bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4118: Fibroblast heterogeneity in oral squamous cell carcinoma is directed by tumor epithelium and promotes keratinocyte invasion in vitro
Authors: Lim Kue Peng , Wei WenBin , Parkinson Kenneth , Prime Stephen Stewart 
Published: February 2011

Abstract
The transformation of human cells requires the accumulation of a broad spectrum of genetic abnormalities that typically lead to unrestrained cell growth. It has now become clear that alterations extrinsic to the tumor cell are also required and there is a considerable body of evidence to show that the cancer microenvironment plays a pivotal role in the initiation, progression and spread of cancer. In this study, we show that fibroblasts isolated from keratinocyte cultures of normal oral mucosa, epithelial dysplasia and mortal and immortal oral squamous cell carcinomas (OSCC) were heterogeneous and, using global gene expression profiling, could be grouped according to their tissue of origin. Fibroblasts from immortal OSCC, for example, showed high levels of activation and were characterized by down regulation of cell cycle-related genes and up-regulation of transmembrane-related genes. The data was validated using real time quantitative PCR to examine the expression of specific up-regulated (IGFBP7, ITGA6, p21) and down-regulated (FOXM1, MCM7) genes identified as having significant fold change in the expression analyses. Further, we examined the inter-relationship between tumor epithelial cells and tumor-associated fibroblasts. Whilst the proliferation of two target keratinocyte cell lines was stimulated by conditioned media from both normal and tumor-associated fibroblasts (in excess of keratinocyte growth in 10% serum), only fibroblasts from immortal OSCC stimulated the invasion of a non-tumorigenic keratinocyte cell line into fibroblast-rich collagen gels in organotypic cultures. Keratinocyte conditioned media stimulated the growth and activation of fibroblasts from normal oral mucosa and mortal OSCC. The results demonstrate a close inter-relationship between tumor epithelium and tumor-associated fibroblasts and show that the diversity of fibroblasts during tumor progression is not only influenced by the tumor epithelium but also, has biological significance in the promotion of tumor cell invasion in vitro.
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 4118.
Abstract 4124: Chronic estrogen and NNK stimulate small airway epithelial cells via modulation of nicotinic acetylcholine receptors
Authors: Al-Wadei Hussein AN , Al-Wadei Mohammed H. , Plummer Howard K. , Schuller Hildegard M. 
Published: February 2011

Abstract
Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer and is particularly prevalent in women. We have previously reported that the proliferation of immortalized human small airway epithelial cells HPL1D is stimulated by a single dose of the tobacco carcinogen NNK via cAMP signaling activated by binding of NNK to the beta-1-adrenergic receptor (β1-AR) and that estrogen enhances this response. In the current study we show that γ-aminobutyric acid (GABA) blocks this cooperative signaling of NNK and estrogen in HPL1D cells by inhibiting the activation of adenylyl cyclase. In addition, HPL1D cells produced the stress neurotransmitters noradrenaline and adrenaline in response to binding of a single dose of NNK to the α7 nicotinic acetylcholine receptor (α7nAChR). Since both stress neurotransmitters are beta-adrenergic agonists, this response further enhanced cAMP-dependent stimulatory signaling. On the other hand, GABA production by these cells was reduced by a single dose of NNK via desensitization of the α4β2 nAChR. Exposure to NNK, estrogen or the combination of both agents for 7 days upregulated and sensitized the α7nAChR, resulting in an enhanced noradrenergic response to agonist. At the same time, chronic NNK and estrogen suppressed the production of GABA by desensitizing its regulatory α4β2nAChR. The resulting predominance of stimulatory cAMP signaling over inhibitory GABA signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke and offer a novel target for the marker-guided prevention of this cancer.
Supported by a grant from the National Lung Cancer Partnership and LUNGevity Foundation.
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 4124.
Abstract 4125: The effects of S100B on cell signaling in malignant melanoma
Authors: Gianni Kira , Wilder Paul T. , Vitolo Michele I. , Shapiro Paul , Weber David J. 
Published: February 2011

Abstract
Establishing the mechanism by which S100B effects ERK and its downstream proteins will provide valuable insight into the role of S100B in the progression of melanoma and potentially aid in developing new pharmacological drugs. The protein S100B is an effective prognostic marker for human malignant melanoma. Increased levels of serum S100B are predictive of disease stage, increased recurrence, and low overall survival. It has previously been found that S100B directly interacts with the tumor suppressor protein p53, down-regulating its protein levels, thereby allowing damaged cells to proliferate and mutations to propagate. S100B has also been implicated in several other signaling pathways, including the MAPK pathway. The initial hypothesis tested was that S100B inhibits the phosphorylation of ERK targets in a calcium-dependent manner. The S100B binding motif has been found to overlap with the ERK binding motif, suggesting that S100B binds the targets and physically prevents ERK from interacting with and subsequently phosphorylating them. ERK kinase assays revealed that the addition of S100B in the presence of calcium decreased ERK phosphorylation of RSK, but more dramatically Elk-1. Additionally, RSK was detected in S100B pull-downs in the presence of calcium; however, it was not detected in the presence of the calcium chelator EDTA. Over-expression of normal human S100B, but not a mutant S100B incapable of binding calcium, results in decreased phosphorylated RSK at Thr573, yet increased phosphorylated ERK, interestingly. Since a rise in serum S100B levels is indicative of tumor progression, it was also of interest to see if the addition of extracellular S100B alone is sufficient to elicit the same signaling response. Preliminary data shows an increase in phosphorylated ERK after the addition of low concentrations of extracellular S100B, as well as effects on ERK targets. We demonstrate that the calcium-binding protein S100B affects the MAPK pathway by simultaneously increasing phosphorylated ERK and decreasing phosphorylated RSK and Elk-1, together which could have a significant impact on cancer 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 4125.
Abstract 4130: Genomic profiling of ovarian tumor cell lines provides a predictive signature of sensitivity to PF-4691502, a dual PI3kinase and mTOR inhibitor
Authors: Sheppard Karen E. , Neilsen Amelia , Ng Gwyn , Chan Joanna , Tothill Richard W. , Ellul Jason , Hannan Ross D. , Johnstone Ricky W. , McArthur Grant , Phillips Wayne , Pearson Richard B. 
Published: February 2011

Abstract
The PI3kinase/AKT/mTOR pathway plays key roles in cell growth, proliferation and survival with mTOR providing a hub for coordinating signaling in response to growth factors, hormones and nutrients. This pathway is one of the most frequently mutated or abnormally activated pathways in ovarian cancer, thus making it an excellent therapeutic target for this disease.
The aims of this study were:
1. To investigate the potency of PF-4691502 (PF502) a dual PI3 kinase and mTOR inhibitor to inhibit ovarian tumor cell proliferation and induce cell death.
2. To profile exponentially growing ovarian tumor cells using gene expression, copy number variations and activation of the PI3 kinase pathway.
3. To define a predictive signature or biomarker that defines ovarian tumor cell sensitivity to PF502.
A panel of 39 ovarian tumor cells were treated with PF502 (1nM-30µM) for 72h and the dose at which proliferation was inhibited by 50% (GI50) determined. Cells showed a 50-fold difference in PF502 sensitivity with GI50 values ranging from 15nM to 700nM, with the majority (85%) of cells having a GI50 of less than 200nM, these cells were classified as sensitive and the remaining 6 cell lines with a GI50 greater than 350nM were classified as resistant. PF502 also caused cell death in a subset of sensitive ovarian tumor cells. Increase in PIK3CA gene copy number was observed in 40% of the cell lines but this did not correlate with PF502 sensitivity nor did activating mutations in PIK3CA or inactivation of PTEN. Gene expression data was generated from exponentially growing cells using high-density oligonucleotide microarrays. A predictive model of response to PF502 was generated using the gene expression data. Exhaustive 10-fold cross validation of the model showed that tumour cell sensitivity could be predicted with high (96%) accuracy using approximately 20-30 genes. A differential gene expression analysis was performed using all data and 89 genes were found significantly different between sensitive and resistant cell lines. Pathway analysis revealed an over expression of inflammatory markers within the resistant class. Gene set enrichment analysis further supported an increased inflammatory signal within resistant cells, and revealed that both MYC and RAS signaling were also elevated providing a clear indication of potential targets for combination therapies in PF502 resistant disease.
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 4130.
Abstract 4132: Down Regulation of the CCK-B/C Receptor Inhibits Growth of Pancreatic Cancer
Authors: Fino Kristin K. , Matters Gail L. , McGovern Christopher O. , Kester Mark , Smith Jill P. 
Published: February 2011

Abstract
Background: Pancreatic cancer has a dismal prognosis with only 1% surviving 5 years. Reasons for this poor prognosis include the inability to diagnosis pancreatic cancer in early stages and its resistance to standard chemotherapy. The gastrointestinal peptide, gastrin, has been identified as a growth factor in pancreatic cancer. Gastrin stimulates growth of pancreatic cancer through the cholecystokinin (CCK)-B receptor and a splice variant of this receptor (CCK-C), which is expressed only in cancer cells.
Hypothesis: It is hypothesized that down regulation of the gastrin binding receptors, CCK-B/C, by small interfering RNAs (siRNAs) will inhibit growth of pancreatic cancer.
Methods: A series of human pancreatic cancer cells were screened by Real-Time RT-PCR for the presence and quantity of CCK-B/C receptor mRNA. Receptor binding was identified in pancreatic cancer cells with a CCK-B polyclonal antibody (1:10,000) by immunocytochemistry. PANC-1 cells were transfected with siRNAs that target a region of mRNA common to both the CCK-B and CCK-C receptor with either Lipofectamine 2000 or pegylated cationic nanoliposomes previously shown to be nontoxic after systemic intravenous administration. RNA was extracted and analyzed by TaqMan Real-Time RT-PCR for the receptor expression 3 days after treatment. Control cells were untreated, vehicle only treated (Lipofectamine 2000 or pegylated cationic nanoliposomes), or treated with a scrambled siRNA control. The effects of CCK-B/C knock-down on growth were evaluated by counting cells at various time points by trypan blue dye exclusion.
Results: The CCK-B/C receptor was detected in several human pancreatic cancer cell lines (PANC-1, MIA PaCa-2, AsPC-1, BxPC-3, and Capan-1) by Real-Time RT-PCR. The receptor was identified by immunofluorescence in the plasma membrane. CCK-B/C receptor expression was down regulated by CCK-B/C siRNA with both Lipofectamine 2000 and pegylated cationic nanoliposomes. PANC-1 cell growth was significantly decreased in CCK-B/C receptor targeted siRNA treated cells compared to untreated cells, vehicle only, and scrambled control on day 3 (p&lt;0.0001, n=9). Control cells more than doubled in number while CCK-B/C siRNA treated cells increased by only 10%.
Conclusion: The CCK-B/C receptor is present in human pancreatic cancer cells and knock-down significantly decreases cell growth. Systemic administration of CCK-B/C siRNAs by pegylated cationic nanoliposomes may be a potential therapeutic modality for pancreatic cancer.
Supported by NIH CA117926.
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 4132.
Abstract 4134: Breast cancer antiestrogen resistance-3 promotes growth in the presence of tamoxifen through a mechanism involving p130cas and c-src
Authors: Guerrero Michael S. , Schuh Natasha R. , Bouton Amy H. 
Published: February 2011

Abstract
Tamoxifen, an antiestrogen and estrogen receptor (ER) ligand, has been successfully used to treat ER-positive breast tumors for almost 40 years. For women with ER-positive disease, tamoxifen treatment can decrease the rate of recurrence by 50% and reduce the risk of death by 25%. Despite such success, resistance occurs in up to one-third of patients. To date, many proteins have been identified that contribute to resistance. Breast Cancer Antiestrogen Resistance-3 (BCAR3) is one such molecule; its expression induces resistance to the antiestrogens tamoxifen and ICI 182, 780 (fulvestrant). To investigate the signaling pathway(s) driving BCAR3-mediated resistance, we generated clones of the ER-positive and antiestrogen-sensitive MCF7 cell line that overexpress BCAR3 (MCF7 B6). Utilizing these cells, we show here that BCAR3 overexpression confers a growth advantage under conditions of both hormone deprivation and tamoxifen treatment. We further employed this inducible cell line to examine the relationship between BCAR3 and two other molecules that have been implicated in both antiestrogen resistance and BCAR3 signaling: the scaffold/adaptor molecule p130Cas (Cas, also known as BCAR1) and the non-receptor tyrosine kinase c-Src (Src). Upon BCAR3 overexpression, we observed an alternative Src-Cas complex, increased Src kinase activity, and an increase in Src-dependent tyrosine phosphorylation of Cas. Interestingly, these BCAR3-induced effects are preserved following tamoxifen treatment. Conversely, upon knockdown of BCAR3 in the ER-negative BT549 breast cancer cell line, Src activity was reduced, as were Cas phosphorylation and Src-Cas interactions. We also examined the expression and subcellular localization of the cyclin-dependent kinase inhibitor and known Src substrate, p27. In MCF7 B6 cells overexpressing BCAR3, we observed a decrease in the nuclear accumulation of p27 under conditions of both hormone deprivation and tamoxifen treatment. Based on these data and the established role of Src-Cas signaling in the induction of antiestrogen resistance, we postulate that these factors play a significant role in the promotion and establishment of BCAR3-mediated tamoxifen resistance.
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 4134.
Abstract 4136: Effects of magnolol on cell cycle, STAT 3, NF-kappa B and AKT signaling
Authors: Chilampalli Shivani , Kaushik Radhey S. , Chandrasekher Gudiseva , Fahmy Hesham , Dwivedi Chandradhar 
Published: February 2011

Abstract
Magnolol is plant lignan isolated from bark and seed cones of Magnolia glaucan has been investigated for its anticancer effects. Previous studies from our laboratory have shown magnolol to be chemopreventive against UVB-caused skin carcinogenesis by inducing apoptosis. The objective of present study is to investigate other mechanisms involved for its chemopreventive effects. For this investigation, A431 human epidermoid carcinoma cells were used. Effects of magnolol on cell cycle were determined by flow cytometry. Expressions of various proteins involved in cell cycle were determined by Western blotting using appropriate antibodies. A431 human epidermoid carcinoma cells were incubated with different concentrations at different time periods. We further investigated the effects of magnolol on signal transducer and activator of transcription (STAT 3), nuclear factor-kappa B (NF-kappa B/p65) and AKT signaling pathways that play an important role in cell proliferation and survival. Magnolol at 100 μM and 125 µM caused G0/G1 cell cycle arrest by decreasing cyclin D1, cyclin D2, and CDK 4 and by increasing CDK inhibitors p21 and p27 at 24 and 48 h. We further found that magnolol inhibited expressions of STAT 3, NF-kappa B and AKT by inhibiting their phosphorylation at 24 and 48 h. These results indicate that chemopreventive effects of magnolol are mediated through multiple mechanisms.
This study is supported by Translational Cancer Research Center funded as one of the 2010 Research Initiative Center by the State of South Dakota.
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 4136.
Abstract 4138: Resveratrol induces COX-2-dependent apoptosis in human ovarian cancer cells
Authors: Lin Cassie , Sebuyira Annette , Davis Faith B. , Davis Paul J. , Lin Hung-Yun 
Published: February 2011

Abstract
Resveratrol is a naturally-occurring trihydroyxl-diphenylethylene compound that has been shown experimentally to have beneficial effects in the treatment of cancer and cardiovascular disease. We have studied the molecular basis of the anti-cancer actions of resveratrol, using human ovarian carcinoma (OVCAR-3) cells. Resveratrol induces programmed cell death (apoptosis) in these cells and activates important signal transducing proteins including extracellular signal-regulated kinases 1 and 2 (ERK1/2) in cancer cells. Resveratrol also causes nuclear accumulation of the enzyme cyclooxygenase-2 (COX-2) and of the oncogene suppressor protein, p53. Expressed constitutively, cytoplasmic COX-2 is a marker of tumor cell aggressiveness, but there is a resveratrol-inducible pool of nuclear COX-2 that is important to activation (Ser-15 phosphorylation) of the oncogene suppressor protein, p53. Our findings include the following: (1) Nuclear accumulation of COX-2 in resveratrol-treated cells is blocked by the ERK1/2 inhibitor, PD98059. (2) An inhibitor of COX-2 activity, NS398, prevents accumulation in the nucleus of ERK1/2, COX-2, activated p53 and SUMO-1. (3) Apoptosis, quantitated by nucleosome ELISA and the nuclear abundance of the pro-apoptotic protein, Bcl-xs, were inhibited by NS398. This finding implicates nuclear COX-2 in p53-mediated apoptosis induced by resveratrol. Sumoylation is important to stabilization of p53 and a COX-2/SUMO-1 interaction suggests sumoylation of COX-2 in resveratrol-treated cells. (4) Chromatin immunoprecipitation (ChIP) studies showed binding of induced nuclear COX-2 to the promoter region of p21, a pro-apoptotic gene target of transcriptionally active p53. In summary, nuclear accumulation of activated ERK1/2 and COX-2 are essential to resveratrol-induced, pSer-15-p53-mediated apoptosis in human ovarian cancer 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 4138.
Abstract 4140: Inhibition of mTOR signaling by psoralidin in breast cancer
Authors: Damodaran Chendil , Kumar Raj , Rohr Jurgen 
Published: February 2011

Abstract
Breast carcinoma is the most common malignancy in women and is the second leading cause of cancer-related deaths in the United States. Mammalian target of rapamycin (mTOR) is a major effector of the PI3Kinase/Akt pro-survival signaling pathway and has received significant attention as a therapeutic target for the treatment of various malignancies. Rapamycin and its analogs are specific mTOR antagonists; however their toxicity hampers wide use in the clinical setting for the treatment of breast cancer. This compels development of new strategies for the treatment of advanced, triple and double negative breast cancers. Psoralidin is one of the major active ingredients in Psoralea corylifolia, herbal plant that is extensively used in Asian and African traditional medicines. In our study we tested the effects of psoralidin on the mTOR pathway in estrogen-responsive (MCF-7) and -refractory (MDA 231) breast cancer cells. Our results suggest that psoralidin inhibits phoshporlyation of mTOR resulting in the inhibition of the phosphorylation of mTOR effectors (p70S6K and 4EBP1) in both MCF-7 and MDA 231 cells. Interestingly, there was no significant down regulation of pAkt expression in either cell lines following treatment with psoralidin. While dissecting the effect of psoralidin on epithelial-mesenchymal transition (EMT), we found that psoralidin inhibits expression of β-catenin with a concomitant increase in the expression of E-cadherin in both estrogen-responsive and -refractory breast cancers cells. In addition, treatment with psoralidin effectively inhibits the growth of both estrogen-responsive (MCF-7) and -refractory (MDA 231) breast cancer cells and induces apoptosis without causing significant toxicity to normal breast epithelial cells (MCF-10A). Currently we are pursuing studies using xenograft models to determine the effect of psoralidin in estrogen-responsive and -refractory breast cancers animal models. The outcome of this study may provide a mechanistic validation of psoralidin as a potent compound that may be used for the treatment of breast 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 4140.