bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3861: Hyaluronan-CD44v3 interaction with oct4/sox2/nanog promotes miR-302 expression leading to self-renewal, clonal formation and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma
Authors: Bourguignon Lilly Y W , Wong Gabriel , Earle Christine 
Published: May 2015

Abstract
Human Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly malignant cancer associated with major morbidity and mortality. In this study we determined that human HNSCC-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high levels of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. These tumor cells also express several stem cell markers (the transcription factors-Oct4, Sox2 and Nanog) and display the hallmark CSC properties of self-renewal/clonal formation and the ability to generate heterogeneous cell populations.
Importantly, hyaluronan (HA) stimulates the CD44v3 (an HA receptor) interaction with Oct4/Sox2/Nanog leading to both a complex formation and the nuclear translocation of three CSC transcription factors. Further analysis reveals that microRNA-302 (miR-302) is controlled by an upstream promoter containing Oct4/Sox2/Nanog binding sites, while chromatin immunoprecipitation (ChIP) assays demonstrate that stimulation of miR-302 expression by HA/CD44 is Oct4/Sox2/Nanog-dependent in HNSCC-specific CSCs. This process results in suppression of several epigenetic regulators (AOF1/AOF2 and DNMT1) and the upregulation of several survival proteins (cIAP-1, cIAP-2 and XIAP) leading to self-renewal, clonal formation and cisplatin resistance. These CSCs were transfected with a specific anti-miR-302 inhibitor in order to silence miR-302 expression and block its target functions. Our results demonstrate that the anti-miR-302 inhibitor not only enhances the expression of AOF1/AOF2 and DNMT1, but also abrogates the production of cIAP-1, cIAP-2 and XIAP and HA/CD44v3-mediated cancer stem cell functions. Taken together, these findings strongly support the contention that the HA-induced CD44v3 interaction with Oct4/Sox2/Nanog signaling plays a pivotal role in miR-302 production leading to AOF1/AOF2/DNMT1 downregulation and survival protein activation. All of these events are critically important for the acquisition of cancer stem cell properties including self-renewal, clonal formation and chemotherapy resistance in HA/CD44v3-activated head and neck cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Lilly Y W Bourguignon, Gabriel Wong, Christine Earle. Hyaluronan-CD44v3 interaction with oct4/sox2/nanog promotes miR-302 expression leading to self-renewal, clonal formation and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3861. doi:10.1158/1538-7445.AM2014-3861
Abstract 3865: ATOH8 depletion can reprogram noncancer stem cells into cancer stem cells
Authors: Song Yangyang , Guan Xin-Yuan 
Published: May 2015

Abstract
Introduction:
The development of hepatocellular carcinoma (HCC), one of the most lethal of human malignancies, is caused by the accumulation of multiple genetic and epigenetic alterations. Recent advances in cancer stem cell (CSC) study have associated the poor prognosis of cancer with CSC. ATOH8 is a nucleus factor with an obvious structural similarity to the Drosophila proneural gene atonal. The aim of this study is to investigated the role of ATOH8 in CSC and its therapeutic potentials for HCC treatment.
Experimental procedures:
The clinical significance of ATOH8 in a cohort of 242 HCC cases was assessed by clinical correlation and Kaplan-Meier survival analyses. ATOH8-overexpressing and scliencing cell model was generated by Lentivirus system to detect its functional roles in HCC both in vivo and in vitro. iPS technology is used to analyze effects of ATOH8 on CSCs.
Result:
Downregulation of ATOH8 was detected in over 40% of 242 pairs primary HCC cases, which was significantly associated with disease free survival (P=0.031), high level of AFP (P=0.03) and diferentiation (P=0.01). Functional studies demonstrate the tumor suppressive role of ATOH8 in HCC, including the inhibition of cell growth, cell proliferation, tumor formation in SCID mice and cell motility when ATOH8 was introduced into HCC cells. Further study finds that ATOH8 depletion can enhance the stemness of HCC including the tumorigenicity and abilities for self-renewal, differentiation and chemo-resistance by repressing the transcription of stemness-related genes such as OCT4, NANOG, SOX2, AFP, and HCC cancer stem cell (CSC) surface markers such as CD24 and CD133. One interesting finding in this study is that knockdown of ATOH8 could increase CD133+ cell population in QSG7701 and BEL7402 cells. CD133+ cells induced by ATOH8 depletion were flow-sorted and their CSC property was characterized. The results found that flow-sorted CD133+ cells induced by ATOH8 depletion possessed most characteristics of CSC including the capacity to self-renew, differentiation, sustained proliferation and chemoresistance. In addition, ATOH8 depletion could enhance the frequency of pluripotent stem cells (iPSC) generation induced by 4 factors (OCT4, Sox2, Klf4 and cMyc). All these data strongly suggest that a non-CSC could be reprogrammed into a CSC under some circumstance such as downregulation of ATOH8.
Conclusion:
This study demonstrates that ATOH8 plays an important role in HCC development, and provides a potential new HCC therapeutic approach that ATOH8 could increase the chemosensitivity of HCC cells to chemotherapeutics as demonstrated in this study.
Citation Format: Yangyang Song, Xin-Yuan Guan. ATOH8 depletion can reprogram noncancer stem cells into cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3865. doi:10.1158/1538-7445.AM2014-3865
Abstract 3867: ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell
Authors: Maurer Jochen , Castro David J. , Kim Mihee , Oshima Robert G. 
Published: May 2015

Abstract
The differentiation of stem-like tumor cells may contribute to the cellular heterogeneity of breast cancers. We report the propagation of highly enriched mouse mammary cancer stem cells that retain the potential to differentiate both in vivo and in culture and their use to identify chemical compounds that influence both self-renewal and differentiation. We identify epithelial tumor initiating cells (ETICs) that express lineage markers of both basal and luminal mammary cell lineages and retain the potential, from even single cells, to generate heterogeneous tumors similar to the tumor of origin. ETICs can progress through a Rho associated coiled-coil containing protein kinase 1 (ROCK1) dependent, epithelial to mesenchymal transition to generate mesenchymal tumor initiating cells (MTICs) capable of initiating tumors of limited heterogeneity. The propagation of ETICs may allow for the identification of new therapeutic compounds that may inhibit or prevent progression of some types of breast cancer.
Citation Format: Jochen Maurer, David J. Castro, Mihee Kim, Robert G. Oshima. ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3867. doi:10.1158/1538-7445.AM2014-3867
Abstract 3872: Identification and characterization of ITGA7 as cancer stem cell marker in esophageal squamous cell carcinoma (ESCC)
Authors: Ming Xiaoyan , Fu Li , Zhang Liyi , Guan Xinyuan 
Published: May 2015

Abstract
Cancer stem cells (CSCs) are widely accepted as a specific subpopulation of cells responsible for cancer initiation and progression. CSCs have yet to be identified in ESCC that have an increasing incidence in developed countries. Our recent study in esophageal squamous cell carcinoma (ESCC) has led to the identification of ITGA7 as a functional CSCs marker. ITGA7+ cell population is endowed with stem cell-like properties and high tumorigenic and metastatic potential. ITGA7+ CSCs isolated from ESCC cell lines possessed higher self-renewal activity and were sufficient for tumor initiation, differentiation, and metastasis compared to ITGA7- ESCC cells. Functional studies using lentiviral-based overexpression and suppression systems demonstrated that ITGA7 can promote tumor initiation and metastasis through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway and epithelial-mesenchymal transition. Further characterization of ITGA7+ population may provide a prognostic biomarker for ESCC outcome prediction and a potential therapeutic target.
Citation Format: Xiaoyan Ming, Li Fu, Liyi Zhang, Xinyuan Guan. Identification and characterization of ITGA7 as cancer stem cell marker in esophageal squamous cell carcinoma (ESCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3872. doi:10.1158/1538-7445.AM2014-3872
Abstract 3879: Crosstalk initiated by endothelial cells endows head and neck cancer stem cells with an invasive phenotype
Authors: Kim Hong S. , Zhang Zhaocheng , Warner Kristy A. , Finkel Kelsey A. , Adams April , Nor Jacques E. 
Published: May 2015

Abstract
Head and neck squamous cell carcinomas contain a sub-population of uniquely tumorigenic cells (named cancer stem cells) that are thought to participate in metastatic dissemination. We have previously shown that head and neck cancer stem cells (HNCSC) can be identified as ALDHhighCD44high and reside within the perivascular niche, in close proximity to blood vessels. Therefore, it is possible that a crosstalk between HNCSC and endothelial cells plays a functional role in metastatic spread. Here, we hypothesize that factors secreted by endothelial cells enhance motility and invasiveness of HNCSC. We observed that endothelial cell-derived factors induced epithelial-mesenchymal transition (EMT) of unsorted head and neck squamous cell carcinoma (HNSCC) cells, as demonstrated by decreased expression of epithelial markers (e.g. Desmoplakin), enhanced expression mesenchymal cell markers (e.g. Vimentin) and transcriptional regulators of EMT (e.g. Snail), and enhanced migration of these cells. Further, endothelial cell-secreted factors enhanced the orosphere forming-ability of HNSCC plated in ultra-low attachment plates, enhanced the fraction of ALDHhighCD44high cells, and expression of Bmi-1. Similarly, HNCSC had increased number of orospheres and enhanced motility in the presence of endothelial cell-derived factors. Taken together, these data indicate that a crosstalk initiated by endothelial cells endows head and neck cancer cells with high motility and a stem-like phenotype, and suggest that endothelial cells may play an active role in the initial steps of metastatic spread. Support for this work was provided by grant R01-DE21139 from the NIH/NIDCR, and grant P50-CA97248 (University of Michigan Head Neck SPORE) from the NIH/NCI.
Citation Format: Hong S. Kim, Zhaocheng Zhang, Kristy A. Warner, Kelsey A. Finkel, April Adams, Jacques E. Nor. Crosstalk initiated by endothelial cells endows head and neck cancer stem cells with an invasive phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3879. doi:10.1158/1538-7445.AM2014-3879
Abstract 3881: A distinct DNA methylation signature defines breast cancer stem cells and predict cancer outcome
Authors: Helou Rita E. , Wicinski Julien , Guille Arnaud , Adelaide Jose , Finetti Pascal , Bertucci Francois , Chaffanet Max , Birnbaum Daniel , Charafe-Jauffret Emmanuelle , Ginestier Christophe 
Published: May 2015

Abstract
Pluripotency of stem cells depends on epigenetic programs that regulate self-renewal and differentiation. During oncogenesis, dysregulation of these two programs leads to the development of cancer stem cells (CSCs). Recent evidence suggests that CSCs are relatively resistant to conventional therapies and responsible for metastasis formation. Deciphering these processes will help gain insight into oncogenesis and allow the development of new targeted therapies. We used a whole-genomic promoter microarray to establish the DNA methylation portrait of breast cancer stem cells (bCSC) and compared it to non-bCSC. bCSC from five breast cancer cell lines were isolated using the ALDEFLUOR assay. We identified a DNA methylation signature with 68 differentially methylated regions (DMRs) that were hypomethylated in bCSCs as compared to non-bCSCs. Using a differentiation assay we demonstrated that DMRs are rapidly hypermethylated within the first six hours following induction of CSC differentiation whereas the cells reached the steady-state within 6 days, suggesting that these DMRs are linked to early CSC epigenetic regulation. DMRs were enriched in genes coding for TGFβ signaling-related proteins. Interestingly, overexpression of TGFβ signaling genes was correlated to DMRs hypomethylation in a series of 109 breast tumors. Moreover, the tumors harboring the bCSC DMRs signature had a worse evolution than the ones with the non-bCSC DMRs signature. Our results provide evidence that bCSCs harbor a distinct DNA methylation landscape with TGFβ signaling as a key epigenetic regulator of bCSCs differentiation.
Note: This abstract was not presented at the meeting.
Citation Format: Rita El Helou, Julien Wicinski, Arnaud Guille, Jose Adelaide, Pascal Finetti, Francois Bertucci, Max Chaffanet, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Christophe Ginestier. A distinct DNA methylation signature defines breast cancer stem cells and predict cancer outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3881. doi:10.1158/1538-7445.AM2014-3881
Abstract 3883: Thyroid cancer cells with low proteasome activity have therapeutic resistance
Authors: Fukusumi Takahito , Ishii Hideshi , Konno Masamitsu , Nishikawa Shimpei , Kano Yoshihiro , Hasegawa Shinichiro , Ogawa Hisataka , Hamabe Atsushi , Noguchi Kozo , Miyo Masaaki , Satoh Taroh , Doki Yuichiro , Mori Masaki , Inohara Hidenori 
Published: May 2015

Abstract
Background
Thyroid cancer is the most frequent endocrine malignancy with a global increasing incidence. Papillary, follicular, and anaplastic thyroid carcinomas arise from endodermal-derived follicular cells, which represent the most abundant cellular population of the thyroid gland. The recent discovery of cancer stem cells (CSCs) in a variety of tumors has changed the view of carcinogenesis and therapeutic resistance. Therefore, the identification of CSCs in thyroid cancer represents a crucial step to elucidate the mechanism of therapeutic resistance, and develop effective therapies. It was previously reported that low intrinsic proteasome activity in glioma, pancreas, prostate, and breast cancer cells correlated with therapeutic resistance and CSCs properties. We hypothesized that a therapeutic resistant cell population with intrinsically low 26S proteasome activity can also be found in thyroid cancer.
Materials and Methods
We engineered human thyroid cancer cell lines (TPC-1, FRO, and WRO) to express a green fluorescent molecule fused to the degron of ornithine decarboxylase from a retroviral vector. The green fluorescence accumulates in a small population of these cells as a result of low activity of the 26S proteasome.
Result
We identified a small population of cells with intrinsically low 26S proteasome activity in all thyroid cell lines. These populations have cisplatin, 5-FU, and radio-resistance. To further investigate differences between thyroid cancer cells with high and low proteasome activity, we studied their self-renewal capacity and tumorigenicity using an in vitro sphere-forming assay and an in vivo xenograft transplantation assay.
Conclusion
We conclude that established thyroid cancer cell lines are heterogeneous with regard to their intrinsic proteasome activity and that they contain a therapeutic resistant subpopulation of cells that can be identified by low proteasome activity. Further studies are needed to elucidate the mechanism that thyroid cancer cells with low proteasome activity have these properties.
Learning Objective
We identified thyroid cancer cells with low proteasome activity have therapeutic resistance and CSCs properties.
Citation Format: Takahito Fukusumi, Hideshi Ishii, Masamitsu Konno, Shimpei Nishikawa, Yoshihiro Kano, Shinichiro Hasegawa, Hisataka Ogawa, Atsushi Hamabe, Kozo Noguchi, Masaaki Miyo, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hidenori Inohara. Thyroid cancer cells with low proteasome activity have therapeutic resistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3883. doi:10.1158/1538-7445.AM2014-3883
Abstract 3888: Expression of ABCG2, ALDH1A1, CD44, and CD44 variant 9 in human oral squamous cell carcinoma and its relationship with clinical factors
Authors: Tamatani Tetsuya , Takamaru Natsumi , Kinouchi Makoto , Kuribayashi Nobuyuki , Uchida Daisuke , Nagai Hirokazu , Miyamoto Youji 
Published: May 2015

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 ATP-binding cassette, G2 subfamily (ABCG2), aldehyde dehydrogenase (ALDH) 1A1, CD44, and CD44 variant 9 (CD44v9), and their expression has been reported to be the potential prognostic values. However, the prognostic values of ABCG2, ALDH1A1, CD44, and CD44v9 expression in patients with oral cancer are less understood.
[Purpose] The aims of present study were to evaluate the expression of ABCG2, ALDH1A1, CD44, and CD44v9 in oral squamous cell carcinoma (OSCC) and to elucidate the relationships among the CSC marker expression, clinical stages, histological differentiation, classification of invasion mode, lymph node metastasis and disease-free survival rate.
[Materials and Methods] Tissue specimens were obtains from 99 patients with OSCC after surgery or biopsy. Immunohistochemistry was used to assess ABCG2, ALDH1A1, CD44, and CD44v9 protein using at least 10% staining-positive cells as the definition of positive staining.
[Results] Immunohistochemical analysis of 99 cases of OSCC showed that CD44 and CD44v9 expression were strongly detected in all OSCC compared with normal epithelial cells. Twenty eight (28.2%) cases of 99 OSCC patients expressed ABCG2. There was no relationship between ABCG2 expression and clinical stages, histological differentiation, metastasis, or disease-free survival rate. There was significant association between ABCG2 expression and classification of invasion mode. Otherwise, thirty one (31.3%) cases of 99 OSCC patients expressed ALDH1A1. There was no relationship between ALDH1A1 expression and clinical stagesor metastasis. However, there was significant association between ALDH1 expression and histological differentiation, or classification of invasion mode or disease-free survivalrate. [Conclusions] These findings suggested that the expression of ALDH1A1 as CSC markers in OSCC may be good marker indicating survival in patients with OSCC.
Citation Format: Tetsuya Tamatani, Natsumi Takamaru, Makoto Kinouchi, Nobuyuki Kuribayashi, Daisuke Uchida, Hirokazu Nagai, Youji Miyamoto. Expression of ABCG2, ALDH1A1, CD44, and CD44 variant 9 in human oral squamous cell carcinoma and its relationship with clinical factors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3888. doi:10.1158/1538-7445.AM2014-3888
Abstract 3891: CD133 is associated with resistance of melanoma to multikinase inhibition
Authors: Zhou Hengbo , Abdussamad Maryam , Alomari Amani , Gaur Anirudh , Rosenthal Cynthia S. , Zapas John L. , Rosenthal Dean S. 
Published: May 2015

Abstract
Purpose: High-risk melanoma is a lethal cancer with a high recurrence rates and variable disease-free intervals, due to tumorigenic cell populations that are resistant to treatment. Prominin 1 (CD133) is a putative stem cell marker in a number of cancers, based on its expression in cells that possess greater tumorigenicity, motility and colony-forming ability in different types of cancer. Furthermore, Prominin 1 is highly expressed in late-stage metastatic melanoma showing its potential as a marker of a resistant cell population. Trametinib and dabrafenib are targeted kinase inhibitors recently approved by the FDA, and now widely used for treatment of melanoma, while the anthelmintic drug mebendazole, a multikinase inhibitor, also exhibits promising anticancer potential. The purpose of this study was to test the relative resistance of CD133+ and CD133- cells to these three agents, as well as to explore potential mechanisms underlying any differences.
Design: Three melanoma cell lines with different kinase mutation profiles were exposed to increasing concentrations of trametinib, dabrafenib, or mebendazole alone, or in combination, either before or after separation into CD133-positive and CD133-negative populations. Cells were then assayed for cell viability and CD133-positivity. Microarray analysis was performed on CD133-positive and CD133-negative cells to explore potential differences in gene expression profiles.
Result: In all parental cell lines, the percentages of the CD133-positive cells increased significantly (P&lt;0.05) after high-dose drug treatment. The CD133-positive, drug resistant cells showed reduced proliferation until after the drug was removed. Correspondingly, the presorted CD133-positive population exhibited significantly higher (P&lt;0.05) IC50s both for single and multidrug treatment. Microarray analysis revealed a significant (P&lt;0.001, &gt;1.5-fold) difference in expression of 265 genes in CD133-positive cells, including putative oncogenes such as POU5F1, NPM1, NES and MYC. Also, 10 of 18 ABC transporter genes were significantly (P&lt;0.05) up-regulated in the CD133-positive population.
Conclusion: Both purified and mixed population-derived CD133 positive cells are more resistant to the three kinase inhibitors. Upregulation of ABC transporter genes and/or oncogenes may contribute to the drug resistance of CD133-positive cells.
Citation Format: Hengbo Zhou, Maryam Abdussamad, Amani Alomari, Anirudh Gaur, Cynthia S. Rosenthal, John L. Zapas, Dean S. Rosenthal. CD133 is associated with resistance of melanoma to multikinase inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3891. doi:10.1158/1538-7445.AM2014-3891