bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 422: (-)-Epigallocatechin-3-gallate inhibits the metastatic potential of colon cancer
Authors: Kaneko Manabu , Tsuno Nelson H. , Kawai Kazushige , Nishikawa Takeshi , Shuno Yasutaka , Sasaki Kazuhito , Hongo Kumiko , Hiyoshi Masaya , Sunami Eiji , Kitayama Joji , Takahashi Koki , Nagawa Hirokazu 
Published: February 2011

Abstract
Objective: Green tea catechins have been shown to be potential chemopreventive agents against various types of cancer Among them, Epigallocatechin-3-gallate (EGCG), which accounts for almost 50% of the total catechin content in green tea extract, has been focused due to its potent antioxidant effects. EGCG inhibits enzyme activities and signal transduction pathways, resulting in the suppression of cell proliferation and enhancement of apoptosis. Also, it is reported to inhibit cell invasion, angiogenesis and metastasis. However, the exact mechanisms of the anti-proliferative/anti-metastatic activities of EGCG are not completely understood. In the present study, we aimed to investigate the mechanisms of the inhibitory effect of EGCG on colon cancer cells, especially focusing on cell adhesion.
Methods: HT-29 human colon cancer cells were used. The effect of EGCG on the proliferative activity was investigated by the MTS assay. The expression of integrins was analyzed by flow-cytometry. Apoptosis induction was analyzed by flow-cytometry after double-staining of cells with AnnexinV/PI. The ability of cells to adhere to extracellular matrix (ECM) proteins was tested by the adhesion assay on fibronectin, collagen and laminin.
Results: EGCG dose-dependently decreased the ability of HT-29 cells to proliferate on and adhere to ECM proteins. The amount of cell surface integrins, however, was not affected by EGCG. Additionally, EGCG treatment did not induce apoptosis of HT-29 cells. Therefore, the affection of the proliferative activity by EGCG was attributed to anoikis.
Conclusions: EGCG dose-dependently decreased the ability of colon cancer cells to proliferate on and to adhere to ECM proteins. It was not dependent on changes in the expression of β1-integrins, but on the affection of the ability of β1-integrins to bind the ECM proteins. Binding to the ECM proteins is an important event for cancer cells to proliferate, migrate, invade, and form metastatic lesions. Therefore, EGCG, by affecting the ability of colon cancer cells to adhere to ECM proteins, may be a potential agent for the prevention and/or treatment of colon cancer metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 422.
Abstract 4226: A luminal epithelial cell line isolated from PTEN−/−;P53−/− mouse protospheres forms adenocarcinoma in vivo
Authors: Hynes Paul G. , Abou-Kheir Wassim G. , Liu Yen-Nien , Martin Philip , Kelly Kathleen 
Published: February 2011

Abstract
Pten deletion in the mouse prostate epithelium results in the expansion of a prostatic stem/progenitor cell subpopulation, which co-fractionates with basal epithelial cells. Progenitor cells in the luminal layer of Pten null prostates also have been suggested as tumor initiating cells. Here we describe the isolation of a protosphere-derived, androgen independent cell line with a luminal epithelial phenotype that displays properties of prostate progenitor cells and forms adenocarcinoma in-vivo. The cell line was generated from Rosa26-CreERPtenfl/flP53fl/fl prostate cells. Cells were plated to form protospheres, which originate from stem/progenitor cells, and the deletion of Pten and p53 was induced by tamoxifen. After spheres were serially passaged for 3 generations, a monolayer cell line capable of growth in minimal serum-free media was established. A clonal line also was generated from the parental cell line. In order to determine the differentiated cell phenotype of the parental and the clonal cell lines, cells were stained over multiple generations for markers of epithelial (CK5, CK8, CK14) and neuroendocrine (beta 3 tubulin) cell lineages. The cell line is entirely CK8 positive with a minor component of CK8/CK14 double positive cells. Cells are capable of forming protospheres both in Matrigel and in suspension, a property of stem/progenitor cells. In addition, based on lentiviral reporter assays, a minor population of cells in the parental and the clonal cell line expressed Nanog, Oct4 and Notch dependent activity. Interestingly, Nanog and Oct4 positive cells showed higher sphere forming ability as compared to negative cells. In order to investigate their tumorigenic potential, the parental and the cloned lines were injected subcutaneously into athymic nude mice. Visible tumor formation was observed after 2 weeks, and histological analysis revealed adenocarcinoma and poorly differentiated carcinoma. In addition to CK8+ cells within the tumors, there were rare CK5+ and neuroendocrine cells, suggesting plasticity in the differentiation potential. In conclusion, we have isolated a prostate luminal epithelial cell line and derivative clones with a defined background (Pten and p53 null) that have stem-like and tumor initiating properties in vitro and in vivo. Future experiments are aimed at deciphering the molecular mechanisms regulating growth and differentiation downstream of Pten and p53 loss.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4226.
Abstract 4233: Dysregulated expression of stem cell transcription factor Nanog in development and progress of ovarian cancers
Authors: Siu Michelle KY , Wong Esther SY , Kong Daniel SH , Wong Oscar GW , Tam Kar Fai , Ngan Hextan YS , Le Xiao Feng , Cheung Annie NY 
Published: February 2011

Abstract
Introduction: Ovarian cancer is the most lethal of all gynecological malignacies due to its lack of symptoms at early stages. In addition, widespread intraperitoneal metastases and malignant ascites frequently develop. Therefore, it is very important to identify novel prognostic and therapeutic targets for this cancer. Many researchers believe that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. Nanog is one of core transcription factors essential for the maintaining self-renewal and pluripotency in stem cells. This study investigated the clinical significance, functional roles and putative downstream targets of Nanog in ovarian cancer. Methods and Results: Differential protein expression profile of Nanog in clinical samples, including benign (n=6), borderline (n=7), carcinomas (n=97) and metastatic foci (n=24) were determined by immunohistochemistry. Differential mRNA expression pattern of Nanog in 3 normal ovarian epithelial cell lines, 16 ovarian cancer cell lines was assessed by quantitative real-time polymerase chain reaction. Subcellular localization of Nanog was performed by Western blotting. Nanog was found to be localized in the nucleus of ovarian cancers. High Nanog expression in ovarian cancers was significantly associated with high grade tumors, serous histological type and chemoresistance (p&lt;0.05). Importantly, Nanog was found to be highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Elevated Nanog expression was associated with poor overall and disease-free survival in the univariate analysis. Nanog expression became one of the independent prognostic factors in the multivariate analysis for overall but not disease-free survival. By Transwell migration and invasion assays, stable knockdown of Nanog in ovarian cancer cell line, OVCAR-3, impeded cell migration and invasion. Stable knockdown of Nanog also increased mRNA expression of E-cadherin (an essential epithelial mesenchymal transition marker, thus related to metastasis) and FOXO1A (an important gene related to chemoresistance). Conclusion: Nanog was associated with progression of ovarian tumors, patients’ overall survival and chemoresistance, suggesting that Nanog can be one of the potential prognostic markers and therapeutic molecular targets in ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4233.
Abstract 4236: Characterization of maternal embryonic leucine zipper kinase in cancer stem/progenitor cells
Authors: Okemoto-Nakamura Yuko , Kornblum Harley I. , Nakano Ichiro 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM) is the most frequent tumor in the adult brain and remains a highly lethal diseases. Recent studies have suggested that lack of targeted therapies for brain tumor stem cells (BTSC) is one of the reasons for the limited efficacy of the current therapies. Identification of the molecular target in BTSC is crucial to the development of GBM therapy.
Maternal embryonic leucine zipper kinase (MELK) is a member of Snf1/AMP serine/threonine kinase family and abundantly expressed in multiple cancers, including GBM. Previously, we demonstrated that the RNA expression of MELK is elevated in patient-derived tumor stem-like cells in GBM. Knockdown of MELK of tumor stem-like cells by siRNA resulted in apoptosis in vitro. In contrast, knockdown of MELK did not induce significant apoptosis in normal neural progenitors derived from mouse brains, raising a possibility that MELK is likely required for survival of tumor stem cells but not the normal counterpart. However, the difference in the mechanism of MELK action between tumor and normal stem cells is unknown. Here we investigated to discriminate the signaling pathways that regulate survival and proliferation of BTSC and normal neural stem cells.
Immunohistochemistry showed that MELK is abundantly expressed in surgical specimens of GBM and is mainly localized in the nuclei. Immunocytochemistry with patient-derived GBM spheres demonstrated that MELK is preferentially expressed by GBM stem-like cells but not in the differentiated tumor cells. We also found that MELK is phosphorylated at serine and threonine residues in GBM stem-like cells. To determine the signaling pathways that regulate MELK phophorylation in GBM stem cells, we treated GBM stem-like cells with a variety of the kinase inhibitors. Interestingly, a mitogen-activated protein (MAP) kinase inhibitor reduced the MELK protein expression in GBM stem-like cells but not in the normal counterpart. The MAP kinase pathway was up-regulated in GBM stem-like cells in comparison to the normal progenitors derived from human fetal brains, further supporting the significance of this pathway in GBM stem cells. Collectively, our data indicate that MAP kinase may regulate MELK phosphorylation and activation specifically in GBM stem cells but not in the normal neural stem cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4236.
Abstract 4243: HMGA1: A driver of the stem cell phenotype in intestinal cyrpt cells and colon cancer
Authors: Belton Amy M. , Gabrovsky Alexander , Iacobuzio-Donahue Christine , Almeida-Porada Graça , Colletti Evan , Huso David , Smith-Resar Linda 
Published: February 2011

Abstract
Although the HMGA1 gene is highly expressed in human embryonic stem cells and high-grade, poorly differentiated cancers, its function in these settings has not been clearly elucidated. The HMGA1 gene encodes the HMGA1a and HMGA1b protein isoforms, which are members of a family of non-histone, chromatin remodeling proteins. These proteins bind to the minor groove of AT-rich regions in the B-form of DNA, which leads to the recruitment of transcriptional factors that modulate gene expression. The HMGA1 gene is highly expressed during embryogenesis and in aggressive human cancers arising from different embryologic origins, including cancers of hematopoietic, lung, breast, prostate, and colon cells. Forced overexpression of HMGA1a or HMGA1b induces a transformed phenotype in cultured cells and inhibiting HMGA1 blocks transformation in human cancer cell lines. Because HMGA1 functions in transcriptional regulation, we hypothesize that it induces neoplastic transformation by dysregulating specific molecular pathways. To investigate the pathways disrupted by HMGA1, we are studying our HMGA1a transgenic mice as a model system. As previously reported, these mice develop aggressive T-cell leukemia with complete penetrance and females also develop uterine cancer. At necropsy, we also discovered polyps involving the small and large intestines. Histopathologically, the transgenic intestines are characterized by a thickened mucosal surface, hyperproliferative changes, and hamartomatous polyps. Immunohistochemical analysis reveals an increase in the population of intestinal cells expressing the colon stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr-5) in transgenic compared to wildtype mice. These data support our observation of an expansion in the crypt progenitor/intestinal stem cell populations. Our preliminary results also show that inhibiting HMGA1 expression in colon cancer cell lines interferes with anchorage-independent cell growth and tumorigenesis, indicating that HMGA1 is required for these transformation phenotypes in colon cancer. In addition, we found that HMGA1 is enriched in &gt;70% of primary tumors with high-grade colon cancer. These findings suggest that HMGA1 is important in maintaining the stem cell niche in the intestine. Moreover, HMGA1 could promote neoplastic transformation and tumor progression in the intestine by driving a stem-like phenotype in colonic cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4243.
Abstract 4261: Inhibition of Bmi-1 suppressed the tumorigenicity of oral cancer-derived ALDH1-positive cells
Authors: Shih-Hwa Chiou 
Published: February 2011

Abstract
Bmi-1, a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal abilities of adult stem cells. Bmi-1 has been demonstrated to play a role in tumorigenesis in head and neck squamous cell carcinomas (HNSCCs). A recent study has further suggested that ALDH1 may be considered to be a putative marker for HNSCC-derived cancer stem cells. However, the role that Bmi-1 plays in HNSCC-derived ALDH1-positive cells (HNSCC- ALDH1+) has yet to be determined. In this study, we demonstrated that HNSCC- ALDH1+ cells possess tumor initiating properties, are capable of self-renewal, and express higher levels of Bmi-1 as compared to HNSCC-ALDH1− cells. To further explore the functional role of Bmi-1 in HNSCC-ALDH1+ cells, we used a lentiviral vector expressing shRNA to knock down Bmi-1 expression (sh-Bmi-1) in HNSCC- ALDH1+ cells. Silencing of Bmi-1 significantly enhanced the sensitivity of HNSCC- ALDH1+ cells to chemoradiation and increased the degree of chemoradiation- mediated apoptosis that occurred. Importantly, knockdown of Bmi-1 increased the effectiveness of radiotherapy and led to the inhibition of tumor growth in nude mice transplanted with HNSCC-ALDH1+ cells. Kaplan-Meier survival analysis indicated that the mean survival rate of HNSCC-ALDH1+ tumor-bearing immunocompromised mice treated with radiotherapy was significantly improved by treatment with sh-Bmi-1 as well. In summary, these results suggest that Bmi-1 is a potential target for increasing the sensitivity of HNSCC cancer stem cells to chemoradiotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4261.
Abstract 4271: Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells
Authors: Li Yanyan , Zhang Tao , Korkaya Hasan , Liu Suling , Lee Hsiu-Fang , Newman Bryan , Yu Yanke , Clouthier Shawn , Schwartz Steven , Wicha Max , Sun Duxin 
Published: February 2011

Abstract
Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells
The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. The purpose of this study was to evaluate sulforaphane, a naturally occurring dietary compound from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs as well as to elucidate the potential mechanisms of its effect. Aldefluor and mammosphere formation assays were used to assess the effect of sulforaphane on breast CSCs in vitro. A NOD/SCID xenograft model was employed to determine the efficacy of sulforaphane in targeting breast CSCs in vivo. The potential mechanism of sulforaphane was investigated utilizing Western blotting and β-catenin reporter assays. The results showed that sulforaphane (1∼5 µM) decreased aldehyde dehydrogenase (ALDH)-positive cell population by 65%∼80% in human breast cancer cell line (P &lt; 0.01), and reduced the size and number of primary mammospheres by 8∼125-fold and 50%∼75% (P &lt; 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for two weeks reduced ALDH-positive cells by more than 50% in tumors (P = 0.003). Furthermore, sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor re-growth in secondary mice (P &lt; 0.01). Western blotting showed that sulforaphane down-regulated the Wnt/β-catenin self-renewal pathway. These data suggest that sulforaphane targets breast CSCs through the down-regulation of the Wnt/β-catenin pathway as a potential mechanism. These findings provide a scientific rationale for use of sulforaphane and potentially broccoli/broccoli sprout dietary interventions for breast cancer chemoprevention.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4271.
Abstract 4280: Color-coded in vivo imaging of tumor stem cells and co-implanted non-stem cancer cells
Authors: Suetsugu Atsushi , Osawa Yosuke , Nagaki Mashito , Moriwaki Hisataka , Bouvet Michael , Hoffman Robert M. 
Published: February 2011

Abstract
We have developed color-coded simultaneous imaging of tumor growth, metastasis and drug resistance of co-implanted cancer stem cells (CSC) and non stem cancer cells (NSCC). In this study, CD 133+ Huh-7 human hepatoma cells were considered as liver cancer CSC, and CD133− Huh-7 cells were considered liver cancer NSCC. CD133+ cells were isolated by magnetic bead sorting. CSC were labeled with GFP and NSCC were labeled with RFP using retroviruses. The same number of GFP CSC and the RFP NSCC were mixed and co-cultured or injected subcutaneously or in the spleen of nude mice. CSC had higher proliferative potential compared with NSCC in vitro. Dual-color imaging demonstrated that CSC were more tumorigenic and more resistant to chemotherapy in vivo than NSCC. To compare the effect of CSC and NSCC on stromal cells or blood vessels in tumors, non-colored CSC or NSCC along with RFP stromal cells were implanted into nestin driven (ND)-GFP transgenic nude mice which express ND-GFP in nascent blood vessels. Extensive RFP-expressing stromal and GFP-expressing nascent blood vessels cells were imaged in the tumors formed from CSC. Tumors formed from NSCCs had less GFP-expressing nascent blood vessels and RFP-expressing stromal cells suggesting that more stromal cells and blood vessels were induced by CSC than NSCC. Thus, liver cancer CSC have more malignant characteristics such as higher proliferation, more resistance to chemotherapy, and induction of stromal cells and blood vessels compared with NSCC. Color-coded imaging of CSC and NSCC is a powerful tool to investigate the characteristics and roles of CSC and NSCC in tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4280.
Abstract 4281: Oncostatin M renders epithelial cell adhesion molecule-positive liver cancer stem cells sensitive to 5-fluorouracil by inducing hepatocytic differentiation
Authors: Yamashita Taro , Honda Masao , Nio Kouki , Kaneko Shuichi 
Published: February 2011

Abstract
Recent evidence suggests that a certain type of hepatocellular carcinoma (HCC) is hierarchically organized by a subset of cells with stem cell features (cancer stem cells: CSCs). Although normal stem cells and cancer stem cells (CSCs) are considered to share similar self-renewal programs, it is uncertain whether differentiation signaling is kept maintained in both types of cells. In this study, we investigated the effect of oncostatin M (OSM), an interleukin 6-related cytokine known to induce the differentiation of hepatoblasts into hepatocytes, on liver CSCs. Recombinant human OSM was used for both in vitro and in vivo experiments. Epithelial cell adhesion molecule (EpCAM) was used for the isolation of liver CSCs. Gene and protein expression was evaluated by quantitative reverse transcription-PCR, immunohistochemistry, and intracellular fluorescence-activated cell sorting. Apoptosis was evaluated by Annexin V and activated-caspase 3 staining. Tumor initiating capability was examined by the subcutaneous tumor formation in NOD/SCID mice. OSM receptor expression was detected in the majority of EpCAM-positive (EpCAM+) HCC with stem/progenitor cell features. OSM treatment (100 ng/ml) resulted in the induction of hepatocytic differentiation of EpCAM+ liver CSCs derived from hepatocellular carcinoma (HCC) cell lines and primary HCCs, in terms of decrease of alpha-fetoprotein and cytokeratin 19 production and increase of albumin production. Furthermore, OSM treated cells exhibited reduced expression of stemness-related genes including Bmi1 and POU5F1. While pretreatment of HCC cell lines with OSM before transplantation in vitro resulted in the decreased tumorigenic capacity, the OSM treatment after transplantation in vivo showed small tumor suppressing effects irrespective of hepatocytic differentiation of the tumor. Intriguingly, when the OSM treatment was combined with chemotherapeutic reagent 5-fluorouracil to eradicate non-CSCs, we observed the dramatic increase of apoptotic cells in vitro and the suppression of tumorigenesis in vivo compared with either OSM or 5-fluorouracil treatment alone. In conclusion, our data suggest that OSM can be effectively utilized for the differentiation and active cell division of dormant EpCAM+ liver CSCs, and the combination of OSM and conventional chemotherapy such as 5-fluorouracil efficiently eliminates HCC by targeting both CSCs and non-CSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4281.