bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 529: Matrix metalloproteinase expression and secretion in papillary thyroid carcinoma
Authors: Kummer Nicolas T. , Bedwell Josh , Nowiki Theodore S. , Schantz Stimson , Shin Edward , Schaefer Steven , Tiwari Raj K. , Geliebter Jan 
Published: February 2011

Abstract
In the last decade, the incidence of thyroid cancer has risen ∼84% and mortality ∼34%. The ACS estimates ∼ 37,200 new cases of thyroid cancer, with 1,630 deaths in 2009. Papillary thyroid carcinoma (PTC) is the most common thyroid and endocrine malignancy, accounting for ∼80% of all thyroid cancer. It typically occurs from a gain-of-function mutation in the RET, RAS or BRAF genes which make up a linear signaling cascade for ERK activation. Recurrent or persistent disease prevails in up to 40% of thyroidectomy cases with a poor prognosis when aggressive cancer is evident. Thus, further research into factors contributing to aggressive disease is merited. Matrix metalloproteinases (MMPs) represent a family of secreted proteases with diverse functions implicated in the pathogeneses of aggressive tumors. Their functions include degrading the extracellular matrix (ECM) to facilitate cell migration, cell signaling through ECM cleavage products that can affect apoptosis and cell growth, and they can act directly on growth factor precursors and receptors. MMP upregulation has been demonstrated in many types of cancers yet its pattern of expression is poorly understood in PTC. Analysis of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the human PTC cell line, BCPAP, and the normal thyroid cell line, NTHY-ori by protein array and real-time RT-PCR revealed significantly elevated levels of MMPs and decreased levels of TIMP-4. Real time RT-PCR demonstrated the following fold increases in expression in BCPAP compared to NTHY-ori: 16. 9 (SE=0.79) for MMP-1, 1.80 (SE=0.41) for MMP-3, 1.40 (SE=0.08) for MMP-9, 7.12 (SE=2.14) for MMP-10, 12.60 (SE=6.90) for MMP-13 and increased levels of TIMP-4 in NTHY-ori compared to BCPAP of 2.38 (SE=1.04). Protein array data from serum free conditioned media of the cell lines reflected a similar pattern of secreted MMP and TIM4 levels. Fold increases in the optical concentration (determined by spot densitometry) of secreted proteins were detected in BCPAP compared to NTHY-ori of 29.48 (SE=1.92) for MMP-1, 16.80 (SE=1.07) for MMP-3, 1.66 (SE=0.07) for MMP-9, 3.66 (SE=0.55) for MMP-10, 1.59 (SE=0.11) for MMP-13 and increased levels of TIMP-4 in NTHY-ori compared to BCPAP of 1.27 (SE=0.06). For the first time, these results demonstrate increased production and secretion of a group of MMPs and down regulation of TIMP-4 which have been characterized in tumor progression in a PTC cell line. Further investigation into the role these agents play in the tumorgenesis of aggressive PTC may yield insight into future treatment and screening alternatives.
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 529.
Abstract 5290: Motility of B16 mouse melanoma cells is driven by phospho-MARCKS
Authors: Rotenberg Susan A. , Chen Xiangyu 
Published: February 2011

Abstract
Phosphorylation of Myristoylated Alanine-rich C-Kinase Substrate (MARCKS) by protein kinase Cα (PKCα) is known to trigger its release from the plasma membrane/cytoskeleton into the cytoplasm, thereby promoting actin reorganization during migration. This study shows that cytoplasmic phosphoMARCKS directly promotes motile behavior of melanoma cells. Aggressively motile B16 F10 mouse melanoma cells express high levels of phosphoMARCKS, whereas weakly motile F1 cells express negligible levels. When treated with okadaic acid (OA) (a protein phosphatase inhibitor), F1 cells exhibit a dramatic increase in phosphoMARCKS coincident with a 5-fold increase in motility. This motility is lost if OA-treated cells are also treated with a shRNA reagent targeted to MARCKS. Pre-treatment of cells with calphostin C (a PKC inhibitor) prevents OA-mediated elevation of phosphoMARCKS. These findings imply that PKC is highly active in F1 cells but that its phosphorylation of MARCKS is efficiently reversed by protein phosphatases. The mechanistic significance of phosphoMARCKS to motility is established with a pseudo-phosphorylated mutant of GFP-MARCKS in which Asp residues replaced Ser residues known to be phosphorylated by PKCα. This mutant localizes to the cytoplasm and engenders three-fold higher motility in F1 cells. However, when the mutant is fused to a nuclear localization signal, motility is substantially decreased. Expression of an unmyristoylated, phosphorylation-resistant MARCKS mutant that localizes to the cytoplasm, blocks motility by 40-50% of both OA-stimulated F1 cells and intrinsically motile F10 cells. These findings demonstrate the importance of phosphoMARCKS to the metastatic potential of melanoma cells, and reveal a previously undocumented cytoplasmic role for this phospho-protein.
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 5290.
Abstract 5291: Exploring mechanisms underlying invasion in HLRCC: Assessing the contribution of HIF and ROS
Authors: Sourbier Carole , Kim Yeong-Sang , Lee Sunmin , Trepel Jane , Neckers Len , Linehan W. Marston 
Published: February 2011

Abstract
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a highly metastatic disease characterized by a disruption of the Krebs cycle due to a germline mutation of the fumarate hydratase gene (FH). We have recently shown that HLRCC kidney cancer cells are in a pseudo-hypoxic state due to normoxic stabilization of both HIF1 and HIF2 and that the expression of HIF1 can be decreased using ROS scavengers such as pyruvate or N-acetylcysteine (NAC). Our objective was to study the involvement on invasion of aberrant HIF1 and HIF2 expression in HLRCC cells. When either HIF1 or HIF2 was knocked down, invasion was dramatically inhibited in vitro. Invasion of HLRCC cells was also inhibited by decreasing the ROS level with NAC. To study further the mechanisms by which HIF1 and HIF2 mediate invasion in HLRCC, we evaluated several markers of glycolysis and ROS formation. Our results show that when HIF1, but not HIF2, is knocked down, Glut1 mRNA level, glucose uptake, and lactate secretion are decreased. Even though N-acetylcysteine treatment decreased HIF1 and HIF2 expression, it did not affect glucose uptake or lactate secretion by HLRCC cells. Moreover transient knock-down of HIF1 or HIF2 by siRNAs did not affect the ROS level in vitro. To study further the mechanism of action of both HIF1 and HIF2, microarrays and in vivo experiments with stably transfected cell lines with shRNA for HIF1, HIF2 and ARNT are in progress. These results suggest that HIF1-mediated invasion may partially involve glycolysis. The mechanisms by which HIF2 and ROS mediate invasion are still under study. Our data support the hypothesis that HIF1, HIF2 and ROS are important for invasion. If one of them is inhibited, invasiveness of the HLRCC cells is compromised.
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 5291.
Abstract 5292: Role of voltage-gated Na+ channels in the metastatic potential of colon cancer cells
Authors: House Carrie , Vaske Charles , Schwartz Arnold , Obias Vincent , Sarvazyan Narine , Hales Tim , Stuart Joshua , Lee Norman 
Published: February 2011

Abstract
Ion channels are major signaling proteins spanning the plasma membrane where they enable the diffusion of specific ions into and out of a variety of cells. Voltage-gated Na+ channels (VGSCs) are responsible for the depolarization phase of neuronal action potentials and their activity is required for neurite extension and neurotransmitter release. Aberrant expression of VGSCs has recently been implicated in cancer. Overexpression of VGSCs appears to be associated with increased motility and invasive potential in vitro, whereas treatment with pharmacological agents that block Na+ currents, significantly reduce invasion. We have recently identified functional VGSCs in SW480, SW620, and HT29 colon cancer cells and examined their role in invasion. Electrophysiological techniques were employed to confirm functional expression of the SCN5A isoform in colon cancer cells. The more invasive SW620 cell line has a higher current density and increased protein expression compared to the less invasive SW480 and HT29 cell lines. Furthermore, we used RNA interference and VGSC blockers (tetrodotoxin and lidocaine) to inhibit channel expression and activity, respectively, and demonstrated a loss of invasive potential. Conversely, treatment with veratridine, a neurotoxin that prevents complete inactivation of VGSCs, increased Na+ influx and led to higher invasive potential. In addition to colon cancer cell lines, the expression of Nav1.5, the protein encoded by SCN5A, was examined in colon cancer patient samples by immunohistochemistry. Expression of this channel was restricted to the lumen of colon cancer specimens when compared to their normal matched controls. The contribution of this channel to metastatic behavior has not been previously demonstrated in colon cancer. To facilitate a further understanding of the mechanism by which this channel induces invasive potential, we have analyzed the involvement of SCN5A in activation of the MAPK pathway, which is deregulated in many cancers. Coincidentally, this pathway is also activated after depolarization in neurons during neurogenesis. Lastly, we show that SCN5A participates in the regulation of a colon cancer transcriptional network important for invasion. Taken together, our data suggest that VGSCs contribute to the metastatic potential of colon cancer cells through activation of the MAPK pathway and transcriptional regulation of genes important for the invasion process.
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 5292.
Abstract 5293: CCN3 increases motility of human chondrosarcoma via PI3K, AKT and NF-κB pathways
Authors: Chen Ruei-Ching 
Published: February 2011

Abstract
Nephroblastoma overexpressed (Nov; CCN3), from the CCN gene family, which is involved in many cellular activities such as growth and differentiation. Most of the CCN family can regulate the cell motility, adhesion and division. Here, we found that CCN3 increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). Activations of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), Akt and NF-κB pathways after CCN3 treatment was demonstrated, and CCN3-induced expression of MMP-13 and migration activity was inhibited by the specific inhibitor of PI3K, Akt and NF-κB cascades. Transfection of cells with FAK, p85, Akt, IKKα and IKKβ mutant also reduced CCN3-mediated cancer migration. Taken together, our results suggest that CCN3 acts through FAK/PI3K/Akt, which in turn activates NF-κB, resulting in the activation of MMP13 andcontributing to the migration of human chondrosarcoma 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 5293.
Abstract 5298: Human enhancer of filamentation 1 induction by Prostaglandin E2 enhances the cell motility of colorectal cancer cells
Authors: Xia Dianren , Menter David G. , DuBois Raymond N. 
Published: February 2011

Abstract
Prostaglandin (PG) E2 promotes cell motility during colorectal carcinogenesis. The mechanism by which PGE2 signaling regulates cell motility is not completely understood. Here, we demonstrated that PGE2 treatment induces HEF1 expression that links with cell motility in colorectal cancer cells. PGE2 rapidly stimulated HEF1 expression in colorectal cancer cells. Both PGE2 treatment and HEF1 overexpression activated Rac 1 and resulted in similar effects on cell spreading. Moreover, knockdown of HEF1 using shRNA suppressed PGE2-driven cell spreading. PKA activator forskolin induced HEF1 expression and cell spreading in a similar manner as PGE2. Inhibition of PKA activity by H-89 attenuated HEF1 expression induced by PGE2. Furthermore, PKA knockdown by siRNA blocked the HEF1 expression and cell spreading induced by PGE2. These data suggest that PGE2 induces HEF1 expression to promote cell motility through a PKA-involved pathway.
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 5298.
Abstract 5299: Separate functions of caspase-3 in cell migration and apoptosis
Authors: Libby Erika , Eble Shannon , Adelson Martin , Mordechai Eli , Trama Jason 
Published: February 2011

Abstract
The cysteine protease function of caspase-3 in the execution phase of apoptosis is well known. However, even though subverting apoptosis is beneficial for tumor development and survival, some tumors maintain high expression levels of caspase-3 in positive correlation with malignancy. Here we show that caspase-3 expression is positively correlated with tumor cell migration and invasion. Furthermore, the enhanced migration and invasion is protease-independent and is specifically conferred by the inactive precursor form of caspase-3. Ectopic expression of caspase-3 in the MCF7 cell line, which is caspase-3 deficient and showed low migration ability, enhanced wound healing and chemotaxis. In contrast, shRNA reducing the expression of caspase-3 in the 5637 cell line, which expressed a high level of caspase-3 and high migration ability, hampered wound healing, chemotaxis, and matrigel invasion. Use of a caspase cysteine protease inhibitor or site directed mutagenesis of caspase-3 either rendering the ectopically expressed precursor form non-processable or inactivating the cysteine protease site did not diminish the caspase-3-dependent increase of cell migration. In addition, only reconstitution of the MCF7 cell line with the wild-type or non-processable precursor form of caspase-3 enhanced cell migration. Ectopic expression of the p17 or p12 fragment alone, the cysteine protease active p17 and p12 fragments together, or the cysteine protease inactive p17 fragment and p12 fragment together did not enhance cell migration. Fluorescence microscopy showed the enrichment of the non-processable mutant of caspase-3 in the leading edge of cells under experimental conditions of wound healing. In summary, the precursor form of caspase-3 induces cell migration by a protease-independent mechanism. This indentifies a new role for caspase-3 in tumor metastasis and represents a novel target for cancer therapeutics. Since the current evidence indicates that the role of caspase-3 in apoptosis and the role in migration are functionally separate, it is conceivable to design a molecule that disrupts the metastasis-inducing function of caspsase-3 while preserving the apoptosis-inducing function. We are currently investigating proteins that associate with caspase-3 under experimental conditions of caspase-3-dependent migration.
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 5299.
Abstract 5302: Overcoming cancer immune evasion in lung carcinoma using EGFR-TKI (Gefitinib)
Authors: Satomi Ryosuke , Naoki Katsuhiko , Yaguchi Tomonori , Yasuda Hiroyuki , Nakayama Sohei , Yoda Satoshi , Terai Hideki , Ikemura Shinnosuke , Sato Takashi , Soejima Kenzo , Ishizaka Akitoshi , Kawakami Yutaka 
Published: February 2011

Abstract
Clinical studies for immunotherapy targeting various types of carcinoma, including lung carcinoma, are currently underway, yet the clinical effectiveness of these therapies is very limited. Recent findings demonstrate that cancer immune evasion is a major contributing factor to this problem. Cancer cells produce a variety of immunosuppressive molecules that inhibit the host cell's immune response, leading to conditions such as cachexia that decrease patients’ quality of life. EGFR mutations in lung carcinoma are known to lead to processes characteristic of malignancies, such as cell cycle progression, metastasis, and angiogenesis. Based on these observations, we tested the hypothesis that EGFR activation leads to immune evasion by cancer cells via the production of various immunosuppressive molecules.
In this study, 6 lung adenocarcinoma cell lines were used, namely A549, RELF-LC-OK, PC-9, HCC-827, NCI-H1650, and NCI-H1975. We demonstrate that these cells secrete immunosuppressive cytokines such as IL-6, TGF-beta and VEGF, which inhibit the maturation of dendritic cells and prevent them to activate T cells. Then, we show that Gefitinib administration at sub-lethal concentration inhibits the production of immunosuppressive cytokines in EGFR-TKI sensitive PC-9 and HCC-827 cells those with EGFR mutations as well as in EGFR-TKI resistant NCI-H1650 cells that have an EGFR mutation but lack the PTEN gene. While, cytokine production is not inhibited by Gefitinib in A549 and RELF-LC-OK cells with wild type EGFR genes and NCI-H1975 cells that have both EGFR-TKI sensitive and resisitant mutations. Additionally, EGFR-TKI administration in PC-9, HCC827, and NCI-H1650 cells restores dendritic cell function, which was initially reduced by the supernatant of tumor cells.
These results show that lung adenocaricinoma harboring EGFR mutations evade immune response through secreteting immunosuppressive agents and that the immune response is restored by Gefitinib administration. Thus, the combination of Gefitinib and immunotherapy may have synergistic effect and will be a promising treatment of lung cancer patients harboring EGFR mutation, including certain population of EGFR-TKI resistant cases.
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 5302.
Abstract 5308: Targeting the Cox2 pathway prostaglandin EP receptors to regulate NK cell functions
Authors: Holt Dawn M. , Ma Xinrong , Kundu Namita , Fulton Amy M. 
Published: February 2011

Abstract
Breast malignancies often have high levels of Cox-2. The Cox-2 product prostaglandin E2 (PGE2) contributes to the high metastatic capacity of breast tumors. Our published data indicates that inhibiting either PGE2 production or PGE2-mediated signaling through the PGE2 receptor (EP4) reduces metastasis by a mechanism that requires Natural Killer (NK) cells. In order to better understand the mechanism by which inhibiting PGE2 production or signaling reduces metastatic disease, we examined the role of PGE2 in regulating protective host effector cells. It is known that NK cell function is compromised by PGE2, but very little is known about the mechanism by which PGE2 affects NK effector activity. NK effector function is regulated by complex interactions of recognition receptors expressed on NK cells and cognate ligands expressed on target cells. Both stimulatory and inhibitory signals are delivered through these receptor-ligand interactions. We have previously shown that both Cox inhibitors and antagonists of the EP4 receptor modulate the expression of NK cell stimulatory (H60) and inhibitory (MHC class I) ligands on the tumor target cell in favor of NK recognition and killing. We now report the direct effects of PGE2 on the NK cell. Murine splenic NK cells express all four PGE2 receptors (EP1-4). We examined the role of EP receptors in three NK cell functions; cytokine release, cytotoxicity, and migration. Activating all four NK-EP receptors with PGE2 leads to inhibited IFNγ secretion, induced TNFα production, less migration of NK cells and reduced ability to lyse tumor target cells. Using agonists and antagonists of individual EP receptors, we showed that only certain EP receptors contribute to loss of function. Next, we showed that all NK-EP receptor expression is downregulated during progressive tumor growth, which produced an environment that induced a less mature NK phenotype. EP2 and EP4 are linked to protein kinase A and elevations in intracellular cAMP. NK cells from tumor bearing mice respond poorly to stimulation with 10µM PGE2 and intracellular cAMP levels were increased by only 1.45-1.78 fold. In contrast, cAMP was induced by 6.08-10.58-fold in NK cells from normal mice. Thus, the tumor milieu results in changes in both NK-EP expression levels and EP receptor functions. NK mediated cytotoxicity, cytokine release, and migration were also compromised in tumor bearing mice. These results taken together support a mechanism whereby inhibiting PGE2 production or preventing signaling through some, but not all EP receptors may prevent suppression of NK functions that are critical to control breast cancer metastasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5308.