bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3319: Characterization of the CD44+/CD49f+/CD24- subpopulation in basal-like DCIS cells
Authors: Duru Nadire , Gernapudi Ramkishore , Lo Pang-Kuo , Yao Yuan , Wolfson Benjamin , Zhang Yongshu , Zhou Qun 
Published: July 2016

Abstract
The molecular mechanisms responsible for Ductal Carcinoma In Situ (DCIS)-Invasive Ductal Carcinoma (IDC) transition have yet to be elucidated. Due to the lack of molecularly targeted therapies, basal-like DCIS has a high risk of recurrence and progression to invasive and metastatic cancers. In this study, using a human DCIS cell line model and a novel single-cell clonogenic approach, we have identified and characterized the aggressive clones derived from single cells with the CD49f+/CD44+/CD24- surface markers. We found that aggressive clones had enhanced self-renewal, migratory and invasive capacities. The aggressive clones had elevated ALDH activity, lower global DNA methylation and increased expression of stem cell related genes including OCT4 and SOX2. Further mechanistic studies showed that linc-ROR and miR-10b were overexpressed in aggressive clones and are key regulators of their self-renewal and invasive abilities. Finally, we confirmed our in vitro results in vivo, demonstrating that aggressive clones were capable of forming tumors in nude mice, whereas non-aggressive clones were not. We believe that characterization of aggressive clones within the heterogeneous CD49f+/CD44+/CD24- DCIS population and having linc-ROR and miR10b as additional markers to distinguish them from non-aggressive clones would provide the basis to develop new chemoprevention agents.
Citation Format: Nadire Duru, Ramkishore Gernapudi, Pang-Kuo Lo, Yuan Yao, Benjamin Wolfson, Yongshu Zhang, Qun Zhou. Characterization of the CD44+/CD49f+/CD24- subpopulation in basal-like DCIS cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3319.
Abstract 3324: Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via inhibition of STAT3 activation in triple-negative breast cancer cells
Authors: Kim Ji Young , An Hyunsook , Oh Eunhye , Cho Youngkwan , Lee Nahyun , Seo Jae Hong 
Published: July 2016

Abstract
Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Triple-negative breast cancer (TNBC) is an aggressive tumor subtype with an enriched CD44+/CD24- stem-like population. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. The objective of the present study was to investigate the effect of salinomycin on cell death, migration, and invasion, as well as CSC-like properties in TNBC. Salinomycin significantly induced anoikis-sensitivity, accompanied by caspase-3 and caspase-8 activation and PARP cleavage, during anchorage-independent growth. Salinomycin treatment also caused a marked suppression of cell migration and invasion with concomitant downregulation of MMP-9 and MMP-2 mRNA levels. Notably, salinomycin inhibited the formation of mammospheres and effectively reduced the CD44+/CD24- stem-like population during anchorage-independent growth. These observations were associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, interleukin-6 (IL-6)-induced STAT3 activation was strongly suppressed by salinomycin challenge. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of CD44, ALDH1 and phopspho-STAT3 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on triple-negative breast cancer stem cells.
Citation Format: Ji Young Kim, Hyunsook An, Eunhye Oh, Youngkwan Cho, Nahyun Lee, Jae Hong Seo. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via inhibition of STAT3 activation in triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3324.
Abstract 3335: The high cMyc expression characterizes a small cell subpopulation in ALK-positive anaplastic large cell lymphoma that carry cancer stem-like properties
Authors: Wu Chengsheng , Zhang Haifeng , Gupta Nidhi , Abdulraheem Alshareef , Wang Qian , Huang Yunghsin , Lai Raymond 
Published: July 2016

Abstract
We have previously identified two phenotypically distinct cell subpopulations in ALK+ anaplastic large cell lymphoma (ALK+ALCL) based on their differential response to a Sox2 reporter (SRR2), with reporter responsive (RR) cells being more tumorigenic and chemoresistant than reporter unresponsive (RU) cells. The regulation of the RU/RR dichotomy remains to be elusive. Our bioinformatics analysis of the SRR2 sequence suggests that cMyc may be an important factor. In support of this concept, we found a substantially higher expression of cMyc and more cMyc and Sox2-SRR2 probe bindings in RR cells than in RU cells. Inhibition of cMyc in RR cells significantly decreased SRR2 luciferase activity, and overexpression of cMyc in RU cells significantly increased SRR2 luciferase activity. Correlating with this, cMyc inhibition in RR cells significantly attenuated the clonogenicity and sensitized cells to doxorubicin; while overexpression of cMyc in RU cells conferred to the potentiated clonogenicity and chemoresistance. Importantly, we found cMyc not only maintains Sox2 protein expression, but also promotes Sox2 SRR2 probe binding and its transcriptional activity. Moreover, we found the highly active Wnt canonical pathway (WCP) contributes to the high expression of cMyc in RR cells. Intriguingly, we observed a positive regulatory loop in RR cells, in which Sox2 up-regulates Wnt2B, which can activate the WCP and cMyc. Furthermore, the significance of cMyc in this context was further highlighted by the fact that RU cells with stably transfected c-MYC are phenotypically similar with RR cells in terms of the elevated activation of WCP and increased tumorigenicity in vivo. Lastly, we found cMyc is heterogeneously expressed in ALK+ALCL tumor cells (n = 5) by immunohistochemcial staining, and it co-localizes with active β-catenin, a marker of active WCP, in tumor cells by immunofluorescence assay. In conclusion, cMyc is a key regulatory factor in the determination of RU/RR dichotomy, which is linked to tumorigenic potential and chemo-resistance in ALK+ALCL.
Citation Format: Chengsheng Wu, Haifeng Zhang, Nidhi Gupta, Alshareef Abdulraheem, Qian Wang, Yunghsin Huang, Raymond Lai. The high cMyc expression characterizes a small cell subpopulation in ALK-positive anaplastic large cell lymphoma that carry cancer stem-like properties. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3335.
Abstract 3337: Targeting acute myeloid leukemia via anti-IL1RAP antibodies
Authors: Jiang Ping , Liu Bob Y. , Huang Jen , Lu Jennifer , Roy Sharmili , Mishra Madhavi , Zhao Xiaoxian , Lin Jeffrey , Hsi Eric D. , Junutula Jagath R. 
Published: July 2016

Abstract
The current standard of care for Acute Myeloid Leukemia (AML) is largely ineffective in terms of achieving long term remission. This is mostly due to inability to remove all of the leukemic cells, and there is accumulating evidence to support the remaining leukemic cells are Leukemic Stem Cells (LSC) which are resistant to standard chemotherapy. We and others (Barreyro L. et. al. 2012) have discovered that IL-1 receptor accessory protein (IL1RAP) is overexpressed on LSC and their progenitors, but not on normal hematopoietic stem cells (HSC). Moreover, knockdown/knockout of IL1RAP expression greatly decreases growth/survival of AML cells. Thus, we have screened anti-IL1RAP therapeutic antibodies by applying FACS based analysis and Complement-Dependent Cytotoxicity (CDC) assays on both AML cell lines and primary patient samples. In a parallel effort, we also applied a functional IL-1β-induced NF-κB signaling assay to identify function-blocking anti-IL1RAP antibodies. Colony Formation Cell (CFC) assay results demonstrated that lead IL1RAP antibodies can significantly impede growth of both AML blast cells and leukemic stem cell-like cells. In contrast, normal HSCs are unaffected by these antibodies. Lead anti-IL1RAP antibodies also showed tumor growth inhibition in an established EOL-1 orthotopic tumor model. One major challenge of targeting IL1RAP by an antibody is that a large amount of IL1RAP protein is secreted into human serum, serving as a potential “sink” that inhibits IL1RAP antibody efficacy. We addressed this by developing a novel IL1RAP antibody that binds preferentially to the membrane-bound IL1RAP protein as compared to the secreted form. We will discuss different therapeutic development strategies to further advance the utilization of these lead anti-IL1RAP therapeutic antibodies for treating AML and other myeloid leukemic indications.
Citation Format: Ping Jiang, Bob Y. Liu, Jen Huang, Jennifer Lu, Sharmili Roy, Madhavi Mishra, Xiaoxian Zhao, Jeffrey Lin, Eric D. Hsi, Jagath R. Junutula. Targeting acute myeloid leukemia via anti-IL1RAP antibodies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3337.
Abstract 3341: Microarray analysis of gastrointestinal stromal tumor-originated spheroids
Authors: Kikuchi Hirotoshi , Miyazaki Shinichiro , Murakami Tomohiro , Matsumoto Tomohiro , Ozaki Yusuke , Hiramatsu Yoshihiro , Kamiya Kinji , Ohta Manabu , Sakaguchi Takanori , Konno Hiroyuki 
Published: July 2016

Abstract
Background: Although the main cause of gastrointestinal stromal tumor (GIST) is gain-of-function mutations in the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit are thought to occur during tumor progression. Although sequential therapy with tyrosine kinase inhibitors (TKIs), imatinib mesylate, sunitinib malate and regorafenib, is an effective and standard treatment strategy for recurrent or metastatic GISTs, it is difficult to cure recurrent GISTs with TKIs alone. It has been reported that viable cells are often seen in tumors resected in response to imatinib therapy and they may cause refractory tumors after interruption of imatinib in responding patients with advanced GISTs. Therefore targeting these persistent clones, which may have stem cell characteristics, can be a novel treatment strategy to cure recurrent or metastatic GISTs. In this study, we generated spheroids from resected GIST and performed microarray analysis to identify gene sets typically expressed in GIST-originated spheroid (GISTOS).
Methods: According to the previous report of cancer tissue originated spheroid (CTOS) (Kondo J et al. PNAS 108:6235-40, 2011), GISTOS was prepared from fresh samples of 6 primary gastric GISTs. Total RNAs were extracted from 6 GISTOS and their original tumors and utilized for cDNA microarray analysis. None of the patients had received imatinib therapy before surgery. Gene expression levels were compared between GISTOSs and their original tumors.
Results: Hierarchical clustering revealed two distinct clusters, and distinguished GISTOS from original tumors. Gene set enrichment analysis (GSEA) revealed that the gene sets CISPLATIN_RESISTSNCE, METASTASIS_STROMAs and TUMOR_INVASIVENESS_2D were upregulated and gene sets CELL_CYCLE_G1_S and MIR21_TARGETS were downregulated in GISTOSs compared with original tumors. These gene sets appear to reflect distinctive features of GISTOS that consists of enriched stem cell populations.
Conclusions: We generated GIST-originated spheroids. Microarray analysis revealed gene sets up-regulated and down-regulated in GISTOS. These gene sets appear to reflect distinctive features of GISTOS and may serve as novel molecular markers of stem cells in GIST.
Citation Format: Hirotoshi Kikuchi, Shinichiro Miyazaki, Tomohiro Murakami, Tomohiro Matsumoto, Yusuke Ozaki, Yoshihiro Hiramatsu, Kinji Kamiya, Manabu Ohta, Takanori Sakaguchi, Hiroyuki Konno. Microarray analysis of gastrointestinal stromal tumor-originated spheroids. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3341.
Abstract 3349: Differential expression of CD44 and CD24 markers discriminates the epithelioid from fibroblastoid subset in a sarcomatoid renal cell carcinoma cell line: evidence of the existence of cancer stem cells in both subsets
Authors: Hsieh Chin-Hsuan , Chuang Cheng-Keng , Pang See-Tung , Chien Samuel , Lin Paul , Liao Shuen-Kuei 
Published: July 2016

Abstract
The co-existence of epithelioid and fibroblastoid subsets in the human sarcomatoid renal carcinoma cell line, RCC52, has been demonstrated previously based on clonal studies, in which only the epithelioid subset was found to be tumorigenic in NOD/SCID mice. Since only few clonal isolates were used to analyze in that study, we argued that the tumorigenicity results might not be truly reflective of this tumor line. We therefore in this study determined to use cytofluorometrically sorted cells to re-evaluate certain biological parameters including xenotransplantation. Using two monoclonal antibodies to CD44 and CD24 markers, we succeeded in identification and isolation of the two populations, and showed the CD44bright/CD24dim and CD44bright/CD24bright phenotypes corresponding to the epithelioid and fibroblastoid subsets, respectively. At variance with the results of clonal studies, both cytofluorometrically sorted subsets displayed different but significant degrees of tumorigenicities, indicating that each subset harbored its own cancer stem cells (CSCs). In consistence with the tumorigenicity findings, both sorted subsets showed in vitro migratory/invasive potential with greater ability exhibited by the CD44bright/CD24bright subset which was associated with higher expression of MMP-7, -8 and TIMP-1 transcripts. On the other hand, the CD44bright/CD24dim subset was found to be associated with higher expression of MMP-2, -9 and TIMP-2 transcripts. Furthermore, both sorted subsets expressed the RCC stem cell marker CD105 in a small proportion of cells (4-5%), and were able to covert to PAX2+ clear cells in areas in the xenografts to a greater extent by the CD44bright/CD24dim subset, highlighting high plasticity of each subset in different ways. Collectively, our findings confirm the co-existence of two morphologically and phenotypically distinct subsets, and document the presence of CSCs in both subsets for the first time in sarcomatoid RCC. The CSCs/mCSCs in the two subsets should therefore be considered as emerging therapeutic targets in the design of future treatment strategies for this subtype of renal cancer.
Citation Format: Chin-Hsuan Hsieh, Cheng-Keng Chuang, See-Tung Pang, Samuel Chien, Paul Lin, Shuen-Kuei Liao. Differential expression of CD44 and CD24 markers discriminates the epithelioid from fibroblastoid subset in a sarcomatoid renal cell carcinoma cell line: evidence of the existence of cancer stem cells in both subsets. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3349.
Abstract 3358: Expression of ALDH1, Bmi-1 and CD24 in human oral squamous cell carcinoma and its relationship with clinical factors
Authors: Tamatani Tetsuya , Takamaru Natsumi , Fujisawa Kenji , Nagai Hirokazu , Miyamoto Youji 
Published: July 2016

Abstract
[Background] A cancer stem cell (cancer initiating cell, CSC) is considered capable of self -replication, self-differentiation, drug resistance, and immune evasion. Recently, CSC has become increasingly important in the treatment of malignant tumors. Cancer stem cells express specific molecules termed CSC marker, including aldehyde dehydrogenase (ALDH) 1, B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) and CD24, and their expression has been reported to be the potential prognostic values. However, the prognostic values of ALDH1, Bmi1, and CD24 expression in patients with oral cancer are less understood.
[Purpose] The aims of present study were to evaluate the expression of ALDH1, Bmi1, and CD24 in oral squamous cell carcinoma (OSCC) and to elucidate the relationships among the CSC marker expression, clinical stages, histological differentiation, the classification of invasion mode, cerebral lymph node metastasis and disease-free survival rate.
[Materials and Methods] Tissue specimens were obtains from 103 patients with OSCC after surgery or biopsy. Immunohistochemistry was used to assess ALDH1, Bmi1, and CD24 protein using at least 10% staining-positive cells as the definition of positive staining.
[Results] Immunohistochemical analysis of 103 cases showed that 31 cases (30%) expressed ALDH1. There was no relationship between ALDH1 expression and clinical stages or metastasis. However, there was significant association between ALDH1 expression and histological differentiation, or classification of invasion mode or disease-free survival rate. Otherwise, 39 cases (38%) cases of 103 OSCC patients expressed Bmi-1. There was significant association between Bmi-1 expression and invasion mode or disease-free survival rate. Sixty four cases (62%) expressed CD24. There was significant association between CD24 expression and histological differentiation.
[Conclusions] These findings suggested that the expression of ALDH1 and Bmi-1 as CSC markers in OSCC may be good marker indicating survival in patients with OSCC.
Citation Format: Tetsuya Tamatani, Natsumi Takamaru, Kenji Fujisawa, Hirokazu Nagai, Youji Miyamoto. Expression of ALDH1, Bmi-1 and CD24 in human oral squamous cell carcinoma and its relationship with clinical factors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3358.
Abstract 3360: EB-virus latent membrane protein 1 potentiates the stemness of nasopharyngealcarcinoma via preferential activation of PI3K/AKT pathway by a positive feedback loop
Authors: Yang Chang-Fu , Yang Guang-Da , Huang Tie-Jun , Huang Jia-Ling , Qian Chao-Nan , Huang Bi-Jun 
Published: July 2016

Abstract
Our previous study reported that Epstein-Barr virus(EBV)-encoded latent membrane protein 1 (LMP1) could induce development of CD44+/High stem-like cells in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms that underlie modulation of cancer stem cells (CSCs) in NPC remain unclear. Here, we show that LMP1 induced CSC-like properties through promotion of the expression of epithelial-mesenchymal transition (EMT)-like cellular markers and through alterations in differentiation markers. Furthermore, LMP1 activated and triggered PI3K/AKT pathway, which subsequently stimulated expression of CSC markers, development of side population (SP) and tumor sphere formation. This suggests that PI3K/AKT pathway plays an important role in the induction and maintenance of CSC properties in NPC. Similarly, PI3K/AKT pathway was also activated by phosphorylase in LMP1-induced CD44+/High cells. In addition, LMP1 greatly increased expression of miR-21 and down-regulated expression of the miR-21 target, PTEN. Overexpression of miR-21 by transfection of miR-21 mimics into LMP1-transformed cells led to phosphorylase-mediated activation of the PI3K/AKT pathway and induction of CSCs. On the contrary, phosphorylation of the PI3K/AKT pathway and the expression of CSC were reversed by a miR-21 inhibitor. The specific inhibitor (Ly294002) of PI3K/AKT pathway significantly decreased expression of miR-21 and CSC markers and up-regulated the expression of PTEN, which indicates that miR-21 and PTEN are the downstream effectors of PI3K/AKT and that expression of these two effectors are related to development of NPC CSCs. Taken together, our novel findings indicate that LMP1, PI3K/AKT, miR-21 and PTEN constitute a positive feedback loop and play a key role in LMP1-induced CSCs in NPC.
Citation Format: Chang-Fu Yang, Guang-Da Yang, Tie-Jun Huang, Jia-Ling Huang, Chao-Nan Qian, Bi-Jun Huang. EB-virus latent membrane protein 1 potentiates the stemness of nasopharyngealcarcinoma via preferential activation of PI3K/AKT pathway by a positive feedback loop. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3360.
Abstract 3362: Expression of CD44v9, a cancer stem cell marker, in human hepatocellular carcinoma
Authors: Wada Fumitaka 
Published: July 2016

Abstract
Background: CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration. This protein has recently been identified as one of the crucial cell surface markers for cancer stem cells (CSCs) in several types of tumor. It has recently been reported that CD44 variant 9 (CD44v9) interacted with the glutamate-cystine transporter xCT, thereby contributing to increased intracellular synthesis of glutathione (GSH), a strong scavenger of reactive oxygen species (ROS). CSCs having such mechanism are highly resistant to ROS (Cancer Cell 2011). Of note, the function of xCT is inhibited by sulfasalazine (Leukemia 2001), a commonly used drug for ulcerative colitis.
Aim: The aims of this study were to assess 1) the expression levels of CD44v9 and xCT in human HCC tissues and HCC cell lines, and 2) possible synergistic anti-tumor effect of cisplatin and sulfasalazine on HCC cells.
Methods: Thirty HCC tissues were subjected to immunohistochemistry for CD44v9 and xCT. The human HCC cell lines HAK-1A and HAK-1B were used. HAK-1B was an aggressive sister cell line derived from HAK-1A, a well-differentiated one (Hepatology 1993). The cells were incubated with cisplatin with or without sulfasalazine at concentrations of 0, 50, 100, and 200 μM under attached and sphere-forming conditions. Western blot analysis was employed to evaluate protein expression levels.
Results: Membranous localization of CD44v9 was found in 2 HCC tissues, that were moderately and poorly differentiated ones. In such cases, the standard isoform CD44s was also strongly expressed. Expression levels of xCT were ubiquitously demonstrated in all HCC cases studied; however, it was robustly upregulated in sphere-formed HAK-1B cells, in concert with the upregulation of CD44v9 in these cells. Sphere formation of HAK-1B was significantly inhibited by co-treatment with cisplatin and sulfasalazine in a dose-dependent manner.
Conclusions: The CD44v9-xCT system was demonstrated in less differentiated HCC tissues. Indeed, poorly differentiated HCC cells (HAK-1B) under sphere formation robustly expressed both CD44v9 and xCT, suggesting that CSC-like cells favored this system. To overcome the ROS resistance of CSCs, delivering sulfasalazine in combination with anti-cancer drugs may open a new avenue to a promising treatment of chemorefractory HCC.
Citation Format: Fumitaka Wada. Expression of CD44v9, a cancer stem cell marker, in human hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3362.