bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C56: High αV integrin level is associated with metastasis to the brain in athymic rat hematogenous models
Authors: Wu Jeffrey , Pagel Michael , Muldoon Leslie L. , Neuwelt Edward A. 
Published: August 2014

Abstract
Brain metastases from systemic cancers occur in approximately 20% of lung cancer patients including both small cell lung carcinoma (SCLC) and non–small-cell lung cancer (NSCLC), and in 5-8% of breast cancer and melanoma. Brain metastases tend to present as multiple brain lesions with high morbidity and poor prognosis. We investigated the expression of αV integrin cell adhesion protein in multiple human cancer cell lines (3 SCLC, 4 NSCLC, 2 melanoma, 1 breast cancer), and its correlation with migration in vitro and brain metastatic ability in vivo using a hematogenous metastasis technique in which cancer cells are infused into the internal carotid artery in athymic nude rats. Expression of αV integrin protein was highly variable among human cancer cell lines. Four cell lines tested had high αV integrin expression and formed multiple brain metastases. H460 NSCLC cells formed 13 ± 6 metastases per brain (mean volume 3 ± 9 mm3) with median survival 34 days (n = 4). A549 lung adenocarcinoma cells formed 9 ± 5 metastases per brain (8 ± 21 mm3 volume, 62 day survival, n = 6). MDA-MB231BR-HER2 breast cancer and A2058 melanoma cells also formed multiple brain metastases. Low αV expressing lung cancer cells, including H146 and DMS79 SCLC, and H520 squamous NSCLC cells failed to form brain metastases by 12-16 weeks after intracarotid cell infusion. In an in vitro gap closure migration assay, A549 cells (high αV integrin) showed a higher rate of migration than H520 cells (low αV integrin). Regardless of αV integrin level, incubation with intetumumab anti-αV integrin monoclonal antibody significantly inhibited cell migration of both A549 and H520 cells. We conclude that cancer cellular αV integrin level is positively correlated to the development of brain metastases and may be a potential biomarker of patients likely to develop brain metastases. We suggest that blocking αV integrin with intetumumab has prophylactic potential to prevent distant metastasis and improve survival in cancer patients.
Citation Format: Jeffrey Wu, Michael Pagel, Leslie L. Muldoon, Edward A. Neuwelt. High αV integrin level is associated with metastasis to the brain in athymic rat hematogenous models. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C56.
Abstract C61: GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN
Authors: Chen Wan-Ting , Zhu Genyuan , Pfaffenbach Kyle , Kanel Gary , Stiles Bangyan , Lee Amy S. 
Published: August 2014

Abstract
Glucose-regulated protein 78 (GRP78), a molecular chaperone widely elevated in human cancers, is critical for endoplasmic reticulum (ER) protein folding, stress signaling, and PI3K/AKT activation. Genetic knockout models of GRP78 revealed that GRP78 maintains homeostasis of metabolic organs, including liver, pancreas, and adipose tissues. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common liver cancers. There is a lack of effective therapeutics for HCC and CC, highlighting the need to further understand liver tumorigenic mechanisms. Phosphatase and tensin homolog (PTEN), a tumor suppressor that antagonizes the PI3K/AKT pathway, is inactivated in a wide range of tumors, including 40-50% of human liver cancers. To elucidate the role of GRP78 in liver cancer, we created a mouse model with biallelic liver-specific deletion of Pten and Grp78 mediated by Albumin-Cre-recombinase (cPf/f78f/f). Interestingly, in contrast to PTEN, deletion of GRP78 was progressive but incomplete. At 3 months cPf/f78f/f livers showed hepatomegaly, activation of lipogenic genes, exacerbated steatosis, and liver injury, implying that GRP78 protects the liver against PTEN-null mediated pathogenesis. Furthermore, in response to liver injury, we observed increased proliferation and expansion of bile duct and liver progenitor cells in cPf/f78f/f livers. Strikingly, bile duct cells in cPf/f78f/f livers maintained wild-type GRP78 level while adjacent areas showed GRP78 reduction. Analysis of signaling pathways revealed selective c-Jun N-terminal protein kinase activation, β-catenin downregulation, along with platelet-derived growth factor receptor α upregulation, which was unique to cPf/f78f/f livers at 6 months. Development of both HCC and CC were accelerated and evident in cPf/f78f/f livers at 8-9 months, coinciding with intense GRP78 expression in the cancer lesions, and GRP78 expression in adjacent normal areas reverted back to the WT level. In contrast, livers of Albumin-Cre; Grp78f/f (c78f/f) mice showed no malignancy even at 14 months. These studies reveal GRP78 is a novel regulator for PTEN-loss mediated liver injury and cancer progression.
Citation Format: Wan-Ting Chen, Genyuan Zhu, Kyle Pfaffenbach, Gary Kanel, Bangyan Stiles, Amy S. Lee. GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C61.
Abstract IA12: The noncoding RNA revolution in cancer research
Authors: Pandolfi Pier Paolo 
Published: August 2014

Abstract
We will discuss exciting new data regarding the role of pseudogenes, lincRNAs and miRNAs in the pathogenesis of human cancer as also studied in vivo in the mouse. We will also focus on competing endogenous RNAs (ceRNAs), circular(circ)-ceRNAs and pseudo-ceRNAs and give important attention to how understanding the ceRNA language will facilitate efforts to deconvolute ceRNA networks and their role in tumorigenesis.
Citation Format: Pier Paolo Pandolfi. The noncoding RNA revolution in cancer research. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA12.
Abstract IA22: PI3K and cancer metabolism
Authors: Cantley Lewis C. 
Published: August 2014

Abstract
Phosphoinositide 3-Kinase (PI3K) is a central enzyme in a signaling pathway that mediates cellular responses to growth factors. The signaling pathway downstream of PI3K is highly conserved from worms and flies to humans and genetic analysis of the pathway has revealed a conserved role in regulating glucose metabolism and cell growth. Mutational events that lead to hyperactivation of the PI3K pathway result in hamartoma syndromes and cancers. Activating mutations in PIK3CA, encoding the p110alpha catalytic subunit of PI3K or inactivating mutations in PTEN, a phosphoinositide 3-phosphatases that reverses the effects of PI3K, are among the most common events in solid tumors. Drugs that target PI3K are in clinical trials for a variety of cancers. It is likely that PI3K pathway inhibitors will need to be combined with other drugs to be broadly effective. We have employed genetically engineered mouse models that develop cancers due to mutations in genes in the PI3K pathway and are using these models to explore the efficacy of PI3K pathway inhibitors as single agents or in combination with other drugs. The role of PI3K inhibitors for treating cancers in these mouse models and in human trials will be discussed.
Citation Format: Lewis C. Cantley. PI3K and cancer metabolism. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA22.
Abstract IA4: Deconstructing p53 pathways in vivo
Authors: Brady Colleen A. , Broz Daniela Kenzelmann , Jiang Dadi , Mello Stephano Spano , Bieging Kathryn , Johnson Thomas M. , Jarvis Leslie A. , Kozak Margaret M. , Basak Shashwati , Attardi Laura D. 
Published: August 2014

Abstract
The activation of the p53 protein by cellular stress signals is fundamental for tumor suppression but also promotes pathological states, such as provoking the side effects of genotoxic cancer therapies. To better understand the mechanisms of p53 action in different contexts, we have leveraged both mouse genetic and genomic approaches. First, we have used mouse genetics to define transcriptional programs involved in p53 function in different in vivo settings, specifically by generating a panel of p53 transcriptional activation domain mutant knock-in mouse strains. These include strains expressing p53 mutants in the first (p5325,26), second (p5353,54), or both transactivation domains (p5325,26,53,54). We have observed that p5325,26 is severely compromised for transactivation of most classical p53 target genes, but retains the ability to activate a subset of p53 targets, while p5325,26,53,54 lacks transactivation activity completely. Interestingly, although unable to induce apoptosis or cell cycle arrest in response to acute DNA damage signals, p5325,26 retains full activity in suppressing cancers of a wide range of types, indicating that robust transactivation of most canonical p53 targets is dispensable for tumor suppression. Importantly, as p5325,26 activates only a subset of p53-dependent genes, yet retains tumor suppressor activity, it has helped to define a small set of novel p53-inducible tumor suppression-associated genes, which we are currently analyzing in detail. Second, we have utilized genomic approaches to better understand p53 function. Using ChIP-sequencing and RNA-sequencing to analyze transcriptional programs in acute DNA damage-treated mouse embryo fibroblasts, our studies have revealed an extensive p53-regulated autophagy program that contributes to p53 responses. Together, these approaches will help better define the transcriptional networks important for p53 action in different settings.
Citation Format: Colleen A. Brady, Daniela Kenzelmann Broz, Dadi Jiang, Stephano Spano Mello, Kathryn Bieging, Thomas M. Johnson, Leslie A. Jarvis, Margaret M. Kozak, Shashwati Basak, Laura D. Attardi. Deconstructing p53 pathways in vivo. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA4.
Abstract PR08: Autophagic degradation of Δ133p53 during replicative cellular senescence: An isoform-specific protein degradation mechanism for p53
Authors: Horikawa Izumi , Fujita Kaori , Jenkins Lisa Miller , Hiyoshi Yukiharu , Mondal Abdul M. , Vojtesek Borivoj , Lane David P. , Appella Ettore , Harris Curtis C. 
Published: August 2014

Abstract
Δ133p53, a p53 isoform that dominant-negatively inhibits full-length p53, is downregulated at replicative senescence in a manner independent of mRNA regulation and proteasome-mediated degradation. We here demonstrate that, in contrast to proteasomal degradation of full-length p53, Δ133p53 is degraded by autophagy. Pharmacological inhibition of autophagy restores the reduced expression of Δ133p53 in replicatively senescent fibroblasts. The siRNA-mediated knockdown of pro-autophagic proteins (ATG5, ATG7 and Beclin-1) also results in restored expression of Δ133p53. The degradation of Δ133p53 via selective autophagy is indicated by its ubiquitination at the C-terminal lysine residues, its colocalization in the cytoplasm with a ubiquitin-binding protein p62/SQSTM1 and an autophagosome component LC3-II upon autophagy induction, and its stabilization by siRNA knockdown of p62/SQSTM1. A chaperone-associated E3 ubiquitin ligase STUB1, rather than MDM2, physically interacts with Δ133p53 and, consistent with the downregulation of endogenous STUB1 at replicative senescence, siRNA knockdown of STUB1 induces autophagic degradation of Δ133p53 and thereby senescence. Our data reveal that Δ133p53 degradation is controlled specifically by STUB1, rather than overall activity of autophagy. This study has identified for the first time a p53 isoform-specific protein turnover mechanism that orchestrates p53-mediated senescence and supports the hypothesis that Δ133p53 functions at the crossroads of senescence and autophagy.
This abstract is also presented as poster B19.
Citation Format: Izumi Horikawa, Kaori Fujita, Lisa Miller Jenkins, Yukiharu Hiyoshi, Abdul M. Mondal, Borivoj Vojtesek, David P. Lane, Ettore Appella, Curtis C. Harris. Autophagic degradation of Δ133p53 during replicative cellular senescence: An isoform-specific protein degradation mechanism for p53. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR08.
Abstract PR12: Bringing the outside in: Macropinocytosis and cancer therapeutics
Authors: Commisso Cosimo , Chenna Venugopal , Grabocka Elda , Ramirez Craig , Anirban Maitra , Bar-Sagi Dafna 
Published: August 2014

Abstract
Oncogenic Ras mutations are prevalent in a variety of tumor types, including adenocarcinomas of the pancreas, colon, and lung. One of the most overt phenotypes associated with the expression of oncogenic Ras mutants is the stimulation of macropinocytosis, an endocytic process that involves extensive membrane remodeling and the internalization of extracellular fluid via large membrane-bound vesicles called macropinosomes. The functional consequences of this stimulation in oncogenic Ras-expressing cancer cells were unknown prior to our recent work where we linked macropinocytic uptake to nutrient delivery and amino acid supply in tumor cells. We found that Ras-transformed cells utilize macropinocytosis to internalize extracellular albumin, which is then lysosomally degraded releasing the constituent amino acids intracellularly. These protein-derived amino acids have the capacity to enter central carbon metabolism and fuel tumor cell proliferation even in a nutrient-depleted environment. Of particular relevance is the finding that the pharmacological inhibition of macropinocytosis compromises the growth of Ras-driven pancreatic xenograft tumors. This discovery raises the question of whether the inhibition of macropinocytosis can be utilized as a therapeutic intervention in a subset of cancers. Moreover, because macropinocytosis is an established mechanism of drug delivery for nanoparticles, our work highlights the possibility of exploiting this feature of Ras-induced tumors for the effective delivery of nanoscale therapeutics. Our recent studies focused on identifying novel modulators of macropinocytosis and examining macropinocytosis as a delivery mechanism for nab-paclitaxel, an albumin-based nanoparticle therapy, will be discussed.
Citation Format: Cosimo Commisso, Venugopal Chenna, Elda Grabocka, Craig Ramirez, Maitra Anirban, Dafna Bar-Sagi. Bringing the outside in: Macropinocytosis and cancer therapeutics. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR12.
Abstract B99: Antimetastatic and apoptosis induction potential of supercritical CO2 extract of Nigella sativa seeds
Authors: Baharetha Hussein M. , Nassar Zeyad D. , Aisha Abdalrahim F. , Kadir Abd , Ismail Zhari , Majid Abdul 
Published: August 2014

Abstract
Nigella sativa Linn. is a famous spice that has been used as a medicinal plant for centuries. Traditionally, it is known to have a magic healing power for different varieties of illness, range from intestinal disturbances to fever to cancer. In this study, essential oil was extract from seeds of Nigella sativa using supercritical CO2 extraction system at extraction pressure of 2500 psi and temperature of 60°C (these extraction conditions of pressure and temperature were reported from our preliminary screening anti-proliferative study against various human cancerous cell lines). The anti-metastatic and anti-invasive properties of the extract were studied using a panel of assays against human breast cancer cell line (MCF 7). Results revealed that the extract showed a potent anti-proliferation activity against MCF 7 cells with IC50 value of 53.34 ± 2.15 μg/ml once tested using MTT assay. The extract also halted MCF 7 cells migration and invasion, where 40 μg/ml of the extract A3 represented 49.80 ± 5.89% of migration inhibition and 79.29 ± 2.09% of invasion inhibition. In addition, the extract significantly induced apoptosis of the MCF 7 cells by activating caspases 3/7 and 8. The result of this study revealed the role of supercritical CO2 extracted oil of Nigella sativa in prevention of metastasis and invasion of breast cancer.
Note: This abstract was not presented at the conference.
Citation Format: Hussein M. Baharetha, Zeyad D. Nassar, Abdalrahim F. Aisha, Abd Kadir, Zhari Ismail, Abdul Majid. Antimetastatic and apoptosis induction potential of supercritical CO2 extract of Nigella sativa seeds. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B99.
Abstract C12: Aberrant promoter methylation of HOPX-β, MUC1 genes and global methylation in esophageal squamous cell carcinoma
Authors: Kao Yu Chun , Lin Sheng Hsiung , Yu Chun Chieh , Li Ruei Nian , Wu Ming Tsang 
Published: August 2014

Abstract
Esophageal cancer ranks as the sixth most deadly cancer and esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer deaths in males in worldwide. Therefore, it is important to identify molecular markers for clinical diagnosis. Homeodomain-only protein X (HOPX)-β is a tumor suppressor gene and its promoter methylation is shown to be frequent in human cancer. Mucin 1 (MUC1) is a transmembrane mucin that is highly expressed in various cancers and correlates with malignant potential. In addition, the degree of whole genome methylation decreases as the lesion progressing from a benign proliferation of cells to an invasive cancer. The aim of this study was to investigate HOPX-β and MUC1 promoter methylation status and global methylation level in different stages of ESCC patients. Methylation-specific PCR (MSP) revealed that the methylation rate of HOPX-β was 26.5% (27/102) in tumor samples and only 9% (9/100) in paired non-tumor samples (p&lt;0.05). In HOPX-β promoter hypermethylation samples, the frequency of lymph node invasion and tumor metastasis was increased about 3-fold and 2-fold, respectively. Furthermore, HOPX-β promoter methylation frequency was increased about 3-fold in advanced stage. On the other hand, the methylation frequency of MUC1 was 90.7% (97/107) in paired non-tumor samples while the methylation frequency was decreased to 53.3% (57/107) in tumor samples. 78.5% (84/107) of tumor samples showed significantly decline in the degree of methylation compared with paired non-tumor samples (p&lt;0.0001). We found a decrease tendency in methylation frequency of MUC1 correlated with clinical stage (early/advanced), the frequency of lymph node invasion and metastasis. Importantly, the methylation rate of MUC1 was inversely related with the tumor size (p=0.0105). The level of global long interspersed nuclear element 1 (LINE-1) methylation in ESCC tissues (mean 65.8%) was significantly lower than paired non-tumor samples (mean 79.5%). However, there is no relation between the level of global LINE-1 methylation and tumor stage or survival rate. Our findings indicate that LINE-1, MUC1 methylation level and HOPX-β hypermethylation in ESCC are useful markers in clinical diagnosis.
Citation Format: Yu Chun Kao, Sheng Hsiung Lin, Chun Chieh Yu, Ruei Nian Li, Ming Tsang Wu. Aberrant promoter methylation of HOPX-β, MUC1 genes and global methylation in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C12.
Abstract C65: Membrane type-1 matrix metalloproteinase (MT1-MMP) is a potent regulator of cancer malignant progression through the heparin-binding EGF-like growth factor activation
Authors: Koshikawa Naohiko , Seiki Motoharu 
Published: August 2014

Abstract
MT1-MMP is a potent proinvasive and growth promoting membrane protease in cancer. The roles of MT1-MMP are mediated by its pericellular proteolysis activity. Major substrates of MT1-MMP are collagen I and other extracellular matrices. MT1-MMP also cleaves membrane proteins and modulates their biological activities in cancer progression. However, little is known about the cell surface substrates of MT1-MMP and identification of the substrates should enable a better understanding of its multiple biological functions. Therefore to identify new substrates of MT1-MMP, we purified proteins associating with MT1-MMP in human carcinoma cells and analyzed them by mass spectrometry. As results, we identified over 40 membrane proteins, and found HB-EGF is a novel component of MT1-MMP complex. MT1-MMP cleaves HB-EGF and removes the N-terminal region that is important for binding heparin. Consequently the HB-EGF processing by MT1-MMP converts it into a heparin-independent growth factor with enhanced mitogenic activity and thereby expression of both proteins co-stimulates tumor cell growth in vitro and in vivo. Furthermore ovarian ascites carcinoma cells expressed both MT1-MMP and HB-EGF at high levels and produced MT1-MMP-cleaved HB-EGF in the ascitic fluids. These data suggest that MT1-MMP acts as a regulator of cancer progression on the cell surface.
Citation Format: Naohiko Koshikawa, Motoharu Seiki. Membrane type-1 matrix metalloproteinase (MT1-MMP) is a potent regulator of cancer malignant progression through the heparin-binding EGF-like growth factor activation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C65.