bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4894: Sorafenib enriches for sarcoma cancer stem cells in vitro.
Authors: Canter Robert J. , Ames Erik , Tellez Joseph , Smith Rachel C. , Murphy William J. 
Published: August 2014

Abstract
Background: Cancer stem cells (CSCs) are a putative source of relapse in many cancers following anti-proliferative therapies. We hypothesized that tyrosine kinase inhibition (TKI) and radiotherapy (RT) would enrich for CSCs in sarcoma cell lines.
Methods: A673 Ewing's sarcoma and SW982 synovial sarcoma cells were exposed to sorafenib and RT in a dose- and time-dependent fashion. Cultured cells were harvested and stained with fluorochrome-conjugated antibodies against human CSC markers including CD133, CD24, CD44, and aldehyde dehydrogenase (ALDH). Cell viability was analyzed using 7-Aminoactinomycin (7-AAD). Data were acquired using a BD Fortessa cell sorter (BD Biosciences) and analyzed with FlowJo software version 7.2. Parametric and non-parametric statistical tests were performed as appropriate.
Results: Short-term exposure (≤1 day) to sorafenib demonstrated a linear dose-dependent cytotoxicity for A673 cells at doses ≥ 4 μM, while SW982 cells required doses ≥ 16 μM. At 24 hours, A673 cell viability decreased from 100% at 1 μM sorafenib to 0% at 32 μM (P&lt;0.05). By day 5, A673 cells exposed to sorafenib doses &lt; 32 μM recovered log-phase growth, while cells exposed to doses &gt; 32 μM remained non-viable. Baseline CSC phenotyping of A673 cells demonstrated 55±5% CD133+, 12±7% ALDH+, 14% CD44+, and 0% CD24+ sub-populations. Baseline CSC phenotyping of SW982 cells demonstrated 0.2±0.9% CD133+, 42±8% ALDH+, 95±5% CD44+, and 40±7% CD24+. A673 cells exposed to 24h sorafenib increased the ALDH+ fraction to 40±3% (&gt; 3-fold increase) at sorafenib 16 μM (P&lt;0.05). SW982 cells showed a non-significant increase in the ALDH+ fraction at doses ≤ 16 μM. Although single fractions of RT were anti-proliferative to A673 cells starting at doses ≥5 Gy, there was not an additive effect of 2.5 Gy RT with sorafenib on cell viability or CSC marker expression.
Conclusion: Sorafenib exerts an anti-proliferative effect on sarcoma cells but enriches for sarcoma CSC. The magnitude of these effects appears to be inversely correlated to baseline ALDH+ levels. Sustained anti-sarcoma therapeutic effects may require targeting of the CSC population following anti-proliferative therapy.
Citation Format: Robert J. Canter, Erik Ames, Joseph Tellez, Rachel C. Smith, William J. Murphy. Sorafenib enriches for sarcoma cancer stem cells in vitro. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4894. doi:10.1158/1538-7445.AM2013-4894
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4896: Real-time imaging of pancreatic cancer stem cells for identification of the selectively targeting therapy.
Authors: Tanaka Shinji , Adikrisna Rama , Matsumura Satoshi , Ban Daisuke , Ochiai Takanori , Irie Takumi , Kudo Atsushi , Nakamura Noriaki , Yamaoka Shoji , Arii Shigeki 
Published: August 2014

Abstract
Identification and purification of cancer stem cells (CSCs) should offer a clue of the therapeutic targets, but their heterogeneous expansion remains the significant obstacle of studies. One of the solutions might be establishment of real-time monitoring of CSC, based on fluorescence imaging with the intrinsically low proteasome activity. The monitoring system in human pancreatic cancer cells proved directly the asymmetric division of CSC to generate non-CSC. Real-time chemoresistance of the CSCs and remarkable tumorigenicity (as few as 10 cells) indicated their preclinical significance. The synthetic lethal screening was applied to identify a novel compound targeting specifically the pancreatic CSCs. It inhibited nuclear accumulation of beta-catenin in the pancreatic CSCs. Anti-CSC effects of the compound were confirmed by in vitro dynamic images and in vivo tumor analyses. The real-time monitoring system of CSCs is an innovative strategy providing a visible target that should lead to the discovery of successful therapies directed toward CSCs of aggressive cancers.
Citation Format: Shinji Tanaka, Rama Adikrisna, Satoshi Matsumura, Daisuke Ban, Takanori Ochiai, Takumi Irie, Atsushi Kudo, Noriaki Nakamura, Shoji Yamaoka, Shigeki Arii. Real-time imaging of pancreatic cancer stem cells for identification of the selectively targeting therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4896. doi:10.1158/1538-7445.AM2013-4896
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 4900: Functional and mechanism analysis of LGR4 in human lung cancer cells.
Authors: Gong Xing , Xiong Wei , Yi Jing , Carmon Kendra S. , Liu Qingyun 
Published: August 2014

Abstract
LGR4 (leucine-rich repeat containing G protein-coupled receptor 4) and its two closely related homologues LGR5 and LGR6 (LGR4-6) are members of the seven transmembrane domain (7TM) receptors with critical functions in embryonic development and adult stem cells. Recently, we and others discovered that LGR4-6 function as receptors of R-spondins (RSPO) to potentiate Wnt signaling. RSPOs are a group of four secreted proteins (RSPO1-4) with essential roles in organ development, sex determination, carcinogenesis, etc. Particularly, RSPO2 is required for normal lung development through enhancement of Wnt signaling and LGR6 is expressed in adult lung stem cells in the mouse. Among the 900 or so 7TM receptors, LGR4 was found to be one of the few that were highly upregulated in both squamous cell carcinoma (SqCC) and adenocarcinoma (AC) of the lung. Alterations in the Wnt signaling pathways were found in a small percentage of lung cancer. Concurrent activation of β-catenin signaling enhances tumor growth and metastasis of lung cancer cells with KRAS mutation. Furthermore, RSPO3 and LGR4 are co-expressed at high levels in ∼20% of lung cancer cell lines. However, potential roles of RSPO3-LGR4 in lung carcinogenesis have not been investigated. We developed and validated a panel of LGR4 antibodies that can detect either native or denatured LGR4 with high specificity and sensitivity. Immunohistochemistry analyses confirmed that LGR4 was highly expressed in the majority of SqCC and AC of the lung. Knockdown of LGR4 in a lung cancer cell line with high levels of and LGR4 and RSPO3 leads to dramatic decrease in endogenous Wnt signaling and significant reduction in cell growth, migration, and colony formation in vitro. The effect of knockdown on tumor growth in vivo is being tested. Data from these expression and functional analyses of LGR4 in human lung cancer will be presented and discussed.
Citation Format: Xing Gong, Wei Xiong, Jing Yi, Kendra S. Carmon, Qingyun Liu. Functional and mechanism analysis of LGR4 in human lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4900. doi:10.1158/1538-7445.AM2013-4900
Abstract 4905: Novel gene expression profiles of poorly differentiated lung cancer are enriched in stem cell factors and predictive of worse clinical outcome.
Authors: Damelin Marc Isaac , Zhong Wenyan , Diesl Veronica K. , Follettie Maximillian T. , Geles Kenneth G. 
Published: August 2014

Abstract
Poorly differentiated non-small cell lung cancer (NSCLC) at the histopathological level has been associated with shorter patient survival. Analogously, at the cellular level, poorly differentiated tumor cells exhibit more aggressive phenotypes than their well-differentiated counterparts, including higher tumorigenic potential and higher metastatic capacity. Effective therapeutic targeting of the malignant undifferentiated cells will require a deeper understanding of their molecular drivers. To investigate the hierarchical basis of heterogeneous NSCLC tumors, we developed an improved method to study the undifferentiated and differentiated states of primary tumor cultures. The cultures were established in defined serum-free media from freshly resected tumors and were induced to differentiate either by culture in serum-containing media or by exposure to the air-liquid interface (ALI) in serum-free media with two variations. Gene expression profiles revealed similar patterns of change in all three conditions, which confirmed the undifferentiated state of the initial culture; however, differentiation in serum caused many extraneous changes in gene expression, which suggested that the ALI method represents a more physiologically relevant condition. Gene Set Enrichment Analysis demonstrated that the profile of the undifferentiated state was enriched in signatures of embryonic stem cell factors, metastasis and drug resistance. In addition, novel gene expression signatures of the undifferentiated state were predictive of shorter patient survival in a clinical dataset of NSCLC. These results establish a robust method for studying the cellular hierarchy in NSCLC that is independent of cell surface markers, and the data reveal several potential avenues for future therapeutic intervention.
Citation Format: Marc Isaac Damelin, Wenyan Zhong, Veronica K. Diesl, Maximillian T. Follettie, Kenneth G. Geles. Novel gene expression profiles of poorly differentiated lung cancer are enriched in stem cell factors and predictive of worse clinical outcome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4905. doi:10.1158/1538-7445.AM2013-4905
Abstract 4914: ABCB5 expression in colorectal cancer circulating tumor cells correlates with metastatic disease progression.
Authors: Guo Qin , Ma Jie , Wilson Brian J. , Gasser Martin , Waaga-Gasser Ana Maria , Frank Markus H. , Frank Natasha Y. 
Published: August 2014

Abstract
Targeted personalized treatment approaches are critical for the development of successful therapies for advanced colorectal cancer (CRC). In this regard, circulating tumor cells (CTC) are of foremost interest as potential predictors of metastatic disease progression and patient therapeutic response. We have previously demonstrated that ATP-binding cassette member B5 (ABCB5) is expressed by cancer stem cells (CSC) in several human malignancies, including CRC, and that ABCB5 identifies therapy-refractory tumor subpopulations in CRC patients that correlate with disease progression. In order to evaluate the potential role of ABCB5 as a clinically relevant CTC marker, we utilized a human-to-mouse xenograft model system to examine the relationship of ABCB5-positive CRC-CTC to CRC metastasis. Human CRC tumor cells were grafted subcutaneously into immunocompromized NSG mice. 7 weeks after xenotransplantation, peripheral blood mononuclear cells and lungs were evaluated by qPCR for expression of human ABCB5 and GAPDH mRNAs. Expression analysis of these specimens revealed a significant positive correlation between peripheral blood human ABCB5 mRNA expression and aggregate metastatic disease load as determined by human GAPDH mRNA expression levels in lungs (r=0.8994, P=0.0147). Remarkably, no significant correlation existed between peripheral blood human GAPDH mRNA expression and metastatic disease load, indicating a unique and essential role of ABCB5-positive CSC-CTC in colorectal cancer metastatic disease progression. Significantly increased peripheral blood ABCB5 expression was also observed in a clinical series of UICC stages I-III colorectal cancer patients (n=105) compared to healthy controls (P&lt;0.001). Thus, our results identify the CSC antigen ABCB5 as a novel molecular marker of metastasis-associated CRC-CTC and point to potential utility of ABCB5 as a prognostic indicator and predictor of therapeutic response in patients with advanced colorectal cancer.
Citation Format: Qin Guo, Jie Ma, Brian J. Wilson, Martin Gasser, Ana Maria Waaga-Gasser, Markus H. Frank, Natasha Y. Frank. ABCB5 expression in colorectal cancer circulating tumor cells correlates with metastatic disease progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4914. doi:10.1158/1538-7445.AM2013-4914
Abstract 4919: Myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation potentiates human lung cancer cell malignancy .
Authors: Chen Ching-Hsien , Thai Phillip , Wu Reen 
Published: August 2014

Abstract
Myristoylated alanine-rich C kinase substrate (MARCKS), a substrate of protein kinase C (PKC), is a key regulatory molecule controlling mucin secretion by airway epithelial cells in vitro and in vivo. Phosphorylated MARCKS (p-MARCKS) has been reportedly to promote inflammatory cell migration in several lung diseases. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy has not been characterized. This study demonstrated MARCKS expression and elevated p-MARCKS in various lung cancer cell lines with high malignancy, such as CL1-0-F3, CL1-5, PC9, A549 and several tyrosine kinase inhibitor (TKI) resistant cell lines (H1650 and H1975), as compared with normal human bronchial epithelial (NHBE) cells and low metastasis cancer cell line. siRNA knockdown MARCKS expression resulted in an inhibition of cell migration, accompanying with a decrease of Slug expression in these malignant lung cancer cell lines. Treatment with myristoylated 24-amino-acid MARCKS N-terminus sequence (MANS) peptide, but not the control myristoylated random N-terminal sequence (RNS) peptide, suppressed MARCKS phosphorylation and impaired cell migration and wound healing ability in these lung cancer cell lines. Importantly, MANS peptide treatment resulted in a suppression of lamellipodia/filopodia formation and an enhancement of cell-cell contacts with increased E-cadherin expression. These results confirmed a crucial role for MARCKS, specifically its phosphorylation, in potentiating lung cancer cell migration and malignancy. This study has also suggested a potential usage of MANS or the MARCKS-related peptides in the treatment of lung cancer metastasis.
Citation Format: Ching-Hsien Chen, Phillip Thai, Reen Wu. Myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation potentiates human lung cancer cell malignancy . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4919. doi:10.1158/1538-7445.AM2013-4919
Abstract 4922: Overexpression of p62/IMP2 in breast cancer promotes cell migration.
Authors: Li Yang , Peng Bo , Lei Ningjing , Francia Giulio , Zhang Jianying 
Published: August 2014

Abstract
Invasion and metastasis are complex processes that are primarily responsible for most cancer-related deaths throughout the world, and which involve several different biological processes. The IMPs (IGF2 mRNA-binding Proteins) are a family of oncofoetal proteins that includes the members IMP1, p62/IMP2, and IMP3. These proteins are expressed during embryogenesis, and after birth their expression is lost in almost all tissues. Re-expression of IMPs is however evident in a number of adult malignancies. Indeed, p62/IMP2 was initially identified as an autoantigen with serum from a patient with hepatocellular carcinoma (HCC). p62/IMP2 is therefore a potential biomarker for the early diagnosis of HCC as well as of other cancers. Nonetheless, its function is largely unknown. To begin to understand the biology of p62/IMP2, we evaluated its expression in breast cancer by carrying out immunohistochemical analysis of 118 human sections from normal and malignant breast tissue samples. We observed a statistically significant (p&lt;0.05) overexpression of p62/IMP2 in human breast tumors (72/104, 69%), compared with normal human breast tissue (2/14, 14%). Transfection of human p62/IMP2 cDNA into human MDA-MB-231 breast cancer cells (which lack p62/IMP2expression) produced clones with stable positive and negative p62/IMP2 expression, a result confirmed by both western blotting and immunofluorescence analysis. Analysis of the transfected clones, using a wound healing assay, showed that p62/IMP2 overexpression can significantly enhance MDA-MB-231 cell migration. Our results show that p62/IMP2 is expressed in human breast cancers, and that its expression can increase cell migration, which suggests is may promote the invasive behavior of breast cancers.
Citation Format: Yang Li, Bo Peng, Ningjing Lei, Giulio Francia, Jianying Zhang. Overexpression of p62/IMP2 in breast cancer promotes cell migration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4922. doi:10.1158/1538-7445.AM2013-4922
Abstract 4923: Identification of invasive and metastatic potential of Tpl2 knockout keratinocytes.
Authors: Decicco-Skinner Katie L. , Jung Sarah , Tabib Tracy , Gwilliam Curtis , Alexander Hepzi , Goodheart Sarah , Morin Adam , Cvitan Alex , Wiest Jonathan 
Published: August 2014

Abstract
Skin cancer is the most common form of cancer in the United States, with an estimated two million cases diagnosed annually. Tpl2 (MAP3K8) is a serine threonine protein kinase in the mitogen-activated protein kinase (MAPK) signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressive function in skin carcinogenesis. Tpl-2 knockout mice develop significantly more tumors than matched wildtype controls and have a larger degree of inflammation when challenged with 12-O-tetradecanoylphorbol-13-acetate (TPA). However, it is unknown whether the tumors that develop in Tpl2 knockout mice are more aggressive and invasive than skin tumors in wildtype mice. Therefore, we compared the invasive and metastatic potential of keratinocytes from wildtype and Tpl2 knockout mice. Using various techniques including gene microarray, real-time polymerase chain reaction, and zymography we found MMP-2 and MMP-9 matrix metalloproteinases to be significantly up-regulated in Tpl-2−/- keratinocytes. Additionally, Tpl-2−/- keratinocytes have altered migration rates, significantly higher malignant conversion rates and increased angiogenesis when compared to wildtype keratinocytes. Moreover, protein arrays identified several angiogenic factors, in addition to the MMP's, induced in Tpl-2−/- keratinocytes. In summary, our studies demonstrate skin tumors from Tpl-2−/- mice have the potential to be more aggressive, invasive, and metastatic than tumors in control animals.
Citation Format: Katie L. Decicco-Skinner, Sarah Jung, Tracy Tabib, Curtis Gwilliam, Hepzi Alexander, Sarah Goodheart, Adam Morin, Alex Cvitan, Jonathan Wiest. Identification of invasive and metastatic potential of Tpl2 knockout keratinocytes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4923. doi:10.1158/1538-7445.AM2013-4923
Abstract 4926: Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer.
Authors: Wang Wei-Jan , Lin Li-Fang , Li Chien-Feng , Yang Wen-Ming , Wang Dennis Ding-Hwa , Chang Wen-Chang , Lee Wen-Hwa , Wang Ju-Ming , Wang Ju-Ming 
Published: August 2014

Abstract
ZBRK1, a zinc finger protein that interacts with breast cancer 1 (BRCA1) and KRAB-ZFP-associated protein 1 (KAP1), has been suggested to serve as a tumor suppressor via repression of tumor metastasis/invasion. To date, the detailed molecular mechanisms for how BRCA1 and KAP1 participate in ZBRK1-mediated transcriptional repression, metastasis and invasion as well as the associated clinical relevance remain unclear. In this study, we demonstrated that both the N- and C-terminal domains of ZBRK1 are important for inhibiting cell proliferation and anchorage-independent growth in cervical cancer. Specifically, the N-terminal KRAB domain of ZBRK1 displayed a more crucial role in inhibiting metastasis and invasion through modulation of KAP1 function in a transcriptionally dependent manner. The loss of ZBRK1 results in an increase of KAP1 expression, which enhanced migration and invasion of cervical cancer cells both the in vitro and in vivo. Moreover, an inverse correlation of expression levels was observed between ZBRK1 and KAP1 following tumor progression from in situ carcinoma to invasive/metastatic cervical cancer specimens. Taken together, the current results indicate that a loss of ZBRK1 contributes to the increased expression of KAP1, potentiating its role to enhance metastasis and invasion.
Citation Format: Wei-Jan Wang, Li-Fang Lin, Chien-Feng Li, Wen-Ming Yang, Dennis Ding-Hwa Wang, Wen-Chang Chang, Wen-Hwa Lee, Ju-Ming Wang, Ju-Ming Wang. Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4926. doi:10.1158/1538-7445.AM2013-4926
Abstract 4928: Mechanisms of microglia-stimulated glioma invasion.
Authors: Coniglio Salvatore J. , Segall Jeffrey E. 
Published: August 2014

Abstract
The ability of glioma tumor cells to infiltrate the surrounding brain parenchyma makes complete removal of these tumors nearly impossible. We investigated how microglia, the resident macrophages of the brain, stimulate glioma cell invasion. Coculture with microglia stimulates the invasion of GL261 glioma cells in-vitro. Pharmacological inhibition of EGFR using Iressa strongly inhibits microglia-stimulated invasion. Furthermore, we demonstrate using novel CSF-1R (c-fms) inhibitors that CSF-1R signaling is also required for microglial enhancement of glioma invasion. GL261 cells were found to constitutively secrete CSF-1, the levels of which are unaffected by EGF stimulation, EGFR inhibition or coculture with microglia. GL261 tumors orthotopically injected into the brains of C57 mice fed with the CSF-1R inhibitor PLX3397 showed a dramatic reduction in microglia/macrophages infiltration compared with tumors from animals fed control chow. Tumors from the PLX3397-fed animals also showed a 50% reduction in invasion into the parenchyma. We discovered that GL261 cell secretion of CSF-1 is involved in upregulating EGFR ligands in microglia including AREG, EREG and TGFA. Microglia isolated from GL261 tumors express AREG mRNA whereas naïve microglia from control animals do not. Depletion of AREG from microglia using siRNA interfered with their ability to promote GL261 invasion in vitro. These data indicate that during invasion, glioma and microglia cells signal to each other using EGFR Ligands and CSF-1 similar to what has been observed in breast cancer models. The results of this study indicate the possibility of inhibiting glioblastoma invasion by targeting functions of tumor-associated microglia in addition to glioma cells.
Citation Format: Salvatore J. Coniglio, Jeffrey E. Segall. Mechanisms of microglia-stimulated glioma invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4928. doi:10.1158/1538-7445.AM2013-4928