bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4231: Epigenetic regulation and tumorigenicity of ovarian cancer cells
Authors: Meng Fanliang , Sun Guiqin , Li Zhong , Zou Changping , Brewer Molly A. 
Published: February 2011

Abstract
Objective: The objective of this study was to investigate changes in CD133 expression and in tumorigenesis that occur in ovarian cancer cell lines treated with drugs that alter gene methylation.
Materials and Methods: We selected two common drugs 5-aza-2′-deoxycytidine, a demethylating agent and Trichostain A(TSA), a histone deacetylase inhibitor and investigated three ovarian cancer cell lines(CD133+ cell lines A2780 and CD133- cell lines Hey and SKOV3) to determine their effect on ovarian cells in vitro and in vivo.
Results: We demonstrated that epigenetic modification did not significantly alter cell viability but suppressed spheroid formation of cancer cells lines. FACS results indicated that the percentage of CD133+ cells increased following treatment with 5uM 5-aza-2′-deoxycytidine and 300nM trichostatin A after 72° incubation. Xenograft assay of the NOD/SCIDmice results demonstrated that both drugs reduced spheroid formation and blocked tumorigenesis.
Conclusions: We concluded that 5-aza-2′-deoxycytidine and TSA can significantly suppress both spheroid formation and tumor formation and could be provide a new strategy for the treatment of resistant 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 4231.
Abstract 4232: Tumor-associated macrophages are responsible for EGF-R triggered upregulation of the Sox-2 signaling pathway in CSCs, which enhance tumorigenicity and tumor metastasis
Authors: Xiang Rong , Liao Debbie , Chen Mei Ting , Chuang Tsung-Hsien , Reisfeld Ralph A. , Luo Yun Ping 
Published: February 2011

Abstract
The cancer stem cell (CSC) hypothesis has gained significant recognition as the descriptor of tumorigenesis. The Sox-2 signaling pathway has an important role in the maintenance of CSCs. Tumor-associated macrophages (TAMs) play an ambiguous role in this process. Here, we demonstrate that the expression of Sox-2 was up-regulated in CSC of 4T07 breast cancer cells, effects induced and enhanced by co-culture of tumor cells with TAMs. In fact, after co-culture, 4T07 tumor cells develop an increased number of CSCs with up-regulated expression of stem cell specific markers (Scal-1 and ABCG2), as well as partner genes of Sox-2, i. e. Oct-4 and Nanog. Down regulation of Sox-2 effectively blocks the ability of TAMs to maintain the phenotype of CSC among 4T07 cancer cells, and enhances tumor development and its pulmonary metastasis in a syngeneic Balb/c mouse model. Most importantly, in a mechanism study, we found that the Sox-2 up-regulation was induced by EGF-R activation in CSC that was triggered by EGF, Macrophage Conditioned Medium (MCM) or by co-culture with TAMs. These effects can all be blocked by inhibitors of EGF-R. Our results suggest that TAMs in the tumor microenvironment(TME) provide a niche which is critical in the development and maintenance of CSCs in breast carcinoma. This critical effect of TAMs on CSC development was achieved by up-regulation of the Sox-2 signaling pathway in CSC. This, in turn, was induced by marked activation of EGF-R achieved through interactions between CSCs and TAMs. In summary, over expression of Sox-2 in CSC of 4T07 breast cancer cells was enhanced by activation of EGF-R, which was induced by TAMs in TME. This series of events is responsible for maintaining the phenotype of CSCs which enhances tumor development and pulmonary metastasis in vivo.
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 4232.
Abstract 4235: Notch ligand-dependent cancer stem cell niche in glioblastoma
Authors: Zhu Thant S. , Hervey-Jumper Shawn , DiMeco Francesco , Vescovi Angelo L. , Heth Jason A. , Muraszko Karin M. , Fan Xing 
Published: February 2011

Abstract
Recent data shows that endothelial cells function as a stem cell niche to promote CD133-positive cancer stem-like cells (CSLCs) self-renewal in glioblastoma (GBM). However, the mechanism by which endothelial cells function as a stem cell niche is largely unknown. To test if endothelial cells and differentiated tumor cells could function as a niche by providing Notch ligands to CSLCs, first we co-cultured GBM neurospheres with primary human endothelial cells (PHECs) which express Notch ligand Jagged/Delta. We found that PHECs promote GBM neurosphere growth, CD133 expression and clonogenicity in vitro, whereas knocking down Notch ligand expression in PHECs abrogates PHEC-induced GBM growth. We also found that the CD133-negative GBM cells express a higher level of Jagged/Delta and glial differentiation marker GFAP compared with CD133-positive population. When GBM neurospheres were forced to differentiate and grow as mono-layer attached cells, CD133-positive population was reduced, whereas expression of GFAP (glial marker), GalC (oligodendrocyte marker), Tuj1 (neuronal marker) and Notch ligands were induced. Furthermore, treatment of GBM neurospheres with a Jagged peptide increases GBM growth in a dosage dependent fashion. In addition, Notch ligands are highly expressed in the blood vessels of GBM primary tumors and intracranial xenografts in mouse, and CSLCs accumulate around the blood vessels within the tumors. Finally, we found that knocking down Notch ligands in PHECs inhibits GBM xenograft propagation in mice through reducing CD133-positive population. In summary, we show that Notch activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells replicating the classical process of lateral inhibition and by stromal niche signals, suggesting that targeting both CSLCs and their niche may provide a profound strategy to deplete GBM CSLCs.
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 4235.
Abstract 4244: Dysadherin can enhance tumorigenesis through conferring properties of stem-like cells to hepatocellular carcinoma cells
Authors: Park Jeong-Ran , Kim Ran-Ju , Lee Yoo-Kyung , Kim Soo-Rim , Roh Kyung-Jin , Nam Jeong-Seok 
Published: February 2011

Abstract
Hepatocellular carcinoma (HCC) is associated with a high potential for metastasis and disease recurrence, even after surgical resection. The cancer stem cell (CSC) hypothesis proposes that CSCs are responsible for chemo-resistance, recurrence and metastasis. Dysadherin is a prognostic indicator of metastasis and poor survival in many different cancer types. In this study, we investigated the possible link between dysadherin and CSC in HCC. The transfection of dysadherin cDNA into the liver cancer cell line PLC/PRF/5 enhanced the properties of CSC, including anti-apoptosis, sphere-forming ability, side population (SP) phenotype and tumor initiation ability in vivo. Furthermore, knockdown of dysadherin in the liver cancer cell line SK-Hep1 suppressed its stem cell-like properties. In particular, SP phenotype is mediated by the ATP-binding cassette (ABC) transporter proteins which are responsible for multidrug resistance (MDR) that is a major obstacle in cancer chemotherapy. Dysadherin was also shown to regulate ABCB1 expression. Taken together, these results show that new roles for the dysadherin in cancer progression that was in part dependent on CSC dynamics. Therefore, these findings suggest that dysadherin may be a potential molecular prognostic marker of HCC and may aid in the development of more effective therapies.
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 4244.
Abstract 4248: NANOG depletion decreases cell proliferation rate in colorectal carcinoma cells and tumor growth in nude mice
Authors: Espinoza Luis A. , Jessup John M. 
Published: February 2011

Abstract
Nanog is a critical transcription factor involved in maintaining embryonic stem cells in a pluripotent, dedifferentiated state and expression of NANOG or its nearly identical retrogene NANOGP8 is increased in human gastric, hepatocellular, and colon cancer. Our postulate is that NANOG/NANOGP8 is critical for the functions of putative CSC in colorectal carcinoma (CRC): self-renewal, pluripotency, spherogenicity, tumorigenicity and resistance to chemotherapy. Five human CRC lines are being used in this study (HCC 2998, KM-12c, Clone A, MIP-101, CX-1). CX-1 cells are more aggressive than the other CRC because they form more spheroids from single cells and are highly metastatic after intrasplenic compared to the other CRC that are tumorigenic but weakly metastatic. qRT-PCR analysis of spheroids of CX-1 and Clone A cultured in suspension in serum free medium indicated that NANOG transcript levels were increased by 43- and 12-fold, respectively, relative to monolayer cultures while the relative increase in transcript levels of several cancer stem cell markers such as EPCAM, ALDH1A1, ALDH3A1, CD44, CD133, and CD166 was less than 5-fold except for POU5F1 and SOX2 in Clone A, which were 5- and10-fold respectively. NANOG promoter activity was low in monolayer culture in CRC stable transfectants with a GFP NANOG promoter, but consistently increased as CRC detached and formed spheroids in serum free media. Stable transfection with lentiviral NANOG shRNA decreased NANOG transcript levels and spherogenicity of Clone A and CX1 cells compared to vector controls in a single cell spherogenicity assay in serum-free medium. NANOG downregulation also induced a S phase cell cycle arrest with inhibition of ATM and WEE1 expression with associated reduction in phosphorylation of other key cell-cycle checkpoint proteins. Finally, marked tumor growth retardation was observed in NOD/SCID mice injected subcutaneously with NANOG shRNA transfected cells compared to parental or vector controls. NANOG shRNA transfected cells were also more resistant to treatment with Topotecan, a camptothecin. In summary, our data suggest that expression of NANOG/NANOGP8 occurs in human CRC and may be critical for such functions of putative CSC as spherogenicity, cell proliferation, tumor formation and resistance to chemotherapy
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 4248.
Abstract 4249: Shape change induces nitric oxide and stemness in colorectal cancer cells
Authors: Jessup J. Milburn , Thorgeirsson Snorri S. , Espinoza Louis A. 
Published: February 2011

Abstract
Shape changes in cancer cells profoundly alter the expression of genes that affect malignant properties. We postulated that shape change may increase expression of NANOG, an embryonic stem cell transcription factor expressed in human colorectal carcinoma (CRC) that regulates pluripotency and proliferation. Since shape change also increases intracellular nitric oxide (iNO) expression, we further postulated that iNO modulates NANOG expression. Clone A and CX-1 human CRC lines were cultured in serum-containing medium in monolayer cultures or in spheroids in serum free medium in low attachment plates. NANOG promoter activity was assessed in stable transfectants expressing promoter-driven GFP. iNO concentrations were determined by fluorescence cytometry with DAF-FM diacetate while Nanog gene and protein expression was analyzed by qRT-PCR and densitometry of western blots, respectively. Spherogenicity was measured by the percentage of spheroids formed from single cells in serum-free medium. Monolayer cultures with flat, spreading cells had low NANOG gene and protein expression, promoter activity and iNO whereas spheroids displayed high NANOG gene expression, promoter activity and iNO. 7 day monolayer cultures initiated with 104 cells/ml (Sparse) grew horizontally compared to cultures initiated with 106 cells/ml (Dense) that grew vertically and formed colonies. Sparse cultures had low NANOG gene expression, low NANOG promoter activity and low iNO. Dense cultures had high NANOG gene expression, NANOG promoter activity and iNO. Since NO stimulates cGMP production, the effects of the NO synthase inhibitor L-NMMA, NOC (a NO donor), 8-Br-cGMP (cGMP agonist) and ODQ (cGMP inhibitor) were tested on CRC monolayers. Physiologic concentrations of NOC increased NANOG and Oct4 gene and protein expression 3-fold in highly metastatic CX-1 cells but not in weakly metastatic Clone A cells. NOC also increased CD44 in CX-1 but not Clone A. cGMP may regulate NANOG expression since 8-Br-cGMP increased NANOG and Oct4 protein expression up to 3-fold in CX-1 but not in Clone A and without affecting CD44 expression. ODQ inhibited NANOG expression. L-NMMA stimulated both NANOG protein expression and the spherogenicity of CX-1 but not Clone A. NOC and 8-Br-cGMP increased inducible NO synthase (NOS2) but not NOS3 gene expression 3-fold in both spheroids and monolayers while ODQ decreased NOS2 levels. Assays are in progress to test the effects of NOC and the cGMP modulators on spherogenicity. Shape change, iNO and cGMP enhance NANOG, NOS2 and CD44 expression to alter CRC cancer stem cell function. cGMP may be an important regulator of stemness genes.
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 4249.
Abstract 4254: The Wnt/ B-catenin pathway regulates colon cancer stem cells proliferation
Authors: Kanwar Shailender S. , Yu Yingjie , Nautiyal Jyoti , Patel Bhaumik , Majumdar Adhip P.N. 
Published: February 2011

Abstract
It is becoming increasingly evident that a small sub-population of self-renewing, multipotent cells termed cancer stem cells (CSCs) is responsible for driving majority of the epithelial cancers including colon cancer. The observation that CSCs display resistance to conventional chemotherapeutics suggests that they may be responsible for the recurrence of cancers. One of the properties of CSCs is that they form floating spheroids (colonosphere) in a defined media. Different signaling pathways such as Wnt, Hedgehog, Notch and Bmi have been implicated in the regulation of colonosphere formation and stem cell self renewal. The current investigation was undertaken to examine the role of Wnt/B-catenin pathway in regulating the growth and maintenance of colonosphere. Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant), HCT 116 (p53 null; K-ras mutant) and HT 29 (p53 mutant) were used. We have observed that colonospheres formed in vitro exhibited higher expression of colon CSCs markers ALDH1, LGR5, CD133, CD44 and Musashi, compared to the corresponding parental cancer cells, indicating the predominance of CSCs in colonosphere. Further support for this inference comes from the FACS analysis that show 95-97% of CD44 positive cells in colonospheres. Additionally, colonosphere showed increased levels of B-catenin, cyclin D1 and C-Myc and down-regulation of Axin-1 and phosphorylated B-catenin. Increased expression of B-catenin was associated with a marked transcriptional activation of TCF-LEF. To determine whether B-catenin plays a role in the maintenance and formation of colonosphere, we transfected the colon cancer cells with B-catenin siRNA and subsequently analyzed colonosphere formation. The results revealed a marked reduction in the colonosphere formation following down-regulation of B-catenin indicating its role in colonosphere formation. Further support for this interpretation comes from the observation that the upregulation of cMYC /cyclin D1 (the target genes of LEF/TCF) results in enhancement of the colonosphere formation. In conclusion, our data suggest that Wnt/B-catenin pathway plays a critical role in the growth of 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 4254.
Abstract 4255: Significance of mesenchymal stem cells in growth and metastasis of colon cancer
Authors: Shinagawa Kei , Kitadai Yasuhiko , Tanaka Miwako , Sumida Tomonori , Kodama Michiyo , Tanaka Shinji , Yasui Wataru , Chayama Kazuaki 
Published: February 2011

Abstract
Background: Recently, mesenchymal stem cells (MSCs) are reported to migrate to tumor sites as well as sites of injury and to incorporate into tumor stroma, but the effects of interactions between MSCs and tumor cells and the mechanisms underlying these effects remain unclear. We examined the role of MSCs in the tumor micro-environment using an orthotopic colon cancer model and a model of liver metastasis from colon cancer. Materials and Methods: Human MSCs labeled with fluorescent dye were injected into tail veins of nude mice bearing KM12SM human colon cancer cells. KM12SM cells alone or KM12SM cells mixed with MSCs were transplanted into the cecal wall or spleen of nude mice. Differentiation of MSCs in primary colon tumors and metastatic liver tumors were also analyzed. Migration assay and invasion assay were performed to examine attraction between KM12SM cells and MSCs in vitro. Results: In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in significantly greater tumor weight than did transplantation of KM12SM cells alone (p &lt; 0.05). The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group (p &lt; 0.001). Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index (p &lt; 0.01), significantly greater microvessel area (p &lt; 0.01), and significantly lower apoptotic index (p &lt; 0.001). Splenic injection of KM12SM cells mixed with MSCs resulted in a significantly greater number of liver metastases than did splenic injection of KM12SM cells alone (p &lt; 0.01). MSCs incorporated into the stroma of primary and metastatic tumors expressed α-smooth muscle actin and platelet-derived growth factor receptor-β as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors (p &lt; 0.05, respectively). Conclusion: MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis and by inhibiting apoptosis of tumor 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 4255.
Abstract 4264: CD133/prominin-1 regulates the tumorigenicity of oral squamous carcinoma cells-derived cancer initiating cells
Authors: Chen Yu-Syuan , Lo Jeng-Fan , Yu Cheng-Chia 
Published: February 2011

Abstract
Background: Oral squamous carcinoma cell (OSCC) is a lethal cancer with clinical, pathological, phenotypical, and biological heterogeneity. Previously, we enriched a subpopulation of oral cancer derived cancer initiating cells (OC-CICs) by tumor sphere formation approach, and identified CD133 as a putative CICs marker. However, the function of CD133 in OC-CICs remains unclear. Herein, we determined the critical role of CD133, an important CICs marker, in the maintenance of stemness characteristics and tumorigenic phenotype in OC-TICs.
Methods: First, side population (SP) assay, a methodology to identify CICs in cancer cells, was performed to characterize the existence of OC-CICs. Next, we want to evaluate the expression of CD133 in OC-CIC isolated from SP cells transcriptionally and translationally. Lentiviral-mediated stable overexpression and down-regulation of CD133 expression in OSCCs and OC-CICs was established. Consequently, we investigated the effect of CD133 down-regulation or overexpression on stemness properties and tumorigenicity of OSCCs and OC-CICs, respectively.
Results: We identified that CD133 was significantly up-regulated in SP cells of OSCCs. Stable overexpression of CD133 enhanced the CICs properties in OSCCs. In opposite, down-regulation of CD133 significantly reduced the self-renewal ability, side population cells, and expression of stemness genes of OC-CICs. Additionally, down-regulation of CD133 enhanced the differentiation capability but inversely diminished “stemness” gene expression of OC-CICs. Finally, knockdown of CD133 in OSCC or OC-CICs lessened both in vitro malignant abilities including cell migration/cell invasion/anchorage independent growth and in vivo tumor growth by xenotransplantation assay.
Conclusion: We showed that SP cells with CICs properties existed in OSCCs. CD133 contributes to the maintenance of stemness and tumorigenicity of OC-CICs. Silencing CD133 might be a potential therapeutic target for OSCC by eliminating CICs.
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 4264.
Abstract 4272: Elimination of human lung cancer stem cells through targeting of the SCF-c-kit autocrine signaling loop
Authors: Levina Vera V. , Marrangoni Adele , Wang Tingting , Parikh Simul , Su Yunyun , Herberman Ronald , Lokshin Anna , Gorelik Elieser 
Published: February 2011

Abstract
Cancer stem cells (CSCs) are thought to be responsible for tumor initiation and tumor regeneration after chemotherapy. Earlier we demonstrated that chemotherapy led to the selection of CSCs and that the high malignancy of lung CSCs was associated with an efficient cytokine network. Here we propose that blocking SCF-c-kit signaling will inhibit CSC proliferation and survival. CSCs were isolated from nonsmal cell lung cancer (NSCLC) cell lines as tumor spheres under CSC-selective conditions, and their stem/progenitor properties were confirmed. A Cellomics ArrayScan HCS Reader was applied to test the cell surface markers, the intracellular protein distribution and cell proliferation. CSCs in contrast to bulk cells expressed high levels of c-kit receptors and produced SCF. Proliferation of CSCs was stimulated by exogenous SCF and was inhibited by antibodies neutralizing SCF and by imatinib (Gleevec), a specific inhibitor of c-kit. Cisplatin treatment eliminated major of bulk cells but not CSCs, whereas imatinib or anti-SCF antibody destroyed CSCs. In combination cisplatin and imatinib or anti-SCF antibody prevented growth of both tumor cell subpopulations.
Our results elucidate the important role of SCF-c-kit signaling axis for the self-renewal and proliferation of lung CSCs. Blocking SCF-c-kit signaling by anti-SCF antibody or imatinib in combination with cisplatin could be more efficient in elimination of human tumor cells than each modality used separately.
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 4272.