bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3211: PTTG1 attenuates drug-induced cellular senescence
Authors: Tong Yunguang , Zhao Weijiang , Wawrowsky Kolja , Melmed Shlomo 
Published: February 2011

Abstract
PTTG1 (pituitary tumor transforming gene) is abundantly expressed in several cancers and levels correlate with invasiveness and clinical outcome. Here we show that colon cancer cells devoid of PTTG1 (PTTG1−/−) demonstrate enhanced sensitivity and development of senescence in response to anti-neoplastic drugs including doxorubicin and trichostatin A (TSA). Doxorubicin (0.005 uM) had no effect on WT HCT116 colon cancer cells but inhibited PTTG1−/− HCT116 cell BrdU incorporation by 37 % (p&lt;0.001). β-Galactosidase staining demonstrated that 43 % of PTTG1−/− HCT116 cells were senescent compared to 3 % of WT cells treated with 0.005 uM doxorubicin. Up to 0.02 uM doxorubicin did not cause apoptosis as measured by Tunel assay and activated caspase 3 levels, suggesting that cell cycle arrest is responsible for enhanced drug sensitivity in PTTG1−/− cells. PTTG1−/− cells exhibit ∼3 fold induction of p21 upon doxorubicin or TSA treatment, while knock down of p21 abrogated senescent effects of these drugs. p21 expression in PTTG1−/− cells after doxorubicin and TSA treatment was increased by enhanced binding of Sp1, p53 and p300 at the p21 promoter. PTTG1−/− cells developed smaller tumors than WT (1.24 ± 0.41 vs 0.39 ± 0.15 g, p&lt;0.001), and were also more sensitive to doxorubicin treatments, with tumor growth inhibition rate 50% and 75 % respectively (p&lt;0.05). PTTG1−/− cells develop less metastatic foci compared to WT (29 ± 8 vs 46 ± 12, p&lt;0.001). Doxorubicin treatment suppressed metastatic foci formation by 49 % in PTTG1−/− tumors, compared to 15 % in WT cell-derived tumors. β-Galactosidase staining indicated that cell senescence was more pronounced in doxorubicin-treated PTTG1−/− tumors than in WT (57 % vs 22 % in subcutaneous tumor, p&lt;0.001, 70 % vs 18 % in metastatic foci, p&lt;0.001,). As senescence is a determinant of the cell response to anti-neoplastic treatments, the results indicate that PTTG1 may decrease anti-neoplastic drug responsiveness through attenuating cell senescence.
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 3211.
Abstract 3218: Bisphosphonates induce premature senescence and impair proliferation and migration of normal human oral keratinocytes
Authors: Kim Reuben H. , Lee Rachel , Woo Jessica , Dong Qing-Hua , Shin Ki-Hyuk , Kang Mo , Park No-Hee 
Published: February 2011

Abstract
Bisphosphonates (BPs) are potent anti-resorptive agents that are widely used to treat metastatic bone diseases in cancer patients. BPs target the mevalonate pathway and inhibit cholesterol synthesis and prenylation (e.g., geranylgernaylation and farnesylation) of small GTPases that are important for cell proliferation and survival. Long-term users of BPs are at the higher risk of developing osteonecrosis of the jaw (ONJ), which commonly occurs at the site of previous tooth extraction or other surgical interventions. Although bisphosphonate-related osteonecrosis of the jaw (BRONJ) is clinically defined as exposed necrotic bone with unhealed and open oral mucosa, the exact role of oral mucosa in the pathophysiology of BRONJ is not fully understood. The current study was undertaken to examine direct effects of BPs on the reepithelialization of oral mucosal cells. When normal human oral keratinocytes (NHOK) were treated with pamidronate (PAM), proliferation and migration were inhibited in dose-dependent manner as determined by MTT assay, proliferation assay, Western blotting against PCNA, and the scratch wound healing assay. Cell cycle analysis revealed increased S-phase content in PAM-treated NHOK, and this was associated with decreased mRNA and protein expressions of Cyclin A2 but not Cyclin D. PAM also induced premature senescence in NHOK as determined by increased β-galactosidase positivity, increased p16 expression, and phosphorylated p-38 MAP kinase pathway. PAM-induced premature senescence and proliferation inhibition were partially reversed by geranylgerniol (GGOH), but not farnesol (FOH), which reconstitute geranylgeranylation and farnesylation of the mevalonate pathway, respectively. Finally, using 3-dimensional (3D) raft culture system, we found that PAM-treated oral mucosal tissue constructs showed diminished immunohistochemical staining of PCNA and loss of reepithelialization in the wounded area, indicating that BPs impair proliferation and migration of oral epithelium constructs ex vivo. Our study demonstrates that BPs induce premature senescence and directly impair proliferation and migration of oral mucosal cells, which may explain the pathophysiology of BRONJ in cancer patients undergoing BP-treatment. This study was supported by NIDCR/NIH (DE017121).
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 3218.
Abstract 322: Loss of Y chromosome in urological tumors
Authors: Minner Sarah , Kilgué Adisa , Stahl Phillip , Handel Christoph , Höppner Wolfgang , Wagner Walter , Dahlem Roland , Rink Michael , Eichelberg Christian , Schlomm Thorsten , Terracciano Luigi , Moch Holger , Fisch Margit , Simon Ronald , Sauter Guido 
Published: February 2011

Abstract
Introduction and Objective
Y chromosome losses have been associated with various malignant tumors including bladder cancer, kidney cancer and prostate cancer. Conflicting data exist on the potential prognostic role of Y chromosome losses in these urological malignancies and on whether Y losses could be age-related. The aim of this study was to further clarify the potential relevance of Y chromosome losses in these tumors with respect to tumor phenotype, clinical outcome and patient age.
Methods
Preexisting tissue microarrays (TMA) of bladder (573 tissue samples from male patients), kidney (447 tissue samples from male patients) and prostate cancer (3261 tissue samples) with long-term clinical follow-up data were used in this study. Y chromosome losses were analyzed by dual-labeling FISH (fluorescence in situ hybridization) using centromere Y and X probe.
Results
Y losses were seen in 22% of bladder cancers. There was no significant age difference between patients having tumors with (67.4 +/-2.1years) or without (67.3 +/-1.2 years) Y losses (p=0.6294). Y losses were unrelated to tumor grade (p=0.7831) and stage (p=0.6140). There was no correlation between Y losses and survival in 224 invasive urothelial cancers (pT2-4; p=0.2324). Y losses were not associated with an increased risk for recurrences in 197 analyzed pTa tumors (p=0.7649) or increased progression risk in 76 analyzed pT1 tumors (p=0.4582). In kidney cancer Y losses were seen in 23% of cases. Likewise, there was no significant age difference between patients having tumors with (59.2 +/-3.6 years) or without (61.2+/-1.5 years) Y losses (p=0.5873). Y losses were unrelated to tumor grade (p=0.3111) and tumor stage (p=0.2511). There was also no correlation between Y losses and survival (p=0.7431). Remarkably, Y losses were seen in only 13 of 2826 (0.5%) analyzable cases of prostate cancers. The number of Y chromosome losses was too low for further statistical analyses.
Conclusions
These data show, that Y losses are frequent in urinary bladder cancer and kidney cancer, but lack association with tumor phenotype, clinical outcome and patient age. While the mechanism for Y losses in these cancers remains unclear, our data do not suggest clinical significance. In contrast to bladder and kidney cancer, Y chromosome losses were almost absent in prostate cancer. This may suggest that prostate epithelial cells are highly dependent on proper function of at least one chromosome Y gene.
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 322.
Abstract 3222: Telomerase expression is upregulated in response to severe oxidative stress
Authors: Sharif Wallace , Butts DeMario , Brown Jamelle 
Published: February 2011

Abstract
Telomerase is aberrantly expressed in 90% of all cancers, and is well characterized for its ability to extend the ends of chromosomes, the telomere. Although telomerase expression is predominantly associated with its ability to extend telomeres, there have been recent findings that suggest that telomerase has multiple cellular functions independent of its catalytic ability, and some of those functions help promote cell survival in response to severe oxidative stress. To date, telomerase expression as been implicated in aiding a cell's response to double strand breaks in DNA, mitochondria dysfunction, inhibition of apoptosis, and the promotion of cell proliferation. The protein component of telomerase, TERT, is also thought to specifically enhance cell viability in response to the hypoxic microenvironment of a tumor. These protective roles of TERT could be vital in promoting cell survival during severe hypoxia. Telomerase expression is upregulated by the kinase Akt, which is in turn induced by the neuregulin/ErbB signaling pathway. Neuregulin is a glycoprotein that is necessary for smooth muscle and neuronal development. Neuregulin activates the ErbB tyrosine kinase family, which promotes cell survival, proliferation, and differentiation. Recently, neuregulin has been shown to be upregulated in response to severe hypoxia, and may reduce the inflammation response to oxidative stress. The mechanism of neuregulin protection is unclear, though microarray data shows that neuregulin expression decreases the expression of several pro-inflammatory cytokines. We hypothesize that neuregulin can regulate the expression of telomerase during severe oxidative stress, and that telomerase expression promotes cell survival during hypoxia. Inducing oxidative stress and hypoxia in differentiated rat neuroblastoma cells caused significant increases in telomerase expression. The addition of physiologic levels of neuregulin was able to induce telomerase expression, indicating that telomerase activation could play an important role in the cellular response to oxidative stress.
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 3222.
Abstract 3225: Cellular and in vivo models for the analyses of B-Raf and c-Src inhibitors
Authors: Ehlert Jan E. , Mutschler Bettina , Müller Melanie , Lingnau Andreas , Hoffmann Steffen , Kubbutat Michael HG 
Published: February 2011

Abstract
Cytosolic kinases c-Src and B-Raf represent proto-oncogenes of which mutant or overexpressed variants have been shown to cause cancer. Efforts are taken to develop inhibitors specifically addressing these kinases, some of which have already been approved such as Src inhibitor Dasatinib and BRaf inhibitor Sorafenib. In the current study we have generated cellular systems to allow for the analyses of Src and BRaf inhibitors in kinase specific cellular phosphorylation assays as well as in subcutaneous in vivo models. For both kinases we are introducing in vivo models allowing for regulatable kinase activity and thereby regulatable, kinase dependent tumor growth.
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 3225.
Abstract 3230: Immortalization of human small airway epithelial cells as a model for studying lung tumor transformation
Authors: Gao Boning , Huang Chunxian , Sullivan James , Raso Gabriela , Wistuba Ignacio , Shay Jerry , Minna John 
Published: February 2011

Abstract
Normal human lung epithelial cells that can be genetically manipulated to study the various steps in lung cancer pathogenesis and stem cell biology would be of great utility and also provide isogenic strains to develop and test new diagnostic (biomarkers), preventative and therapeutic strategies for lung cancer. Previously we immortalized normal proximal human lung bronchial epithelial cells (HBECs) for studying lung tumors arising in the central compartment of the lung and now have over 40 of these strains (growing in defined KSFM media) including many isogenic derivatives with various oncogenic changes (Can Res 2004, Can Res 2006). We have extended this by immortalizing normal distal (small airway) epithelial cells that serve as models for studying tumors arising in the peripheral compartment of the lung. Using Cdk4 and hTERT exogenous expression vectors (as used for HBECs) and SAGM defined media routinely immortalized (N= 15) human small airway epithelial cells (HSAECs) from peripheral lung. These HSAEC strains are highly enriched (&gt;50%) for cells with stem like properties (e.g. Aldehyde dehydrogenase positivity), express basal cell markers but not Clara cell, type 1 or type 2 differentiation markers., However, HSAECs can be induced to express Clara cell, type 1 or type 2 cell markers when they are grown in matrigel (where they form cyst like structures which express such differentiation markers) and under other conditions favoring differentiation (such as insulin depletion, Ca2+ addition). HSAECs show anchorage dependent growth, do not form colonies in soft agar, and are non-tumorigenic in NOD/SCID mice. However, HSAECs can be genetically manipulated by introducing oncogenes (such as KRASV12, missense p53 and other oncogene combinations) which now allow HSAECs to progress towards a transformed phenotype (e.g. formation of soft agar colonies), and selection of a subset of HSAEC(KRAS, p53) large soft agar colonies identifies sublines that can now form poorly differentiated carcinomas. Thus, we have developed conditions to routinely immortalize lung epithelial cells derived from distal small airways (HSAECs) which grow in defined media, exhibit stem cell like characteristics, and can be genetically manipulated to give rise to poorly differentiated cancers.
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 3230.
Abstract 3235: Creation of novel rat models for cancer research using zinc finger nuclease (ZFN) technology
Authors: McCoy Aaron M. , Ji Diana , Carbery Iara , Cui Xiaoxia , Weinstein Edward 
Published: February 2011

Abstract
The rat resembles human physiology more closely than the mouse, partially because of its larger size. Rats are the preferred model for many disease fields, including cancer research, such as studies in breast and prostate cancers and bone metastasis. However, the lack of convenient experimental tools to manipulate the rat genome has largely limited the use of rat models, until the recent creation of the first targeted knockout rats by using zinc finger nuclease technology (Geurts et al., 2009).
At SAGE Labs, we are uniquely positioned to create rat knockout models for all major disease categories. In regards to cancer research, we have developed p53 knockout rats, which may be used to significantly shorten the time required for carcinogenicity studies in the same capacity as the p53 knockout mice have been used since the mid-nineties. We are also in the process of creating a suite of immunocompromised rats, such as knockouts of RAG1, RAG2, and DNAPK, which may be used, for example, in the generation of xenografts for metastasis studies and bone marrow transplantation for cancer therapy. In addition, we have developed a set of toxicology models, including knockouts of Mdr1a, PXR, BCRP, Mrp1 and Mrp2, which can benefit studies on cancer drug delivery and metabolism. Model generation, their applications and future models will be discussed. Together, our goal is to help advance cancer research with the creation of novel rat models.
Geurts, A. et al. Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325, 433 (2009)
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 3235.
Abstract 3237: Establishment of a new invasive urinary bladder cancer model using human c-Ha-ras proto-oncogene transgenic rats
Authors: Wei Min , Yamano Shotaro , Ishii Naomi , Kakehashi Anna , Obo Yumi , Wanibuchi Hideki 
Published: February 2011

Abstract
To establish animal models for identifying mechanisms of urinary bladder cancer (UBC) invasion, male human c-Ha-ras proto-oncogene transgenic rats (Hras 128) were divided into 5 groups and treated with 0.05% N-butyl-N-(hydroxybutyl)nitrosameine (BBN) in drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in diet, respectively, as follows: BBN (8 wks)→PEITC (8 wks); PEITC (8 wks)→BBN (8 wks); PEITC alone (16 wks); BBN alone (16 wks); non-treatment. At the end of week 16, incidences of invasive UBC in BBN→PEITC and BBN alone groups were 77% (10/13 rats) and 56% (5/9 rats), respectively. The average number of invasive UBC in BBN→PEITC and BBN alone groups were 1.3 ± 0.9 and 0.7 ± 0.7/rat, respectively. Both incidence and numbers of invasive UBC tended to be higher in BBN→PEITC group compared to the BBN alone group. Furthermore, non-invasive UBC were also found in all rats of above 2 groups. No tumors were found in other groups. p53 positive staining were observed in 58% of invasive UBC and 9% of non-invasive UBC in BBN→PEITC group that is similar to positive incidences in human UBCs. These findings indicated that treatment of Hras 128 rats with BBN followed by PEITC induced high incidences of both non-invasive and invasive UBC, and therefore provide a useful comparison model for explore the mechanisms of UBC invasion.
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 3237.
Abstract 324: A NUT-variant midline carcinoma showing a complex karyotype
Authors: Thompson Katherine , Beesley Alex H. , Baker Elizabeth , Grumball Tanya , Kennedy Dagmara A. , Murch Ashleigh R. , Philips Marianne B. , Charles Adrian K. , French Chris A. , Kees Ursula R. 
Published: February 2011

Abstract
NUT-midline carcinomas (NMC) are rare, almost uniformly lethal malignant tumours arising in the midline organs. Originally diagnosed predominantly in the young, they have since been identified in people ranging in age from 3 to 78 years. The tumours are typically very aggressive in behaviour, with an average survival of only nine months. NMCs are typified by a single, conserved underlying genetic translocation t(15;19)(q14;p13.1), that results in a fusion of the BRD4 and NUT genes. There are a few cases described in which NUT is fused to a different gene (primarily BRD3) and these are known as NUT-variants. It is very rare however, for translocations other than the primary one, to be present. We present an NMC case with a far more complex karyotype, with the translocations t(6;19)(q14;p13.1) and t(1;18;7)(q42;q11.2;q21) present in all cells, as well as approximately 10% of cells demonstrating t(12;15)(q13;q22). Initial FISH experiments, using break-apart probes, established a translocation of the 19p13.1 (BRD4) region, and demonstrated no translocation of the 15q14 (NUT) region. Subsequent experiments, using BRD4 specific probes in a cell line derived from the patient specimen, have shown that BRD4 was inserted into chromosome 15, in a region proximal to the NUT gene. We are currently determining whether BRD4 was fused directly to NUT through a cryptic translocation in this case. Illumina Human-Cyto-SNP-12 BeadChip array analysis has also shown that a 3.3MB region of 6q14 (adjacent to the region translocated onto chromosome 19) was deleted in the tumour cells. The array indicated no deletions or duplications at the sites of any of the other translocations. Given the aggressive nature of these tumours, a better understanding of the underlying genetic causes and precipitating factors of the disease processes remains imperative to improving the outcome for such patients.
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 324.
Abstract 3241: Multipotential PTEN−/− p53−/− prostate tumor initiating cells give rise to adenocarcinoma which displays epithelial-to-mesenchymal transition, metastasis, and androgen independent growth
Authors: Pierce Rachel M. , Martin Philip L. , Kelly Kathy 
Published: February 2011

Abstract
Determining the cell lineage and differentiation potential of tumor initiating cells is fundamental to understanding mechanisms of progression and metastasis. We describe the differentiative, tumorigenic, and metastatic properties of primary, transplanted secondary, and clonally-derived tumors in a model of prostate cancer initiated by prostate epithelial cell specific deletion of the tumor suppressors, PTEN and p53. Although adenocarcinoma is the majority tumor type that develops in this mouse model, other histological tumor types, including a late developing sarcomatoid carcinoma were observed. The heterogeneity displayed in transgenic mouse prostate tumors may be due to the transformation of multiple lineage specific tumor initiating cells, or a common tumor progenitor/stem cell capable of plasticity in differentiation potential. Orthotopic transplantation of PTEN−/− p53−/−prostate carcinoma cells was undertaken to determine whether a single tumor initiating cells is capable of giving rise to the diversity of tumor phenotypes observed in the parental prostate carcinoma. Direct orthotopic transplantation of mixed populations of PTEN−/− p53−/− tumor cells favored the development of adenocarcinomas, while transplantation of cells grown as protospheres in matrigel favored the development of basal/squamous carcinomas. This indicates a developmental plasticity in transplantable tumor initiating cells that can be influenced by extracellular matrix components. Transplantation of clonal cell lines that were derived from orthotopic carcinomas produced adenocarcinomas with lesser amounts basal/squamous carcinoma with one line undergoing EMT to form sarcomatoid carcinomas. Lung and lymph node metastases were common. Tumor growth, metastasis, and response to androgen deprivation were assayed with in-vivo bioluminescent imaging. The orthotopic tumors recapitulated the diversity of tumor phenotypes observed in the probasin-cre, PTEN fl/fl p53 fl/fl transgenic donor mouse including: adenocarcinoma, spindle cell carcinoma, urothelial carcinoma, and basal/squamous carcinoma. In a pattern that mimics a phenotype observed in metastatic human prostate carcinoma, CK8+ adenocarcinomas displayed heterogeneous labeling for the neuroendocrine marker synaptophysin. Our data suggests that a multi-potential CK8+/CK5+ tumor stem cell can be a progenitor for CK8+ adenocarcinoma.
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 3241.