bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5167: Notch1 is required for endothelial cell lineage differentiation from adult bone marrow stem cells in vitro
Authors: Shao Hongwei , Xiao Min , Cai Long , Radtke Freddy , Velazquez Omaida C. , Liu Zhao-Jun 
Published: February 2011

Abstract
Background and Objectives. Adult bone-marrow stem cells (BMSCs) are able to differentiate into endothelial progenitor cells (EPCs) and subsequently endothelial cells (ECs) under appropriate conditions. BMSCs-derived EPCs/ECs contribute to post-natal neovascularization and are important tools for regenerative medicine. However, the molecular mechanism determining specific differentiation of endothelial lineage remains unknown. The Notch signaling pathway plays an integral role in the differentiation of a variety of cell lineages. We hypothesize that Notch signaling is involved in controlling endothelial lineage differentiation from BMSCs and examined the role of Notch1 signaling in this process.
Methods and Results. An in vitro method for differentiation of endothelial cell lineage from murine BMSCs was developed. Mononuclear cells were isolated from mouse whole BM cells by light density separation using Ficoll-Paque® Plus, and cultured in the differentiation medium to differentiate endothelial cells. The endothelial phenotype of differentiated cells was characterized by immunostaining and flow cytometry analyses. Those fractions of cells with VEGFR2+/CD31+ or Tie2+/CD31+ were isolated and tested. VEGFR2+/CD31+ cells could form networks on the MatrigelTM, indicating that these cells are ECs. mRNA expression of Notch pathway components in VEGFR2+/CD31+ cells was examined by real-time RT-PCR. Multiple components of the Notch signaling pathway were expressed in the differentiated ECs. The effect of loss-of-function in Notch1 on the differentiation of endothelial cell lineage was examined using BMSCs from Notch1Flox/Flox mice. Cells expressing VEGFR2 were significantly decreased when Notch1 is deleted.
Conclusions. A novel and reliable method has been developed to differentiate murine adult bone marrow stem cells into endothelial cell lineage in vitro. The role of Notch1 in determining endothelial cell differentiation was tested on this platform. Our results implicated that Notch1 is required for the differentiation of endothelial cell lineage from BMSCs.
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 5167.
Abstract 5168: Interaction of sonic hedgehog and TP53/TP63 networks in lymphoma cells
Authors: Chari Nikhil S. , Teo Albert E.K. , Medeiros L. Jeffrey , McDonnell Timothy J. 
Published: February 2011

Abstract
Cellular homeostasis requires a delicate balance between proliferation, apoptosis and differentiation be maintained. These processes are regulated by a number of tumor suppressors and proto-oncogenes that are frequently deregulated during tumor progression. Amongst these are the TP53/TP63 family of tumor suppressors and the sonic hedgehog (SHH) pathway. The SHH network associated with proliferative stem cell niches of many organs has been shown to affect disease progression and metastasis in diverse cancers. We investigated the possibility of interactions between the SHH and the TP53 networks in cancer cells. Using a Ponasterone A inducible TP53 H1299 cell line as a model system we were, able to show alterations in RNA and protein levels of SHH signaling intermediates on TP53 activation suggesting a regulation at the transcriptional level. A preliminary screening of a number of hematological cancer cell lines showed a majority of cell lines having aberrant SHH activation. A panel of diffuse large B-cell lymphoma (DLBCL) cell lines that included activated B-cell (ABC) like DLBCL and germinal center B-cell (GCB) like DLBCL subgroups were selected for further study. These cell lines also varied from p53-deficient to wild type p53. Treatment of these cell lines with nutlin, an HDM2 antagonist showed alterations in the SHH pathway at the protein and transcript levels. In silico analysis of the promoters of genes in the SHH network reveal multiple potential TP53/TP63 binding sites. Luciferase promoter constructs of SHH pathway genes were generated including SHH-luciferase and SUFU-luciferase promoter constructs and confirmed that these promoters were regulated by both TP63 and TP53. Further validation was provided using in vivo chromatin immunoprecipitation (ChIP) studies and site-directed mutational analysis. These findings suggest that there are multiple interacting nodes between the components of the SHH network and TP53/TP63 family of transcription networks. Additionally, a therapeutic strategy involving specific and simultaneous targeting of these networks in DLBCL cells would be expected to result in a more robust therapeutic response.
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 5168.
Abstract 5171: EGFR induction of SOX9 is required in a cellular migration program induced by urothelial injury and maintained in cancer
Authors: Ling Shizhang , Chang Xiaofei , Lee Thomas , Marchionni Luigi , Netto Georges , Sidransky David , Berman David M. 
Published: February 2011

Abstract
Data from a variety of tissue types and experimental systems indicate that the transcriptional regulator SRY-related HMG box 9 (SOX9) can be induced by injury and promote migration as well as tumor growth. We hypothesize that in cancers associated with chronic injury, such as urothelial carcinoma (UroCa), SOX9 may mediate epithelial injury repair. We found that urothelial SOX9 was induced during times of rapid proliferation during bladder organogenesis and injury repair. High levels of epidermal growth factor (EGF) ligands have been noted in urine and represent a potential trigger for urothelial injury repair programs. Using specific antagonists, we found that EGF receptor activation by cognate ligands heparain binding EGF-like growth factor (HB-EGF) and/or amphiregulin was responsible for Sox9 induction in urothelial cells and tissues. As expected, EGFR activation occurred through the mitogen associated protein kinase (MAPK) pathway. With chronic breaches of urothelial integrity, EGFR-Sox9 stimulation may promote urothelial carcinogenesis, as Sox9 expression was significantly upregulated in invasive human UroCa samples and cell lines. When expressed in established tumors, SOX9 may confer a selective advantage to cancer cells by promoting their ability to invade and colonize new sites. As support for this idea, small interfering RNA inhibition of SOX9 levels abrogated in vitro wound healing and invasion, suggesting a role for SOX9 in tumor spread. These results indicate a potential mechanism for urothelial carcinogenesis through an EGFR-MAPK-SOX9 cascade, and a further function for this axis in established cancers. Future studies will examine the potential mechanisms supporting perseverative SOX9 expression in cancer and opportunities for disrupting this pathway as a therapeutic strategy.
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 5171.
Abstract 5173: Adipocytes attract leukemia cells
Authors: Pramanik Rocky , Sheng Xia , Mittelman Steven D. 
Published: February 2011

Abstract
Obesity is associated with increased progression and relapse of various types of cancer. We have previously found that obesity impairs leukemia treatment by mitigating chemotherapeutic drug. In addition, we observed the presence of acute lymphoblastic leukemia (ALL) cells in adipose tissue during chemotherapy treatment. Therefore, we have investigated whether adipocytes stimulate leukemia cell migration in addition to exerting their protective effect against chemotherapies. We used a cell migration assay in which murine ALL cells were cultured in 5μm pore Transwell inserts in an upper chamber, and test medium or adipocyte-conditioned medium (ACM) was used in the bottom chamber. The number of cells which migrated into the lower chamber in 90 minutes was counted using trypan blue exclusion and expressed as % of total cells initially plated in the transwell. When the upper Transwell inserts contained regular medium and the lower chamber contained ACM, 31.2±5.8% of cells migrated to the lower chamber. By contrast, when the lower chamber contained regular medium, only 0.3±0.2% of cells migrated (p&lt;0.01, vs ACM, n=4). Preadipocyte-conditioned medium also stimulated migration, but less than ACM (18.2±4.8% cells migrated, p&lt;0.05 vs. ACM, n=4). The ACM-stimulated migration had both directional and non-directional components, in that when both the upper and lower chamber contained ACM, 13.2±0.2% of cells migrated to the lower chamber, which was significantly more than with regular media (p&lt;0.05), but less than with ACM (p&lt;0.01). The above results suggest that adipocyte-secreted molecules increase ALL cell motility and attract leukemia cells in a directional fashion. It is plausible that adipose tissue, particularly in obese people, might attract leukemia cells and act as a safe heaven for leukemia cells against chemotherapy, thereby promoting leukemia relapse.
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 5173.
Abstract 5179: Inflammatory breast cancer cell motility: Understanding the role of E-cadherin and gli1 in IBC migration and the development of a novel high content assay to assess cell migration
Authors: Thomas Zainab , Sexton Jonathan Z. , Devi Gayathri R. , Williams Kevin P. 
Published: February 2011

Abstract
Inflammatory Breast Cancer (IBC) is a highly aggressive subtype of breast cancer and is now regarded as clinicopathologically distinct from neglected locally advanced breast cancer (LABC). In addition, African-Americans, native Americans and younger women are disproportionately affected with IBC having the worse survival. The molecular mechanisms underlying the invasiveness of IBC are not clear. Interestingly, upregulation of the integral membrane protein E-cadherin is the marker reported to be seen most consistently in IBC. In contrast to IBC, E-cadherin is typically reduced in most cancers and the subsequent loss in cell-cell adhesion results in the rapid progression to an invasive and metastatic phenotype. Inactivation of the E-cadherin cell adhesion system can occur by a number of genetic and epigenetic mechanisms. Gli1, the main transcriptional activator of hedgehog signaling, can promote loss of E-cadherin. Gli1 induces expression of Snail which is then found to downregulate E-cadherin expression.
In an IBC cellular model, SUM149, we have identified elevated levels of Gli1. Further, inhibition of Gli1 using siRNA caused apoptosis in these cells. We hypothesize that the invasiveness of IBC cells is modulated in part by a connection between E-cadherin and Gli1 levels in IBC and that modulating this pathway will lead to changes in IBC cell motility. This project has two main objectives: 1), Investigate the expression levels of E-cadherin and Gli1 in IBC cells and their roles in IBC motility, and 2), Develop and validate a high content microscope-based assay for measuring motility of IBC cells. Cell motility assays were performed in six-well plates with Gli1 siRNA treated SUM149 cells that resulted in reduced motility and viability of these cells compared to control siRNA treated cells. These results suggest that targeting Gli1 can reduce IBC's invasiveness. This pathway provides opportunities for identifying molecules that might affect tumor invasiveness.
We have also developed a novel live cell high content phenotypic screen for modulators of IBC cell motility that may potentially lead to new therapeutics for IBC. An understanding of how any of these molecules affect the Gli-Snail-E-cadherin system would provide useful tools for better probing the role of this pathway in IBC. Furthermore, the high content migration phenotypic assay should be generally applicable to investigating a range of invasive cancer types.
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 5179.
Abstract 5187: Migration and proliferation of colon carcinoma cells are importantly affected by leptin and adiponectin via diverse pathways
Authors: Ratke Janina , Niggemann Bernd , Zänker Kurt S. , Dittmar Thomas , Lang Kerstin 
Published: February 2011

Abstract
Obesity is a dramatically increasing public health problem worldwide. Traditionally, fat tissue was considered to be solely an energy storage depot. However, recent studies have shown that adipose tissue exerts important endocrine functions, which are predominantly mediated by a network of various soluble factors derived from adipocytes. New evidence has come to light elucidating a modulatory role of this adipocytokines in the regulation of cancer development. The most prominent adipocytokines are leptin and adiponectin, which are predominantly secreted by differentiated adipocytes. Depending on the energy status of adipocytes, the secreted concentrations of leptin and adiponectin vary drastically. In obesity, serum level of leptin is considerable increased (greater than or equal to 100 nanogram/ml), whereas the adiponectin concentration is very low. In contrast, adiponectin concentration accelerates by weight reduction (greater than or equal to 10 microgram/ml). The aim of our study was to investigate the influence of adipocytokines on cancer cells. Using our three-dimensional, collagen-based migration assay we found a strong impact of leptin and adiponectin on the migration of colon cancer cells. Both adipocytokines alone significantly enhanced the migratory activity of SW480 colon carcinoma cells from 30.3±7.4% spontaneously locomoting cells to 50.9±8.2%. In contrast, both adipocytokines in combination reduced the migration of colon carcinoma cells to control level. Moreover, treatment of the cells with leptin alone enhanced the proliferation of SW480 cells up to 50%, whereas adiponectin mediated an anti-proliferative function by 30%. Surprisingly, addition of leptin and adiponectin together did not have any effect on the proliferation. On the molecular level, leptin-induced migration was mediated by phosphorylation of focal adhesion kinase (FAK) and activation of phosphatidyl-inositol-3-kinase (PI3K). The pro-migratory effect of adiponectin was accompanied by an activation of PI3K/AKT and various transcription factors. In contrast, incubation with both adipocytokines in combination led to a decreased phosphorylation of FAK and AKT. Understanding the impact of leptin and adiponectin alone and their interplay on the carcinogenesis of colon cancer as well as the underlying molecular mechanisms have a major clinical significance, and provide the basis for the development of novel therapeutics to treat obesity-associated colorectal cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 5187.
Abstract 5190: GnRH promotes peritoneal adhesion and dissemination of ovarian cancer cells
Authors: Cheung Lydia W. T. , Leung Peter C. K. , Wong Alice S. T. 
Published: February 2011

Abstract
Ovarian cancer has the highest mortality of all gynecological cancers. It is often diagnosed at a late stage characterized by widespread peritoneal dissemination and malignant ascites. A key initial step in metastasis is the adhesion of ovarian cancer cells to the peritoneal mesothelium and extracellular matrix (ECM). Gonadotropin-releasing hormone (GnRH) receptor is present in 80% of ovarian carcinomas and its role in ovarian cancer cell migration/invasion has recently been revealed. Here, we show for the first time a role for GnRH in promoting ovarian cancer cell adhesion to the peritoneum. We observed that GnRH agonist (GnRHa)-stimulated cells were able to adhere to the peritoneal mesothelium efficiently. Moreover, the expression of integrins (α2, α5 and β1) in ECM recognition for collagen I, laminin, and fibronectin were upregulated and activated by GnRHa. The adhesion of ovarian cancer cells to the mesothelium/ECM components activated by GnRHa could be blocked by neutralizing antibodies to α2, α5 and β1 integrin. Knockdown of the GnRH receptor using small interfering RNA significantly abrogated the GnRH-induced cell adhesion and integrin expression, confirming that these effects were GnRH receptor specific. Furthermore, we showed that downregulation of β1 integrin and GnRH receptor with short hairpin RNA-mediated gene silencing significantly reduced ascites formation and intra-abdominal metastasis in intraperitoneal xenografts of human ovarian cancer in nude mice. These results indicate that GnRH may play a critical role in the peritoneal adhesion and dissemination of ovarian carcinomas and could be a promising target in ovarian cancer (This work is supported by the Hong Kong Research Grants Council Grant HKU778108 to A.S.T.W.).
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 5190.
Abstract 5195: Shh/Gli signaling pathway promotes tumor metastasis and lymphangiogenesis via activation of PI3K/Akt and Erk pathway in gastric cancer
Authors: Yoo Young-A , Kang Myoung-Hee , Kang Han-Na , Kim Jung-Lim , Seo Jae-Hong , Kim Jun-Suk , Oh Sang-Cheul 
Published: February 2011

Abstract
The activation of Sonic hedgehog (Shh)/Gli signaling is involved in the progression and invasion of various tumors types, including gastric carcinoma. Epithelial-mesenchymal transition (EMT) and matrix metalloproteinases (MMPs) have been implicated in facilitating the invasion and metastatsis. Herein, we investigated the impact of phosphoinositide 3-kinase (PI3K)/Akt and Erk pathway and MMPs activity on the Shh/Gli-mediated EMT and invasion of gastric cancer cells. We found that overexpression of Shh significantly enhanced cellular motility/invasiveness, lymphangiogenesis, and metastatic ability of tumor cells in gastric cancer cell lines and mice. Stimulation of Shh in gastric cancer cells also induced a full EMT process (characterized by Snail induction and E-cadherin down-regulation) and expression and activity of MMP-9. Meanwhile, blockade of Shh/Gli signaling by Cyclopamine (a Shh signaling inhibitor), anti-Shh neutralizing antibodies, or Gli siRNA inhibited Shh-induced motility/invasiveness and lymphangiogenesis in gastric cancer by subsequently restoring these changes of EMT markers and activity of MMP-9. The phosphorylation of Akt and Erk was also enhanced by treatment with Shh, but not cyclopamine, anti-Shh neutralizing antibodies, or Gli siRNA. Blockade of the Akt and MEK kinase using kinase-dead Akt, LY294002, or PD98059 significantly inhibited the Shh-induced EMT, activity of MMP-9, lymphangiogenesis, and metastasis in tumor cell lines and mice over-expressing Shh. Furthermore, knock-down of MMP-9 by its siRNA results in an decrease in invasiveness of gastric cancer cells treatment with Shh. Immunohistochemistry on gastric tumor biopsies showed that the levels of Gli, E-cadherin, MMP-9, D2-40 (lymphangiogenic factor), and phospho-Akt expression were enhanced in cases of metastatic gastric cancer than in cases of primary gastric cancer. Moreover, the strong correlation between Gli and E-cadherin, MMP-9, D2-40, phospho-Akt, or phospho-Erk expression was also observed in lymph node metastasis specimens. These data indicate that Shh/Gli signaling pathway promotes tumor metastasis in gastric cancer through activation of PI3K/Akt and Erk pathway followed by up-regulation of EMT, MMP-9, and lymphangiogenesis, which results in the stimulation of invasiveness 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 5195.
Abstract 5199: Promotion of prostate cancer cell migration and invasion via CXCR3 signaling
Authors: Wu Qian , Wells Alan 
Published: February 2011

Abstract
Tumor cells exist within, and cross-communicate with their local milieu that includes non-neoplastic cells using a variety of soluble chemokines. CXCR3-binding chemokines have recently been implicated in breast cancer metastasis, though inversely correlated with prostate tumor growth. There are two CXCR3 isoforms differing by a 5′ splice variant, that vary in their distribution, with CXCR3A found mainly on cells of the hematopoietic lineage and CXCR3B the predominant species on adherent cells. These isoforms vary in their predilection for the four common ligands, and the consequences of signaling through these different isoforms can be divergent. How these two isoforms inform tumorigenesis and invasion still remains unclear. Here, we examined the expression and function of the two different variants of CXCR3 in prostate cancer cells. In contrast to normal prostate epithelial cells (RWPE-1), in which CXCR3B was the primary splice variant, CXCR3A was highly expressed in two tested prostate cancer cell lines (DU-145 and PC-3). Two known ligands of CXCR3, CXCL10/IP10 and CXCL11/IP9/I-TAC, were down-regulated in these two prostate cancer cell lines, while the CXCR3B-selective ligand CXCL4/PF4 was overexpressed, allowing for autocrine stimulation. Instead of inhibiting cell migration as in RWPE-1 cells, CXCL4/PF4 and CXCL10/IP10 promoted cell motility and invasiveness in both DU-145 and PC-3 cells in vitro, which might be a result of PLCβ3 activation. Overexpression of CXCR3B in DU-145 cells slightly decreased cell chemoattractant movement and invasion. These data suggest that the aberrant expression of CXCR3A and down-regulation of CXCR3B may promote prostate tumor metastasis via stimulating cell migration. (Funded by a VA Merit Award)
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 5199.