bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4123: Induction of motility, invasion, and proliferation by wild-type EGFR depends on c-Met in NSCLC
Authors: Dulak Austin M. , Gubish Christopher T. , Siegfried Jill M. 
Published: February 2011

Abstract
The complex signaling networks promoting non-small cell lung cancer (NSCLC) progression are currently being dissected to identify novel therapeutic targets or potential drug combinations. One cascade that is at the forefront of drug discovery in NSCLC is the Epidermal Growth Factor Receptor (EGFR) pathway. EGFR is a receptor tyrosine kinase (RTK) that interacts with ligands Epidermal Growth Factor (EGF), Transforming Growth Factor-alpha, and Amphiregulin, to promote invasive growth, a program requiring growth, motility, and invasion. Recently, there has been strong evidence linking c-Met to EGFR tyrosine kinase inhibitor (TKI) resistance. c-Met is a RTK that interacts with its natural ligand Hepatocyte Growth Factor (HGF), also known as Scatter Factor, to activate invasive growth, similar to EGFR, in many cancers including NSCLC. We previously reported an HGF independent mechanism of c-Met activation through EGFR that required c-Src. Here, we demonstrate that c-Met activation is necessary for known EGF-induced phenotypes in 201T and A549 NSCLC cell lines expressing moderate levels of wild-type (wt) EGFR and c-Met. Stimulation with EGF (50 ng/mL) in serum-free media induced cell invasion at 48 h that was inhibited by ∼74% when pretreated with the c-Met TKI, PF2341066 (1 uM) (Pfizer). Motility, initiated through EGFR, was reduced by 47% and 42% in 201T and A549 cells, respectively by PF2341066. Similarly, c-Met inhibition partially abrogated EGF-induced proliferation by 31% in 201T cells and 43% in A549 cells. To confirm these findings, the invasion assay was repeated with c-Met siRNA in 201T cells. Knockdown of c-Met resulted in an 80% reduction in EGF-stimulated invasion. Together, this suggests that EGFR action relies, in part, on activation of c-Met to modulate invasive growth in wt-EGFR NSCLC cell lines. Based on these data, it was addressed whether combined EGFR (gefitinib) and c-Met (PF2341066) targeting in a 3-week 201T xenograft murine model could lead to enhanced anti-tumor effects. PF2341066 (50 mg/kg) alone had no significant effect on inhibiting tumor xenograft growth, whereas gefitinib (150 mg/kg) alone significantly reduced tumor volume by 51%. Combining TKI therapies produced a 66% decrease in tumor volume, a significantly greater effect compared to PF2341066 and gefitinib groups, individually. These findings indicate that EGFR activation of c-Met plays a critical role in lung tumor progression and that combined EGFR and c-Met targeting hold strong therapeutic potential in lung cancer without EGFR and c-Met mutations.
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 4123.
Abstract 4129: Effects of the metabolism of omega-3 fatty acid EPA by CYP1A1 in breast cancer proliferation and survival
Authors: Rodriguez Mariangellys , Mitra Ranjana , Guo Zhijun , Becker Marc A. , Yee Douglas , Potter David A. 
Published: February 2011

Abstract
Omega-3 fatty acids are widely known for their importance in heart disease. However, the impact of omega-3 fatty acids in breast cancer is not fully understood. Through these studies we seek to understand the role of the metabolism of the omega-3 fatty acid known as eicosapentaenoic acid (EPA) in breast cancer and determine whether it may affect breast cancer progression. It is known that high levels (60uM) of EPA have anti-proliferative effects in various cancer lines. Consistent with these reports, we found that EPA treatment (60uM) of the estrogen receptor positive line MCF7 and the estrogen receptor negative line MDA-MB-231 decreases cell proliferation. Interestingly, lower dosing of EPA (15uM-40uM) significantly stimulated the proliferation of these lines. It has been shown that cytochrome P450 1A1 (CYP1A1) selectively epoxygenates EPA to 17(18)-epoxyeicosatetraenoic acid (17,18-EpETE). Measurement of cell growth by MTT assay shows that 17,18-EpETE promotes the proliferation of the MCF7 and MDA-MB-231 lines in a dose- (≥ 1uM) and time-dependent (max effect at 48-72hrs) manner. Together, these results led us to hypothesize that CYP1A1 metabolizes EPA into 17,18-EpETE, thereby promoting breast cancer proliferation and survival. To better understand this epoxygenase mechanism, we studied the impact of CYP1A1 and the 17,18-EpETE metabolite of EPA on cell proliferation by MTT assay, cell cycle progression by propidium iodine staining, and apoptosis by Annexin V flow cytometry. We found that CYP1A1 is expressed in MCF7 and MDA-MB-231 lines and siRNA-mediated knock down significantly inhibits the proliferation of these lines. CYP1A1 knock down also blocks the proliferative effect of treatment with 15uM EPA. Our preliminary data also indicate that 17,18-EpETE promotes growth of the MDA-MB-231 line, in part, by decreasing apoptosis and increasing the S- and G2/M cell populations. Consistently, knock down of CYP1A1 in MDA-MB-231 line increases the G0/1 cell population and decreases number of cells in the S and G2/M phases, consistent with a G1 block. The mechanism of action in MCF7 cells is yet to be determined. Better understanding of the mechanism by which EPA metabolism affects breast cancer may impact our understanding of breast cancer prevention and therapeutics. We propose that CYP1A1 may be of significant importance in breast cancer progression through novel mechanisms that depend on biosynthetic pathways promoting EPA epoxygenation.
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 4129.
Abstract 4139: Development of a transcription factor decoy for efficient systemic administration in head and neck cancer
Authors: Sen Malabika , Thomas Sufi Mary , Ly Danith , Rapireddy Srinivas , Grandis Jennifer Rubin 
Published: February 2011

Abstract
This study was aimed to develop a transcription factor decoy for efficient systemic administration in head and neck cancer. Signal Transducer and Activator of Transcription-3 (STAT3) is upregulated in numerous human cancers including head and neck squamous cell carcinoma (HNSCC). Small molecules that target STAT3 are limited by lack of specificity. We developed a transcription factor decoy targeting STAT3 consisting of a 15-mer double-stranded oligonucleotide with three phosphorothioate modifications (PTO) at the 3′ and 5′ end of the double-stranded structure. This decoy exhibits antitumor efficacy in preclinical cancer models and is now being tested in a phase 0 human trial with intratumoral inoculation. To enable systemic administration, the STAT3 decoy formulation has been modified to enhance stability and uptake into tumors. A series of chemically modified STAT3 decoys have been designed to increase resistance to nucleases and enhance stability when administered in vivo. These include tetra-nucleotide single stranded DNA sequences (DN4), 18-atom hexa-ethyleneglycol spacers (DS18), and locked nucleic acid (LNA-1) modifications to enhance stability in serum. The modified STAT3 decoys were tested for serum nuclease degradation, melting temperature, binding to pSTAT3 protein, uptake and biologic activity. LNA-1 showed increased half-life of up to 8 h in serum, whereas DN4 is stable up to 4 h, DS18 up to 3 h compared with the parent STAT3 decoy, which is resistant only up to 2 h. The melting temperature demonstrated increased thermal stability for all the modified decoys compared to the parent STAT3 decoy. The DN4, DS18 and LNA-1 modified decoy bound to recombinant STAT3 protein as well as the parent decoy and inhibited head and neck cancer cell proliferation in vitro at nanomolar concentrations. The modified STAT3 decoys (DN4, DS18 and LNA-1) showed increased uptake into head and neck cancer cells similar compared with the parent STAT3 decoy. These modified decoys will be tested for their effect on STAT3 target gene expression and in vivo antitumor efficacy when administered systemically with anticipation of implementing a phase I clinical trial if tumor growth inhibition is observed upon intravenous injection.
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 4139.
Abstract 4141: Notch signaling: A new potential target in the treatment of uveal melanoma
Authors: Asnaghi Laura , Coonfield Michael L. , Schreck Karisa C. , Bar Eli E. , Handa James , Merbs Shannath , Ebrahimi Katy , Harbour J. William , Eberhart Charles G. 
Published: February 2011

Abstract
Uveal melanoma is the most common primary intra-ocular malignancy in adults, and causes significant mortality due to its propensity to metastasize. Our aim is to investigate the role of Notch signaling in promoting uveal melanoma proliferation and invasion. We examined five established uveal melanoma cell lines, and found using qPCR that the Notch 1-2-3 receptors, Jag1-2 ligands and the pathway target Hes1 were expressed to varying degrees in all lines. We then blocked Notch signaling using the gamma-secretase inhibitor (GSI) MRK003, and found that only three of the lines (OCM1, OCM3, OCM8) had their growth inhibited by the drug. Interestingly, these three lines had significantly higher levels of Hes1 mRNA as compared to the two lines resistant to GSI treatment (Mel 285, Mel 290). GSI treatment induced a dose-dependent reduction of anchorage-independent clonogenic growth, with 50% inhibition in OCM1, 70% in OCM3, and 40% in OCM8, as well as a significant reduction in Hes1 mRNA and protein levels. Apoptosis, as measured by cleavage and activation of caspase-9, was also induced. Finally, we observed inhibition of cellular invasion in GSI treated cultures using transwell migration and scratch assays. Preliminary studies of snap-frozen primary tumors indicate that Notch pathway components are expressed in primary uveal melanoma in vivo at levels as high or higher than those in our cell line models. In addition, oligonucleotide microarray analysis showed a significant increase in Jag2 and Notch3 expression levels in primary uveal melanomas that metastasized as compared to those that did not. Our findings suggest that the Notch pathway plays an important role in inducing cellular proliferation and invasion in uveal melanoma, and that inhibiting this pathway using pharmacological agents may be effective in preventing tumor growth and 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 4141.
Abstract 415: Identification of colon cancer recurrence related CNVs using array-CGH
Authors: Park Chan Hee , Rha Sun Young , Jeung Hei-Cheul , Kim Nam Kyu , Roh Jae Kyung , Chung Hyun Cheol 
Published: February 2011

Abstract
Colon cancer is one of the leading causes for cancer-related death in the Western world. The most important factor in colon cancer-related death is recurrence. Recently, many studies have reported that copy number variation (CNV) is related to genetic diseases such as cancer and Alzheimer's disease. In this study, we selected the different aberration CNVs from non-tumor colon tissues by comparing recurred and non-recurred colon cancer patients using 44K oligonucleotide microarray. We selected 1359 different aberration probes, which contained cancer-, neurological disease- and cell signaling-related pathway genes between 22 non-recurred and 19 recurred patients. In 1359 probes, Ingenuity Pathway Analysis software showed that 89 genes composed of cell to cell signaling, cellular movement, and nervous system developmental pathway. In these 89 genes, LIMS2 was known as ILK-related molecular function of cancer cell migration and invasion. ILK-related pathway had important role in cancer cell migration and invasion through function of secretory protein such as MMP9, MMP11. LIMS2 showed copy number amplification and up-regulation of mRNA expression in non-recurrence patient group. In vitro experiment, protein and mRNA of LIMS2 were down-expressed in 5 colon cancer cell lines compared to 3 normal epithelial colon cell lines. In LIMS2 siRNA treated HCT-116 colon cancer cell, protein level of LIMS2 was decreased about 90%, while MMP9, MMP11 protein expression increased. Also, migration and invasion rate of HCT-116 cell increased in LIMS2 siRNA treated group and LIMS2 siRNA treated condition media compared to the control group using wound-healing and trans-well assay. According to array-CGH and in vitro experiment, we found that LIMS2 could play an important role in colon cancer metastasis through paracrine effect.
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 415.
Abstract 4157: Genetic and dietary complementation in risk for mouse intestinal tumorigenesis
Authors: Wang Donghai , Peregrina Karina , Dhima Elena , Mariadason John , Augenlicht Leonard H. 
Published: February 2011

Abstract
Dietary factors are significant in determining probability for intestinal tumor development even in the presence of strong genetic initiation. For example, a rodent Western-style diet (WD1), modeled to reproduce intake of nutrient risk factors in the human diet associated with sporadic colon cancer, potentiates the formation of intestinal tumors in Apc1638N/+ mice, even when the genetic initiation by Apc is augmented by targeted inactivation of the p21Waf1/cip1 locus. To investigate mechanisms of this synergistic effect, we profiled gene expression along the mouse crypt-villus axis (CVA) using cells isolated as a function of their position along this axis from WT, Apc1638N/+ and p21−/− mice fed control AIN76A diet, and WT mice fed the WD1. Modulation of sequence expression by the WD1 was enriched in the villus compartment, while changes induced by targeting either genetic locus (Apc1638N/+ or p21−/−) were largely in the crypt, where the overlap in altered gene sets was greatest for the genetic models. There was greater overlap among expression changes between Apc1638N/+ and p21−/− mice, than between these genetic mice models and mice fed the WD1, in both the villus and crypt. Paneth cell markers, whose deregulation has been reported in intestinal tumors, were up-regulated in the p21−/− mouse crypt and in WD1 mouse villus. Moreover, there was attenuated expression of secretory cell lineage markers (ie goblet and enteroendocrine cells), but enhanced expression of enterocyte markers, for both the genetic and dietary models. Genes that encode tricarboxylic acid (TCA) cycle enzymes were uniformly decreased in the crypt of both genetic models, with fewer changes in this pathway altered in the WD1 mouse. Gene ontology and biological pathway analysis also showed that Wnt pathway and c-myc target genes were overrepresented in the villus of the WD1 mouse. Supplementation of WD1 with calcium and vitamin D (WD2) reversed aberrantly up-regulated cyclin D1, cyclin D2, defensins and lysozymes in the WD1 villus back to control levels. In summary, complementary changes in cell reprogramming contributed by a western style diet and targeted inactivation of the p21 gene are important in the synergy of these factors in elevating probability of intestinal tumorigenesis.
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 4157.
Abstract 4183: Modeling soft tissue sarcomas by conditional inactivation of p53 and Rb tumor suppressor genes
Authors: Choi Jinhyang , Roy David M. , Curtis Stephen J. , Flesken-Nikitin Andrea , Hwang Chang-il , Wang Wei , Nikitin Alexander Yu. 
Published: February 2011

Abstract
Soft tissue sarcomas, particularly its most common type, undifferentiated pleomorphic sarcomas (also known as malignant fibrous histiocytomas), frequently carry mutations in p53 and Rb tumor suppressor genes. We have established the sarcoma mouse model using conditional inactivation of p53 and Rb by a single subcutaneous injection of adenovirus carrying Cre-recombinase into transgenic mice with floxed copies of p53 and Rb genes. The majority of sarcomas in this model are malignant fibrous histiocytomas, which is a neoplasm consisting of intermixed fibroblast- and histiocyte-like cells. By using irradiation chimeras that have been generated by transplanting bone marrow cells from mice carrying the Rosa26StopLacZ or the Z/EG reporter, as well as floxed p53 and Rb genes, to irradiated p53loxP/loxPRbloxP/loxP mice, we have determined that sarcomas in this model do not originate from hematopoietic cells but arise from the local resident cells. Although the majority of dermal cells infected with AdCMVCre-eGFP have shown expression of fibroblast marker procollagen type I or macrophage marker F4/80, we have observed that cells expressing stem cell markers Sca-1 and nestin also have been targeted by adenovirus. Notably, isolated mesenchymal multipotent cells characterized by strict plastic adherence and low levels of Sca-1 expression have shown enhanced potential for malignant transformation according to proliferation, invasion, and soft agar assays, following conditional inactivation of p53 and Rb. Additionally, we have determined that sarcomas have increased expression of CXCR4, while its ligand SDF-1 is expressed by infiltrating macrophages. Treatment of sarcoma cells with SDF-1 leads to their increased invasion in Boyden chamber assay while CXCR4 knockdown with siRNA abrogates this effect. Taken together, our results indicate that local Sca-1low multipotent dermal stem/progenitor cells may be a preferential target for malignant transformation associated with p53 and Rb deficiency. Furthermore, accumulation of SDF-1 producing macrophages may stimulate sarcomagenesis.
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 4183.
Abstract 4201: AP1 factor inactivation in suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation
Authors: Rorke Ellen A. , Jans Ralph , Adhikary Gautam , Berman David , Eckert Richard L. 
Published: February 2011

Abstract
AP1 (jun/fos) factors comprise a family of transcriptional regulators (c-jun, junB, junD, c-fos, FosB, Fra-1 and Fra-2) that are key controllers of epidermal keratinocyte survival and differentiation, and are important drivers of cancer development. Previous studies indicate that targeted inactivation of epidermal basal layer AP1 factor function by expression of dominant-negative c-jun (TAM67) in the basal epidermis produces no overt phenotypic impact, but does inhibit UVB and carcinogen-dependent epidermal tumor formation. We hypothesized that the role of AP1 factors is likely to be different in basal versus suprabasal epidermis. To test this hypothesis, we targeted TAM67 to the suprabasal epidermis using a tetracycline-inducible construct. Induction of suprabasal TAM67 expression results in marked epidermal hyperproliferation and hyperkeratosis. This is characterized by expression of basal layer and hyperproliferation-associated keratins in the suprabasal epidermis, suggesting that the cells are undergoing incomplete differentiation. We further demonstrate global changes in the AP1 factor signaling including changes in level and subcellular distribution of selected AP1 factors. Surprisingly, these animals display reduced susceptibility to carcinogen-dependent tumor induction. These novel observations, which suggest that perturbing AP1 factor function in the basal versus suprabasal layer produces different biological outcomes, is cancer relevant and points to the complexity of AP1-associated regulation and that fact that AP1 factor function differs as the tissue differentiates.
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 4201.
Abstract 4215: Hypoxia regulates the breast cancer stem/progenitor cell population
Authors: Santos Sarah , Heath Amber , Wicha Max 
Published: February 2011

Abstract
There is increasing evidence from our lab and others supporting the “cancer stem cell” hypothesis in breast cancer, which proposes that tumors are driven a small population of cells exhibiting stem cell properties. These cancer stem/progenitor cells may also be responsible for mediating tumor metastasis and resistance to cancer treatments. Recently, several new cancer therapies targeting tumor angiogenesis have been developed and validated in clinical trials. Specifically, the VEGFR and multikinase inhibitors sunitinib and sorafenib have been approved for treatment of some tumor types. However, clinical trials in breast cancer and other malignancies have demonstrated that these therapies ultimately result in drug resistance and only modestly prolong patient survival. Recent reports have suggested that these angiogenesis inhibitors may promote tumor invasiveness and metastasis in rodent breast cancer models. We hypothesize that the tumor stem/progenitor cell population increases in response to hypoxia in anti-angiogenic treated cancers, leading to increased tumor aggressiveness. We have used in vitro and in vivo assays to study the possible role of hypoxia in regulating mammary cancer stem/progenitor cells. We demonstrate that moderate hypoxia (2% oxygen) enriches for stem/progenitor cells in several breast cancer cell lines grown in vitro. The percentage of cells expressing ALDH as assessed by the Aldefluor assay approximately doubles in response to hypoxia. In vivo, sunitinib treatment increases the proportion of Aldefluor positive cells in SUM-159 and MDA-MB-231 breast cancer xenografts in NOD/SCID mice. In addition, tumor cells obtained from sunitinib treated mice exhibit enhanced tumor initiation and growth upon transplantation into secondary NOD/SCID mice. These studies indicate that tissue hypoxia results in expansion of the breast cancer stem/progenitor cell population. This may contribute to the increased aggressiveness and metastasis of cancers that evolve during therapy with angiogenesis inhibitors. If this is the case, then the addition of cancer stem cell targeting agents to antiangiogenic agents may reduce the development of treatment resistance and enhance treatment efficacy.
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 4215.