bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3262: Mitochondrial haplotype effects on tumor formation and metastasis are both cell autonomous and non-cell autonomous
Authors: Brinker Amanda E. , Vivian Carolyn J. , Feeley Kyle P. , Ballinger Scott W. , Welch Danny R. 
Published: August 2015

Abstract
Increasing data support roles for mitochondrial genomes in complex diseases, including cancer. We hypothesize that primary tumor formation and metastasis can arise from inherited mitochondrial differences. To test directly the role of mitochondrial DNA (mtDNA) in mammary cancer tumorigenicity and metastasis, we generated Mitochondrial Nuclear Exchange (MNX) mice. This unique animal model is created by moving the nucleus from an oocyte of one strain into an enucleated oocyte of a different strain. By exchanging the nucleus of mouse strains promoting or inhibiting metastatic efficiency, mtDNA effects can be distinguished from phenotypes which would occur due to nuclear admixing. To determine if a change in the mtDNA background impacts metastasis in a cell autonomous manner, two FVB transgenic mouse strains encoding either Her2 or PyMT oncogenes were crossed with MNX mice with FVB nuclear DNA and mtDNA from either BALB/cJ or C57BL6J strains. The mtDNA were chosen because of higher or lower metastatic efficiency, respectively (PMID9679770, PMID16491073). Latency of mammary tumor formation in MNX mice with C57BL/6 mtDNA is longer for both Her2 and PyMT. Lung metastases are smaller in C57BL6 but larger in BALB/c MNX crosses with the PyMT. Studies measuring metastasis efficiency in the MNX crosses with Her2 are still in progress. To determine whether the mitochondrial haplotype alters tumorigenicity or metastasis in a non-cell autonomous manner, syngeneic tumor cells were injected orthotopically and ectopically (i.v.). Tumor formation and metastasis differ in a tumor and mtDNA-dependent manner. For example, E0771 forms significantly more lung metastases in C57BL/6n:C3H/HeNmt mice compared to controls. To explore underlying mechanisms, metabolic differences were observed in MNX and matched wild type mouse embryonic fibroblasts using the Seahorse bioanalyzer. Conclusion: mtDNA affects mammary cancer development and progression via both genetic and non-cell autonomous mechanisms in the tumor microenvironment. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res, Steiner Family Fund for Metastasis Research, Kansas Bioscience Authority, CA134981, P30-CA168524
Citation Format: Amanda E. Brinker, Carolyn J. Vivian, Kyle P. Feeley, Scott W. Ballinger, Danny R. Welch. Mitochondrial haplotype effects on tumor formation and metastasis are both cell autonomous and non-cell autonomous. [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 3262. doi:10.1158/1538-7445.AM2015-3262
Abstract 3263: Investigating TIP60's role in regulating cancer metastasis
Authors: Zhang Yanzhou 
Published: August 2015

Abstract
HIV-Tat-interacting protein 60 KDa (TIP60) is a lysine acetyltransferase implicated in multiple cellular pathways such as transcription, DNA damage-induced checkpoint activation, and apoptosis. TIP60 is a haploinsufficient tumor suppressor and known to be down-regulated in cancers, including virus induced cancers. Cell migration or epithelial-mesenchymal transition (EMT) is a highly conserved cellular program that allows polarized, immotile epithelial cells to convert to motile mesenchymal cells. Recent studies show that down-regulation of TIP60 correlate with cancer metastasis with higher tumor node metastasis (TNM) and poor survival rates. Yet the mechanism of how TIP60 regulate EMT remains unknown. In this study we found TIP60 acts as an inhibitor of cell migration and negatively regulates metastasis capability of breast cancer cells. By using in vitro and in vivo models we show that overexpression of TIP60 inhibit breast cancer metastasis. Furthermore, analyses of our expression data reveal that the levels of cell adhesion genes are significantly changed in the absence of TIP60. Mechanistically, we show TIP60 to interact with Snail2 and regulate its ability to bind to its target promoters. Interestingly, we also found that TIP60 is significantly down-regulated in the breast cancer patient, and levels of TIP60 were significantly decreased as the disease progressed and its expression negatively correlates with metastasis. In summary, our data suggests that patients with lower TIP60 expression have a poor prognosis of overall and disease free survival.
Citation Format: Yanzhou Zhang. Investigating TIP60's role in regulating cancer metastasis. [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 3263. doi:10.1158/1538-7445.AM2015-3263
Abstract 3264: Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC)
Authors: Sasaki Ken , Kurahara Hiroshi , Natsugoe S , Iwakuma Tomoo , Welch Danny R. 
Published: August 2015

Abstract
Background: PDAC is a leading cause of cancer-related death worldwide, and most patients have incurable disease at diagnosis. Life expectancy is only 3-6 months post-diagnosis, ostensibly due to early dissemination to liver and other vital organs. Results: By transfecting a shRNA library into non-metastatic PDAC line S2-028 followed by experimental metastasis assay, ITIH5 was identified. Metastatic PDAC cell lines (e.g., S2-007, MIAPaCa-2, Panc-1) had significantly lower ITIH5 protein expression compared to immortalized pancreatic ductal epithelial cells and non-/poorly-metastatic PDAC cell lines (e.g., S2-028 and BxPC3). By manipulating expression in different PDAC cell lines (over-expression in S2-007 and MIAPaCa-2, knockdown in non-metastatic S2-028 with two different shRNA) functional and selective regulation of metastasis was observed. Orthotopic tumor growth of PDAC cells was not blocked. Thus ITIH5 qualifies as a metastasis suppressor. Overexpression of ITIH5 significantly inhibited invasion and migration, while down-regulation increased these cellular properties. Immunohistochemistry of a human PDAC tissue microarray (n = 81) revealed that negative expression of ITIH5 showed significantly higher incidence of liver metastasis (P = 0.0482) corresponding with worse prognosis after surgery (P = 0.0299). Conclusions: ITIH5 is a potent metastasis suppressor with suggestive prognostic value in PDAC. Future studies will continue to characterize biochemical properties of ITIH5, identify interaction partners, and investigate the molecular mechanism(s) of action. Support: National Foundation for Cancer Research, Steiner Family Fund and CA168524.
Citation Format: Ken Sasaki, Hiroshi Kurahara, S Natsugoe, Tomoo Iwakuma, Danny R. Welch. Genome-wide shRNA screen identifies ITIH5 gene as a metastasis suppressor of pancreatic ductal adenocarcinoma (PDAC). [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 3264. doi:10.1158/1538-7445.AM2015-3264
Abstract 3283: The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis
Authors: Snapkov Igor , Öqvist Carl Otto , Figenschau Yngve Anton , Kogner Per , Johnsen John Inge , Sveinbjørnsson Baldur 
Published: August 2015

Abstract
The formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor with pattern recognition properties and is mainly expressed by myeloid cells. It is involved in a broad range of host defense mechanisms and a variety of host-derived agonists of FPR1 have been identified, including formyl peptides released from disrupted mitochondria of necrotic cells.
In the present study, we demonstrate the expression of FPR1 in 7 different neuroblastoma cell lines and in primary tumors. Furthermore, FPR1 is expressed at increased levels in high stage tumors. Addition of the FPR1 agonist N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) to neuroblastoma cells in vitro caused enhanced proliferative activity, increase of intracellular calcium response and activation of STAT3 and MAPK/ERK signal transduction pathways. All these signal transduction events were abrogated by the use of Cyclosporin H, a specific FPR1 antagonist.
To assess the significance of this receptor in vivo, we developed a set of neuroblastoma cell clones with different expression levels of FPR1. Xenograft models showed that cells with overexpression of the receptor developed tumors significantly faster compared to control group.
Our findings so far suggest that FPR1 may play a significant role in neuroblastoma tumorigenesis and that therapeutic intervention of the FPR1 pathway may be an important clinical strategy in neuroblastoma therapy.
Citation Format: Igor Snapkov, Carl Otto Öqvist, Yngve Anton Figenschau, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson. The role of formyl peptide receptor 1 (FPR1) in neuroblastoma tumorigenesis. [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 3283. doi:10.1158/1538-7445.AM2015-3283
Abstract 3297: Cell phone use and cytokines expression in saliva of the parotid glands
Authors: de Souza Fabrício TA , Gomes Carolina C. , De Marco Luiz Armando , Siqueira Elisa C. , Costa Samuel M. , Correia-Silva Jeane F. , Gomez Ricardo S. 
Published: August 2015

Abstract
The association between cell phone use and the development of parotid tumors is controversial. Because there is unequivocal evidence that the microenvironment is important for tumor formation, we investigated in the parotid glands whether cell phone use alters the expression of cytokines. We used the saliva produced by the parotid glands to assess cytokines levels, comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to the saliva from the opposite, unexposed parotid (contralateral) of each individual. We compared salivary flow, total protein, IL-1 β, IL-6, IFN-γ and TNF-α between the ipsilateral and contralateral parotids of forty-three individuals. No difference was found for any of these parameters. Our study provides evidence that the exposure of parotid glands to cell phone use does not alter cytokines levels in the parotid. Supported by CAPES, FAPEMIG and CNPq, Brazil.
Citation Format: Fabrício TA de Souza, Carolina C. Gomes, Luiz Armando De Marco, Elisa C. Siqueira, Samuel M. Costa, Jeane F. Correia-Silva, Ricardo S. Gomez. Cell phone use and cytokines expression in saliva of the parotid glands. [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 3297. doi:10.1158/1538-7445.AM2015-3297
Abstract 3302: Subtype-specific radiation response in a mouse model of human breast cancer
Authors: Lee Chen-Ting , Zhou Yingchun , Siamakpour-Reihani Sharareh , Choudhury Kingshuk R. , Dewhirst Mark W. , Horton Janet K. 
Published: August 2015

Abstract
Radiation therapy is an important component of multimodal treatment for women with breast cancer. However, breast radiotherapy is currently delivered uniformly, regardless of breast cancer subtype. Recent clinical data have suggested that different subtypes of breast cancer may respond differently to radiation. Understanding the intrinsic variation of radiation response in breast cancer subtypes would lay the foundation for individualized radiotherapy designed to limit toxicity in those with radiation responsive cancers. Furthermore, identification of molecular targets can be used to modulate treatment outcomes in patients with radiation resistant tumors.
Our previous in vitro studies have identified an association between breast cancer subtype and gene expression profiles in response to radiation in breast tumor cell lines. Cell lines with the greatest response to radiation were luminal subtype and exhibited preferential induction of genes involved in programmed cell death, such as FAS. In this study, we investigated tumor growth and FAS induction in response to radiation in a mouse model of breast cancer. MCF7 (luminal) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of athymic nude mice. These mice were then treated with different doses of radiation. Our results showed that radiation treatment inhibited MCF7 tumor growth in a dose-dependent manner, while radiation treatment had little effect on SUM159 tumor growth. In addition, FAS was induced in MCF7 tumors 24 hour after radiation, but there was no change in FAS expression in SUM159 tumors. However, injection of FAS-stimulating antibody intratumorally led to downstream caspase 8 and PARP activation, suggesting that the FAS signaling pathway remains intact and can be used to modulate radiation response in the resistant SUM159 cells.
In conclusion, these results suggest that there is intrinsic variation in radiation response among breast cancer subtypes and that stimulation of FAS may have the potential to modulate radiation response.
Citation Format: Chen-Ting Lee, Yingchun Zhou, Sharareh Siamakpour-Reihani, Kingshuk R. Choudhury, Mark W. Dewhirst, Janet K. Horton. Subtype-specific radiation response in a mouse model of human breast cancer. [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 3302. doi:10.1158/1538-7445.AM2015-3302
Abstract 3305: The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response
Authors: Sobus Samantha L. , Balasubramanian Sundaravadivel , Romano Michelle A. , Warren Graham W. 
Published: August 2015

Abstract
Tobacco use is the single largest preventable risk factor for developing cancer. Furthermore, tobacco is associated with poor therapeutic outcomes in part because its continued use has been shown to decrease the efficacy of conventional chemotherapy and/or radiotherapy (RT). Preclinical data suggests that nicotine administration decreases RT efficacy by activating the alpha-7-nicotinic acetylcholine receptor (a7-nAChR). Our study evaluated the effects of nicotine and selective a7-nAChR agonists (LY 2087101, PHA 543613, PNU 282987, and TC 1698) administration on radiotherapeutic efficacy. H460 and A549 human lung cancer cell lines were dose escalated with nicotine and the a7-nAChR agonists alone or in combination with single fraction X-ray radiation (2, 6 Gy) and cell survival was assessed by clonogenic assay. Nicotine administration and activation of a7-nAChR by LY 2087101 or PHA 543613 was found to have a radioprotective effect in both cell lines by increasing cell survival following RT. Conversely, activation of a7-nAChR by PNU 282987 or TC 1698 did not modulate radiotherapeutic response. Western blot analysis demonstrated that although all four tested a7-nAChR agonists increased phosphorylation of AKT (S473), only PHA 543613 and LY 2087101 were found to also activate mTOR (S2448). Additional clonogenic studies were performed to further examine the role of mTORC1 in governing response to RT. Inhibition of mTORC1 by rapamycin alone sensitized both A549 and H460 cells to the effect of RT. Interestingly, rapamycin treatment was sufficient to block the radioprotective effects of nicotine, PHA 543613, and LY 2087101 in A549 cells, however, in H460 cells rapamycin did not restore radiotherapeutic efficacy. Moreover, examination of Deptor, a key component of mTOR complexes shown to be associated with RT response, demonstrated that a7-nAChR activation by nicotine, PHA 543613, or LY 2087101 increased Deptor degradation in A549 cells, while a7-nAChR activation decreased Deptor degradation in H460 cells. These observations suggest that differences in the regulation of Deptor level may contribute to the variation in both rapamycin sensitivity and restoration of therapeutic efficacy to RT between H460 and A549 cell lines. Additional studies will be necessary to further elucidate the role of the mTOR complexes in mediating a7-nAChR induced modulation of response to RT.
Citation Format: Samantha L. Sobus, Sundaravadivel Balasubramanian, Michelle A. Romano, Graham W. Warren. The role of mTOR in mediating nicotine induced alpha-7 nicotinic acetylcholine receptor activation and the regulation of radiotherapeutic response. [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 3305. doi:10.1158/1538-7445.AM2015-3305
Abstract 3318: Phosphoproteomic profiling of glioblastoma stem cells to uncover mechanisms of radiation resistance
Authors: Bassett Emily , Palanichamy Kamalakannan , Chakravarti Arnab 
Published: August 2015

Abstract
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. GBM tumors universally develop resistance to chemotherapy and radiation therapy; thus, there is an urgent need to develop novel treatment strategies. In this study, we identify signaling pathways altered specifically in radioresistant glioblastoma stem cells (GSCs) following radiation treatment, in order to identify mechanisms of radiation resistance. Protein phosphorylation is a highly regulated and dynamic post-translational modification that is the primary mechanism of signal transduction. We hypothesized that phosphoproteomic profiling of GSCs can be used to identify novel signaling pathways involved in GBM radioresistance. Phosphopeptides were isolated from three GSC lines and one differentiated GBM cell line before and after radiation treatment. Mass spectrometry-based global phosphoproteomic profiling was then utilized to quantify radiation-induced changes in protein phosphorylation. About 6,000 phosphopeptides mapping to about 2,300 phosphoproteins were quantified at two post-radiation timepoints (relative to untreated) across all four cell lines. Three biological replicates of each sample were analyzed by mass spectrometry to obtain statistical significance. Fold changes of phosphoproteins following radiation treatment were then mapped to canonical signaling pathways, and pathways altered specifically in radiation-resistant GSCs were identified. We conclude that different pathways are activated in GSCs compared to differentiated GBM cells following radiation treatment, and some of these pathways may mediate radioresistance. Future efforts will focus on validation of the mass spectrometry results in vivo, and cell-based assays to identify the role of specific phosphoproteins in radioresistance pathways. Results of this study will guide future efforts to develop radiosensitizing agents that, when used in combination with current treatments, may increase the survival of patients with this devastating disease. This study was supported by funds from The Ohio State University Comprehensive Cancer Center (to AC); NIH/NCI 1U10CA180850-01(to AC); NIH/NCI 1RC2CA148190 (to AC); NIH/NCI 2K12CA133250-06 (to AC); NIH/NCI/CTEP 1R01CA169368 (to AC); NIH/NCI 1R01CA11522358 (to AC), RTOG (to AC).
Citation Format: Emily Bassett, Kamalakannan Palanichamy, Arnab Chakravarti. Phosphoproteomic profiling of glioblastoma stem cells to uncover mechanisms of radiation resistance. [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 3318. doi:10.1158/1538-7445.AM2015-3318
Abstract 3319: Identification of cervical cancer stem cells by using an imaging system for proteasome activity
Authors: Tamari Keisuke , Ishii Hideshi , Hayashi Kazuhiko , Konno Masamitsu , Kawamoto Koichi , Nishida Naohiro , Kozeki Jun , Fukusumi Takahito , Doki Yuichiro , Mori Masaki , Ogawa Kazuhiko 
Published: August 2015

Abstract
Cervical cancer is one of the most common cancers among women worldwide and the fourth most common cause of cancer death in women worldwide (275,100 deaths in 2008). For advanced cervical cancer, concurrent radiotherapy and chemotherapy are commonly administered. However, the 5-year survival rate remains at only ∼60%, indicating the need for significant improvements in clinical outcomes. Recurrence and metastatic potential can be due to a specific radioresistant subpopulation of cells with stem-like characteristics, cancer stem cells (CSCs) which maintain the capacity to regenerate entire tumors. Targeting of the CSCs is a promising avenue to explore to develop new therapies for this devastating cancer. Recently, cancer cells with low proteasome activity have been identified as CSCs in breast cancer, glioma, and pancreatic cancer with a fluorescence marker system for level of proteasome activity. We stably infected two cervical cancer cell lines, HeLa and CaSki, with an expression vector for a fusion protein between the green fluorescent protein, ZsGreen, and the C-terminal degron of murine ornithine decarboxylase to monitor 26S proteasome activity in living cells. we divided these cells into ZsGreen-high (low proteasome activity) and ZsGreen-low (high proteasome activity) groups according to their fluorescence intensity. Sphere forming assay revealed that the self-renewal ability of the ZsGreen-high population was significantly higher than that of the ZsGreen-low population. Tumorigenicity assay confirmed that the ZsGreen-high population exhibited higher tumorigenic potential than the ZsGreen-low population. The radioresistance of the ZsGreen-high population of both HeLa and CaSki cells and the chemoresistance of the ZsGreen-high population of CaSki cells were confirmed by clonogenic survival assay and the MTT assay, respectively. These results indicated that ZsGreen-high populations of both the HeLa and CaSki cell lines possess CSC-like properties and therapeutic resistance. We conclude that established cervical cancer cell lines are heterogeneous with regard to their intrinsic proteasome activity and that they contain CSCs-enriched subpopulations that can be identified by low proteasome activity.
Citation Format: Keisuke Tamari, Hideshi Ishii, Kazuhiko Hayashi, Masamitsu Konno, Koichi Kawamoto, Naohiro Nishida, Jun Kozeki, Takahito Fukusumi, Yuichiro Doki, Masaki Mori, Kazuhiko Ogawa. Identification of cervical cancer stem cells by using an imaging system for proteasome activity. [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 3319. doi:10.1158/1538-7445.AM2015-3319