of JAK2 or inhibition of JAK2 kinase activity in A549 cells resulted in loss of IFN-γ-regulated IRF1 and cell surface HLA-ABC, whereas expression of exogenous JAK2 in H1573 cells restored IFN-γ responses. These findings reveal a previously unrecognized significance of chromosome 9p deletion in NSCLC and point to chromosome 9p24.1 as a determinant of immune checkpoint therapy.
Citation Format: Tao Shen, Jie Wu. Chromosome 9p24.1 deletions as a determinant of tumor immune surveillance and immune checkpoint blockade therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 585. doi:10.1158/1538-7445.AM2017-585
Abstract 5850: Salicylate sensitizes prostate cancer (PrCa) to radiotherapy; activation of AMPK and suppression of lipogenesis
Authors: Tsakiridis Theodoros , Marcinko Katarina , Broadfield Linsday , Villani Linda , Gerdes Carrie , Maharaj Danitra , Farell Tom , Wright James , Steinberg Gregory 
Published: July 2017

Abstract
Radiotherapy (RT) is a key therapeutic modality for PrCa that achieves reasonable disease control rates in localized disease. However, this requires dose-escalated RT, which is associated with increased toxicity to surrounding tissues and leads to deterioration of patient quality of life. Improving the therapeutic ratio in PrCa RT is of high clinical importance. Aspirin has an established role in cancer prevention and studies suggested association with improved PrCa outcomes. It was shown that its metabolite salicylate (SAL) binds directly and activates the metabolic stress sensor AMP-activated kinase (AMPK). This is likely achieved through direct binding to the AMPK β1 subunit, leading to enhanced AMPK activity through suppression of AMPK α-subunit T172 de-phosphorylation. In this study we examined the ability of SAL to sensitize PrCa to RT. Hormone insensitive (PC3) and sensitive (LnCap) human PrCa cells, as well as PC3 xenografts grown in immunocompromised nude mice were subjected to SAL and RT treatments. SAL mediated a dose-dependent inhibition of proliferation and clonogenic survival in both PrCa cell lines and suppressed de novo lipogenesis (DNL). This was detected at μM concentrations of the drug, which can be safely achieved in human circulation. SAL (100-500 μM) radio-sensitized PC3 and LnCap cells, and enhanced the ability of SAL to inhibit DNL. In animals treated with conformal RT (10Gy) to the tumor xenografts, Salsalate feeding (chow diet containing 2.5gr/kg) enhanced the cytotoxicity of RT detected as reduced tumor growth kinetics and weight and volume at sacrifice. Salicylate treatment of cells or salsalate feeding of mice led to increased AMPK activity in cells and tumors, inhibitory phosphorylation of Acetyl-CoA Carboxylase and reduction of AktThr308 phosphorylation. These results indicate that SAL could improve radiation response in PrCa through a mechanism involving the suppression of DNL. This is achieved at clinically attainable doses of SAL. This work supports prospective investigation of SAL as a radio-sensitizer in early phase clinical trials of localized PrCa.
Note: This abstract was not presented at the meeting.
Citation Format: Theodoros Tsakiridis, Katarina Marcinko, Linsday Broadfield, Linda Villani, Carrie Gerdes, Danitra Maharaj, Tom Farell, James Wright, Gregory Steinberg. Salicylate sensitizes prostate cancer (PrCa) to radiotherapy; activation of AMPK and suppression of lipogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5850. doi:10.1158/1538-7445.AM2017-5850
Abstract 5852: DUOX2, a key player for chemopotentiation by low-dose fractionated radiation therapy in gastric cancer cells
Authors: Parekh Palak R. , Chang Elizabeth , Sharma Navesh K. , Carrier France 
Published: July 2017

Abstract
One of the most conventional therapy for solid tumors is radiotherapy. Still, this modality presents a challenge when it comes to managing highly disseminated gastrointestinal cancers due to increased toxicity to surrounding tissues. Recent laboratory and clinical data indicate that Low Dose Fractionated Radiation Therapy (LDFRT) can potentiate systemic chemotherapy and presents the possibility to revisit the concept of Whole Abdominal Radiotherapy (WART) for disseminated intra-abdominal gastric cancers. Earlier work considered LDFRT ineffective for tumor removal but we now know that LDFRT induces hyper-radiosensitivity (HRS) in a number of proliferating cells. We have recently shown that dual oxidase (DUOX2) is a major contributor to induce HRS at radiation doses as low as 0.15 Gy and sensitize human gastric cancer cells to chemotherapy. The aim of our study is to determine the utility of DUOX2 as a potential biomarker for the clinical application of chemopotentiation by LDFRT. First, we performed immunohistochemistry (IHC) on 48 human gastric samples with progressive grades. Our data indicate that only about 50% of human gastric cancers are positive for DUOX2. The reason for DUOX2 variability of expression is not clear but may be linked to inflammation since six of the seven (86%) gastritis samples we examined expressed strong levels of DUOX2 in the surface of epithelial cells. Our data also indicate that expression of DUOX2 significantly increases the levels of macrophages infiltration in tissue expressing DUOX2 as well as in the stroma surrounded by cells expressing DUOX2. This suggests that expression of DUOX2 could impact on the dynamic of the tumor microenvironment. Expression of DUOX2 in response to LDFRT is conserved since we also observed this in mice primary gastric cancer cells as well as cancer stem cells. Furthermore, as a first step to develop DUOX2 as an accessible biomarker, we studied DUOX2 activity by measuring the accumulation of oxidative serum proteins in gastric cancer cells media. Our data indicate that down regulation of DUOX2 significantly reduces the levels of serum protein oxidation. Taken together these data suggest that DUOX2 could potentially be used as a biomarker to stratify patients and follow the efficiency of clinical application of chemopotentiation by LDFRT.
Citation Format: Palak R. Parekh, Elizabeth Chang, Navesh K. Sharma, France Carrier. DUOX2, a key player for chemopotentiation by low-dose fractionated radiation therapy in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5852. doi:10.1158/1538-7445.AM2017-5852
Abstract 5853: Peroxiredoxin I-targeted AMRI-59 has a role of radiosensitizer by promoting induction of ROS/γH2AX/caspase pathway and suppression of ERK
Authors: Hong Wan Gi , Cho Jeong Hyun , Kim Ju Yeon , Lee EunAh , Hwang Sang-Gu , Chang Tong-Shin , Um Hong-Duck , Park Jong Kuk 
Published: July 2017

Abstract
We have identified AMRI-59, one of small molecule, is specific pharmaceutical inhibitor of peroxiredoxin (PRX) I enzyme activity in our previous study. In this study, we tried to prove whether AMRI-59 has role of radiosensitizer against non-small cell lung cancer cells - NCI-H460 and NCI-H1299. The radiosensitizer effects of AMRI-59 were tested with clonogenic assays. The intracellular mechanism underlying this effect was determined by performing immunoblotting and measuring ROS generation, mitochondrial potential and cell death. The radiosensitizer activity of AMRI-59 in vivo was tested in nude mice by treating with AMRI-59 and IR, and measuring tumor volume and assessing apoptosis. Dose-enhancement ratios of 30 μM AMRI-59 in NCI-H460 and NCI-H1299 are 1.57 or 3.38, respectively. Combination with AMRI-59 and IR also increased the production of ROS and disruption of mitochondrial potential via enhancement of PrxI oxidation, which subsequently induced one of DNA damage markers - phospho-γH2AX, and suppressed phosphorylation of ERK, and, finally, activated caspase-3. Notably, inhibition of ROS production prevented ERK suppression, and inhibition of ERK in addition of combination with AMRI-59 and IR increased caspase activation and apoptosis. In a xenograft assay, combination with AMRI-59 and IR delayed tumor growth by 11.4 days compared with controls, yielding an enhancement factor of 1.48. Collectively, these results indicate that AMRI-59 functions as a Prx I - targeted radiosensitizer by induction of apoptosis through activation of a ROS/γH2AX/caspase pathway and suppression of ERK.
Citation Format: Wan Gi Hong, Jeong Hyun Cho, Ju Yeon Kim, EunAh Lee, Sang-Gu Hwang, Tong-Shin Chang, Hong-Duck Um, Jong Kuk Park. Peroxiredoxin I-targeted AMRI-59 has a role of radiosensitizer by promoting induction of ROS/γH2AX/caspase pathway and suppression of ERK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5853. doi:10.1158/1538-7445.AM2017-5853
Abstract 5863: Identifying the radiosensitizing effects of PARP inhibitor in ovarian cancer
Authors: Bi Yue , Verginadis Ioannis , Dey Souvik , Guo linlang , Lin Lilie , Zheng Yanfang , Koumenis Constantinos 
Published: July 2017

Abstract
Ovarian cancer is the seventh-most common cancer with a high mortality rate among women. Radiation therapy (RT) is used in ovarian cancer for local relapse, but doses are limited due to concern for small bowel obstruction in patients who have had multiple surgeries and chemotherapeutic regimens. Therefore, it’s an ideal setting to improve the therapeutic window by combining RT and a radiosensitizer. Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in the recognition of DNA damage and the facilitation of DNA repair by recognizing DNA single-strand breaks (SSB). Inhibition of PARP1, especially in tumors driven by BRCA1 or 2 mutations, has been shown to potentiate the DNA-damaging effects of radiation in vitro and in vivo and to increase tumor vasculature perfusion and oxygenation. Approximately half of ovarian cancers have germline or somatic BRCA gene mutation, epigenetic silencing or other mutations that affect homologous recombination (HR) competency resulting in DNA repair defects, making this tumor particularly susceptible to the radiation-sensitizing effects of PARP inhibitors. Here, we investigated the therapeutic effects of the PARP inhibitor olaparib in preclinical models of ovarian cancer. Basic BRCA1 and PARP1 protein and mRNA levels were characterized in a panel of ovarian cancer cell lines. The radiosensitizing effects of olaparib were tested on both HR-proficient and HR-deficient ovarian cancer cells by evaluating the colony formation, DNA damage, apoptosis, and PARP1 activity. Survival benefit of olaparib was also examined in xenograft models of ovarian cancer. Our results demonstrate that combination of olaparib with IR decreased colony formation, inhibited DNA damage (γH2AX) repair, and induced more apoptosis compared to olaparib or IR alone. In addition, HR-deficient cells were more sensitive to IR than HR-proficient cells in the presence of olaparib. Furthermore, olaparib inhibited PARP1 activity in vivo, significantly decreased tumor growth and increased overall survival when combined with IR in mice bearing subcutaneous xenografts of HR-deficient OVCAR8 cells while producing a relative modest effect on overall survival of mice bearing xenografts of HR-proficient SKOV3 cells. These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in ovarian cancer, particularly in tumors with HR-deficiencies.
Citation Format: Yue Bi, Ioannis Verginadis, Souvik Dey, linlang Guo, Lilie Lin, Yanfang Zheng, Constantinos Koumenis. Identifying the radiosensitizing effects of PARP inhibitor in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5863. doi:10.1158/1538-7445.AM2017-5863
Abstract 5869: Resistance mechanism against trastuzumab in HER2-positive cancer cells and its negation by Src inhibition
Authors: Jin Meihua , Nam Ah Rong , Park Ji Eun , Bang Ju Hee , Bang Yung Jue , Oh Do Youn 
Published: July 2017

Abstract
Background: Trastuzumab in combination with chemotherapy is a standard of care for patients with HER2-positive breast and gastric cancer. Resistance mechanism to trastuzumab, anti-HER2 therapy, includes multiple pathways. Among them, Src is not well known especially in HER2-positive gastric and biliary tract cancers. We investigated the role of Src involved in trastuzumab resistance and explored the potential of Src inhibition as a trastuzumab resistance overcoming strategy.
Methods: Four trastuzumab-resistant (HR) cells (SNU216HR, N87HR, SNU2670HR, SNU2773HR) were established from 2 HER2-amplified gastric cancer cells (SNU216, NCI-N87) and 2 HER2-amplified biliary tract cancer cells (SNU2670, SNU2773). For Src inhibition, bosutinib was used. MTT assay, colony formation assay, cell cycle analysis by FACS Calibur flow cytometer, and cell migration assay were done. Animal experiments were conducted to test anti-tumor effect of bosutinib using SNU2670 and SNU2670HR xenograft models.
Results: SNU2670HR/NCI-N87HR cells showed pSrc activation, in contrast, SNU216HR/SNU2773HR cells exhibited decreased pSrc expression. In these pSrc decreased HR cells, pFAK was elevated. Bosutinib downregulated Src-FAK signaling more obviously in Src activated HR cells than parental cells. In pSrc decreased HR cells, bosutinib reduced Src-dependent FAK phosphorylation to affect cell fate. Bosutinib inhibited the growth of both parental cells and HR cells, and induced apoptosis and G1 arrest in HR cells. Bosutinib suppressed HR cell migration more effectively compared with parental cells. Bosutinib exhibited potent tumor growth inhibition in both SNU2670 and SNU2670HR xenograft models and more significantly suppressed tumor growth in HR models.
Conclusion: Src activation may contribute to trastuzumab resistance in part in HER2-positive gastric and biliary tract cancer cells. Targeting Src might be a candidate strategy to overcome trastuzumab resistance in HER2-positive cancers.
Citation Format: Meihua Jin, Ah Rong Nam, Ji Eun Park, Ju Hee Bang, Yung Jue Bang, Do Youn Oh. Resistance mechanism against trastuzumab in HER2-positive cancer cells and its negation by Src inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5869. doi:10.1158/1538-7445.AM2017-5869
Abstract 5872: Stat3 feedback activation-induced PTGIS expression is associated with acquired resistance to EGFR-TKI in lung cancer
Authors: Yeh Hsuan-Heng , Wu Shang-Yin , Hung Chun-Hua , Su Wu-Chou 
Published: July 2017

Abstract
Targeted cancer therapies can effectively promote tumor regression in clinical responses. Eventually, most tumors develop resistance to these drugs. Stat3 activation has been suggested as one of the mechanisms that cause acquired resistance to EGFR-tyrosin kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are not well studied. In this study, we found that treatment of gefitinib (EGFR-TKI) in NSCLC cell lines harboring EGFR-TKI sensitive mutation induced feedback activation of Stat3 in a time- and dose-dependent manner. High levels of IL-6 were detected in the conditioned medium of gefitinib-treated cells by cytokine array and were confirmed by ELISA. We demonstrated that IL-6 treatment could induce Stat3 activation and conditioned medium treatment-induced Stat3 activation was suppressed by IL-6 neutralizing antibody. We also demonstrated that gefitinib treatment-induced IL-6 secretion could be inhibited by knockdown of Stat3 expression. Moreover, pharmacological inhibition and genetic inhibition of Stat3 activation increased cell cytotoxicity of gefitinib in both PC9 and HCC827 cells that harboring EGFR-TKI sensitive mutation. Our data suggested that gefitinib treatment could induce activation of IL-6/Stat3 signaling loop and modulate cell cytotoxicity of gefitinib. Microarray and Ingenuity Pathway Analysis (IPA) analysis revealed prostaglandin I2 synthase (PTGIS) as a downstream target gene of IL-6/Stat3 signaling and PTGIS was up-regulated by gefitinib treatment. The induction of PTGIS by gefitinib via Stat3 feedback activation was confirmed in vitro genetically and pharmacologically. Moreover, we showed that cotreatment with PTGIS inhibitor improves the efficacy of EGFR inhibition in PC9 and HCC827 cells. Importantly, high expression of PTGIS was found in gefitinib-resistant PC9 cells (PC9/gef) compared with gefitinib-sensitive PC9 cells. Targeting PTGIS was also effective in decreasing viability of cells with acquired resistance to gefitinib in PC9/gef cells. Taken together, our study indicated that Stat3 feedback activation-induced PTGIS expression participates in modulating gefitinib efficacy and Stat3/PTGIS inhibition could potentially overcome acquired resistance to gefitinib in NSCLC.
Note: This abstract was not presented at the meeting.
Citation Format: Hsuan-Heng Yeh, Shang-Yin Wu, Chun-Hua Hung, Wu-Chou Su. Stat3 feedback activation-induced PTGIS expression is associated with acquired resistance to EGFR-TKI in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5872. doi:10.1158/1538-7445.AM2017-5872