bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3456: Nicotine and the alpha-7 nicotinic acetylcholine receptor in the regulation of response to radiotherapy
Authors: Sobus Samantha L. , Romano Michelle A. , Mackowiak Janelle , Warren Graham W. 
Published: August 2012

Abstract
Purpose: Nicotine is a systemically available component of tobacco known to decrease the effectiveness of chemotherapy and/or radiotherapy (RT) however, the mechanisms of decreased RT response are not well characterized. The purpose of this study is to evaluate the effects of nicotine and activation of the alpha-7 nicotinic acetylcholine receptor (a7-nAChR) on regulating cell survival following RT and to identify potential mechanisms of regulation. Methods: Human lung cancer (A549, H460) and oropharyngeal cancer (FaDu) cell lines were treated with nicotine alone or in combination with nAChR inhibitors, MEK inhibitors, PI3K inhibitors, or mTOR inhibitors followed by treatment with RT to evaluate cell survival using clonogenic assays. The effects of a7-nAChR agonists on RT were also evaluated. Western blots were performed to evaluate nAChR subunit expression profiles in a broad spectrum of cancer cell lines and to evaluate the effects of nicotine (alone or with inhibitors listed above) or agonists on downstream signal transduction. Results: Nicotine administration 2 hours prior to RT increased survival in all cell lines. nAChR expression was confirmed in several cell lines including A549 and H460 cells. Inhibition of specific nAChRs in A549 and H460 cells demonstrated that the a7-nAChR prevented the effects of nicotine on RT in both cell lines. Nicotine administration increased p-ERK 1/2, p-Akt (Ser-473), mTOR (S2448), activated matrix metalloproteinase 2 (MMP2), and hypoxia inducible factor 1-alpha (HIF-1a). Inhibition of MEK prevented ERK 1/2 phosphorylation, but did not prevent the effects of nicotine on RT. Inhibition of PI3K prevented Akt phosphorylation, MMP2 activation, and HIF-1a induction with concomitant inhibition of the effects of nicotine on RT. Administration of an mTOR inhibitor (rapamycin) significantly sensitized cells to RT, but did not prevent the pro-survival effects of nicotine. Administration of selective a7-nAChR agonists (LY 2087101, PHA 54613, PNU 282987, TC 1698) demonstrated that all increased p-ERK 1/2 and p-Akt; however, only LY 2087101 and PHA 54613 increased cell survival with RT. Further analysis demonstrates that only LY 2087101 and PHA 54613 increased mTOR (S2448) while there was no change in mTOR (S2448) with PNU 282987 or TC 1698. Conclusions: Data demonstrates that activation of the a7-nAChR can decrease the effectiveness of RT. Results suggest that PI3K and mTOR may play a central role in conferring resistance to radiation by nicotine or during a7-nAChR activation. Further analyses of critical mechanisms are required to understand the adverse systemic effects of tobacco on cancer treatment.
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 3456. doi:1538-7445.AM2012-3456
Abstract 3463: The role of Atg13 in response to radiotherapy in cervical cancer cells
Authors: Roossink Frank , Boers Aniek , Wisman Bea , Schuuring Ed , van der Zee Ate , de Jong Steven 
Published: August 2012

Abstract
Introduction The role of autophagy protecting cancer cells against anti-cancer therapy, especially via the Beclin-1 axis, has become more clear. In cervical cancer, functionality of the Beclin-1 axis can be questioned, since promoter methylation and silencing of two components of this axis, C13ORF18 (Rubicon-like) and DAPK, is frequently observed. The involvement of another autophagy pathway, the ULK1 axis is less well studied in this tumor type. The ULK1 axis, consisting of ULK1, Atg13 and FIP200 is under control of mTOR. Here, we investigated the role of the essential component of the ULK1 complex, Atg13 in the response to (chemo)radiation in cervical cancer. Methods and Results Using immunohistochemistry we first analyzed expression of Atg13 in a large cohort of 375 pretreatment tissue samples of advantaged stage cervical cancer patients primarily treated with (chemo)radiation. Positive expression of Atg13 was more frequently observed in adenocarcinoma, known to have a poor response to chemoradiation, compared to squamous carcinoma (75% versus 56 % positive tumors, p&lt; 0.03). Transient overexpression of GFP-tagged Atg13 in HEK293T kidney cells increased radiotherapy resistance (1.5-2 fold). Western blot showed that Atg13 was expressed in several cervical cancer cell lines, including the adenocarcinoma model HeLa. Downregulation of Atg13 expression with siRNA, resulted in a 2-fold increase in radiotherapy sensitivity in HeLa cells as determined with clonogenic assays. In HeLa-GFP-LC3 cells, we found that irradiation caused a strong increase in LC-3 containing autophagosomes, which co-localized with Atg13. The autophagy inhibitor bafilomycin A1 blocks the conversion of autophagosomes into autolysosomes. Bafilomycin A1 treatment indeed resulted in an accumulation of radiation-induced autophagosomes, demonstrating that autophagy was occurring after irradiation. In addition, HeLa cells were sensitized to irradiation, when autophagy was inhibited with bafilomycin A1. These results were confirmed using the less specific autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin (an mTOR inhibitor). Conclusion We showed that the Atg13 expression is related to the presence of cervical adenocarcinoma. Our in-vitro results indicate that the autophagic ULK1 pathway plays an important role in protecting cervical cancer cells to irradiation. Thus, inhibition of autophagy may be an interesting strategy to sensitize cervical adenocarcinoma to radiotherapy.
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 3463. doi:1538-7445.AM2012-3463
Abstract 3470: HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: Implications for efficacy of adjuvant trastuzumab
Authors: Malik Fayaz , Ithimakin Suthinee , Day Kathleen , Ignatoski Kathy , Zen Qin , Thomas Dafydd , Bersano Tom , Dawsey Scott , Hall Christopher , Davis April , Quraishi Ahmed A. , Tawakkol Nader , Clouthier Shawn G. , Day Mark , Hayes Daniel F. , Korkaya Hasan , Wicha Max S. 
Published: August 2012

Abstract
Although current breast treatment guidelines limit the use of HER2 blocking agents such as trastuzumab to women whose tumors display HER2 gene amplification, recent retrospective analysis by Paik et al., have suggested that a wider group of patients may benefit from this therapy. Utilizing breast cancer cell lines, mouse xenograft models and primary human tumors and metastatic tissues, we provide a potential molecular explanation for these unanticipated clinical finding by demonstrating that HER2 is selectively expressed in the cancer stem cell (CSC) population in luminal ER+ breast cancers that do not display HER2 amplification. Furthermore, we demonstrate that the effects of trastuzumab on mouse tumor xenografts are highly dependent on the timing of administration. While the effects of trastuzumab on established tumors are limited to those with HER2 amplification, when this HER2 blocker is given immediately after tumor inoculation simulating an adjuvant setting, it significantly inhibits the growth of luminal tumors in the absence of HER2 amplification. In addition, HER2 expression is increased in luminal tumors propagated in mouse tibias as compared to primary tumors grown in mammary fat pads. Utilizing co-culture experiments with human osteocytes, we provide evidence that this regulated expression of HER2 is mediated by RANK ligand present in the bone microenvironment. The clinical relevance of these studies is demonstrated in breast cancer tissues by the co-expression of HER2 and CSC marker ALDH1 in a subset of cells which are selectively found at the invasive tumor front in luminal breast cancers. Recapitulating the mouse xenograft studies, we demonstrate increased expression of HER2 in bone metastasis compared to matched primary tumors in 8 patients with luminal breast cancer. Our results have significant clinical implications since they suggest that the benefits of adjuvant HER2 targeting therapies may extend to patients with luminal breast cancers who are currently classified as HER2-negative. Furthermore, these results support the cancer stem cell hypothesis and emphasize the clinical importance of targeting cancer stem cells in the adjuvant setting.
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 3470. doi:1538-7445.AM2012-3470
Abstract 348: Extracellular heat shock protein 90 (eHsp90) initiates EMT events and enhances cell motility in prostate cancer
Authors: Hance Michael W. , Gopal Udhayakumar , Bohonowych Jessica , Isaacs Jennifer S. 
Published: August 2012

Abstract
Prostate Cancer (PCa) is the most commonly diagnosed malignancy in men, responsible for the second highest lethality. Although early cancer detection and treatment is often curative, subsequent metastatic spread of tumor cells renders the disease incurable. Activation of the epithelial to mesenchymal transition (EMT) genetic program is considered a key event contributing to metastatic potential and subsequent lethality. Although targeting EMT may be a promising approach for improving treatment outcome, the main, potentially druggable, targets driving this pathway in PCa remain poorly defined. Multiple reports indicate that extracellular Hsp90 (eHsp90) promotes cell motility, invasion, and metastasis in a number of cancer cell types. Intriguingly, eHsp90 has been preferentially detected in the serum or plasma from aggressive cancers. Its presence in the serum of metastatic PCa patients implicates a potential causative role in PCa. Therefore, our objective was to investigate whether eHsp90 may influence EMT events, thereby influencing the metastatic potential of PCa. We now report that paired sets of differentially aggressive PCa tumor cell lines exhibited higher expression of eHsp90. Functionally, exposure of PCa cells to eHsp90 elicted a significant increase in cell motility. Inversely, blockade of eHsp90 attenuated the activation of several pro-motility effectors, concomitant with the significant suppression of cell migration. These events were associated with a profound alteration of cellular morphology towards a mesenchymal phenotype. Changes in cell phenotype were coupled with a loss and redistribution of the EMT suppressive gatekeeper protein E-cadherin. eHsp90 was also found to impact on the localization of other junctional proteins known to maintain a cuboidal epithelial phenotype. Finally, eHsp90 was found to transcriptionally upregulate several of the established transcriptional factors known to initiate EMT events. Confirmation of the EMT inducing ability of eHsp90 was determined by focused quantitative real time EMT PCR arrays. Our results therefore highlight a novel role for eHsp90 as a central regulator of EMT events in PCa. Our findings further support the premise that therapeutic targeting of eHsp90 may have the potential to suppress EMT activation and diminish the dissemination and metastatic propensity of PCa tumor cells.
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 348. doi:1538-7445.AM2012-348
Abstract 3484: Distinct cancer cell with stem cell like properties contribute to doxorubicin and paclitaxel resistance
Authors: Sharma Bhawna , Varney Michelle L. , Singh Rakesh K. 
Published: August 2012

Abstract
Resistance to therapy and disease relapse is major concerns in the field of breast cancer management. Accumulating evidence suggests the existence of breast cancer stem cells and it has been proposed that their induction after chemotherapy could be contributing to therapy resistance and relapse. Our preliminary data demonstrate that expression of CXCL1 and CXCL8 (CXCR1/2 ligands) increases after chemotherapy. We also observed that expression of RANKL (ligand of RANK) goes up in a dose dependent manner in both Cl66 and 4T1 cells after treatment with paclitaxel and doxorubicin. Recently, the involvement of RANK/RANKL signaling in mammary tumorigenesis by maintaining the stem cell pool has been elucidated. Given that RANK-RANKL signaling and CXCR1/2 signaling share the common mediator, NFkB, our working hypothesis is that chemotherapy-induced expression of CXCR1/2 ligands and the RANK/RANKL signaling axis plays an important role in selecting a subset of mammary tumor cells with stem cell-like characteristics. We selected Cl66, mammary tumor cells against doxorubicin and paclitaxel. We observed that cells selected against these drugs express higher levels of CXCR1/2 ligands at both the mRNA and protein level. Moreover, 4T1 (6-thioguanine resistant cells) and Cl66 Dox 500 (cells resistant to doxorubicin) express RANK whereas Cl66-parent and Cl66 Pac 400 (cells resistant to paclitaxel) do not. This suggests that doxorubicin specifically selects RANK expressing cancer cells and 4T1 inherently express this receptor. Cl66 resistant cells injected in BALB/c mice grew slower than parent cells. Furthermore, the extent of neovascularization in doxorubicin resistant Cl66 tumors was significantly higher as compared to parent Cl66 tumors and paclitaxel resistant Cl66 tumors. As a result of their slow growth and difference in neovascularization, we analyzed the expression of stem cell markers in these cells. We observed that both Cl66-parent and paclitaxel resistant cells express ALDH1, but the expression was higher in paclitaxel resistant cells. Moreover, resistant cells showed enhanced expression of the mesenchymal marker, vimentin in comparison to parent cells. Overall, our results suggest that use of a particular chemotherapeutic agent may influence the selection of different sub-type of cancer cells with stem cell-like properties. This data also proposes the importance of a chemotherapy-induced cytokine-chemokine axis in maintaining the cancer stem cell pool.
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 3484. doi:1538-7445.AM2012-3484
Abstract 3490: Targeting E3 ligases in liver cancer stem cells with disruption of TGF-β signaling
Authors: Chen Jian , Zhixing Yao , Saha Tapas , Piao Hai-Long , Song Shumei , Jogunoori Wilma , Mishra Bibhuti , Mishra Lopa 
Published: August 2012

Abstract
Introduction: Hepatocellular Cancer (HCC) remains the 4th common cause of cancer deaths worldwide. Because it is often diagnosed at an advanced stage in a fragile cirrhotic patient, effective therapies whether they are chemotherapy or biologically based are disappointingly few, with a narrow therapeutic index. Recent studies support a key role for TGF-β signaling in suppressing these tumors. We have previously found that deletion of Smad3/4 adaptor β2SP results in a dramatic and spontaneous formation of liver (HCC) with exon 15 mutations in 11% of human HCC. β2SP+/− and β2SP+/−/Smad3+/− mice develop visceromegaly and multiple cancers (70% of mice), including HCC spontaneously presenting a strong model of the hereditary human cancer syndrome, Beckwith-Wiedemann (BWS) as well as the stages of human HCC. High levels of E3 ligases KEAP1 and PRAJA are observed in human HCCs and in tumors of these mutant mice. Our hypothesis is that disruption of the TGF-β tumor suppressor pathway (through β2SP, Smad3 and Smad4) leads to a proliferative potential in cells that then acquire secondary events such as activation of E3 ligases (KEAP 1, PRAJA and others), presenting these as potentially powerful new targets for HCC. Methods & Results: (1) β2SP+/− and β2SP+/−/Smad3+/− mice are ideal models for a human stem cell disorder (BWS) and HCC progression. (2) Inhibition of PRAJA in the developing Zebrafish embryo leads to high levels of apoptosis. (3) PRAJA is a key E3 Ligase that modulates β2SP and Smad3. (4) PRAJA levels markedly over- expressed in human HCC cell lines and tumor tissues and promotes HCC cell growth. (5) KEAP1 levels are raised in β2SP knockout tissues and human HCCs (6) Knocking-down KEAP1 inhibits HCC tumor cell growth. (7) Seven tumor suppressors are discovered to be potential targets of KEAP1 in HCC. (8) Triterpenoid derivates (Oleanolic Acid/RTA 402/RTA 405) inhibit KEAP1/Nrf2 pathway, as well as PRAJA and inhibit HCC tumor cell growth. Conclusions: Our studies demonstrate that E3 Ligases KEAP1 and PRAJA are dramatically raised in human and mouse hepatocellular cancers when TGF-β signaling is inactivated, inhibiting KEAP1 or PRAJA reduces HCC growth. Determining the synergistic therapeutic effects by targeting both KEAP1 and PRAJA will provide us important insights into development of new therapeutic targets for HCC.
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 3490. doi:1538-7445.AM2012-3490
Abstract 3503: Enhanced delivery of T cells to tumor after chemotherapy using membrane-anchored, apoptosis-targeted peptide
Authors: He Xiaofeng , Lee Eun-Kyu , Kim In-San , Lee Byung-Heon 
Published: August 2012

Abstract
Chemotherapy-induced apoptosis of tumor cells enhances the antigen presentation and sensitizes tumor cells to T cell-mediated cytotoxicity. Here we harnessed the apoptosis of tumor cells as a homing signal for the delivery of T cells to tumor. Jurkat T cells were anchored with ApoPep-1, an apoptosis-targeted peptide ligand, using the biocompatible anchor for membrane (BAM), an oleyl acid derivative. The ApoPep-1-BAM conjugate was efficiently anchored to cell membrane, while little anchoring was obtained with ApoPep-1 alone. The retention period of the ApoPep-1-BAM conjugate on cells was approximately 40 and 20 minutes in the absence and presence of serum, respectively. The apoptosis-targeted T cells that were anchored with the ApoPep-1-BAM preferentially bound to apoptotic tumor cells over living cells. When intravenously injected into tumor-bearing mice, the number of the apoptosis-targeted T cells and in vivo fluorescence signals by the homing of the cells to doxorubicin-treated tumor were higher than those of untargeted T cells. These results suggest that the chemotherapy-induced apoptosis and subsequent enhancement of T cell delivery to tumor by the membrane anchoring of the apoptosis-targeted peptide could be a novel strategy for cancer immunotherapy.
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 3503. doi:1538-7445.AM2012-3503
Abstract 3523: Preclinical characterization of MT114, a novel CD33/CD3-bispecific BiTE antibody for the treatment of acute myeloid leukemia (AML)
Authors: Henn Anja , Friedrich Matthias , Kischel Roman , Lutterbuese Ralf , Schneider Katja , Mueller Peter , Baeuerle Patrick A. , Raum Tobias , Kufer Peter , Rattel Benno 
Published: August 2012

Abstract
There has been little improvement of standard of care for AML patients over the past 20 years, creating a large demand for therapies with improved benefit/risk profile and potential to cure. The CD19/CD3-bispecific, T cell-engaging (BiTE) antibody blinatumomab has shown high response rates and durable remissions in patients with acute lymphocytic leukemia and non-Hodgkin lymphoma. In order to employ this novel therapeutic modality for the treatment of patients with CD19-negative AML, we have constructed a panel of CD33/CD3-bispecific BiTE antibodies and selected MT114 as lead candidate for pre-clinical development for its superior pharmacological and pharmaceutical properties. Its target antigen CD33 (SIGLEC-3) is frequently expressed on AML blasts and leukemic stem cells, and extensive clinical experience has been gained by the CD33-targeting antibodies Mylotarg®, lintuzumab and AVE9633. Here, we report on the biological activities of MT114. MT114 recognized epitopes in the V domain of CD33 and of CD3 epsilon that are conserved between human and macaque antigen, allowing pharmacological and nonclinical safety investigations of the BiTE antibody in macaques as a relevant primate species. MT114-induced redirected lysis of 10 human AML cell lines by unstimulated peripheral blood mononuclear cell (PBMC) at half-maximal concentrations of MT114 between 23 and 328 pg/ml (0.4-7 pM). The 10 AML lines expressed CD33 at 20,000-50,000 molecules/cell. Redirected lysis was specific for CD33-expressing cells, reached completion after 28-h of co-culture, and was effective even at PBMC-to-target ratios of α1:2. MT114 induced the expression of activation markers CD69 and CD25 on T cells and the transient release of IFN-γ, TNF-α and IL-2, -6 and -10 by T cells, but only in the presence of CD33+ target cells. Redirected lysis and T cell activation by MT114 was not affected by up to 100 ng/ml of shed CD33, serum levels of which were found to be associated with AML progression. Neoexpression of CD33 on BiTE-activated T cells did not exceed 8% of total activated T cells when tested with 10 human T cell donors. The BiTE antibody significantly delayed growth of the subcutaneously injected human AML cell line HL60, and induced a robust infiltration of T cells into tumor tissue. MT114 is a highly active novel BiTE antibody with promise for the treatment of AML.
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 3523. doi:1538-7445.AM2012-3523